The occurrence of low insulin response to glucose infusion in children

Summary Insulin response to glucose infusion was studied in 42 children with a normal intravenous glucose tolerance, 7–16 years of age. The majority of these children had at least one first degree relative with diabetes mellitus. Low and delayed insulin response similar to the one found in 15–20% of healthy adult subjects also occurred in 15–20 per cent of the children in this material. These findings support our previous suggestion that the low and delayed insulin response to glucose is probably genetically determined.

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Das Vorkommen von verringerter Insulinausschüttung nach Glukoseinfusion bei Kindern

Zusammenfassung Die Insulinausschüttung nach Glucoseinfusion wurde bei 42 Kindern, 7–16 Jahre alt, mit normaler intravenösen Glucosetoleranz untersucht. Die Mehrzahl dieser Kinder hatte einen diabeteskranken Eltern-oder Geschwisterteil. Eine verzögerte und verringerte Insulinfreisetzung, ähnlich denen, die bei 15–20% von gesunden Erwachsenen gefunden worden waren, war bei 7 von 42 Kindern zu sehen. Dieser Befund stützt unsere frühere Ansicht, daß die verzögerte und verringerte Insulinausschüttung bei Hyperglykämie wahrscheinlich genetisch bedingt ist.

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L'existence de réponse insulinique réduite à la perfusion de glucose chez l'enfant

Résumé La réponse insulinique à la perfusion de glucose a été étudiée chez 42 enfants âgés de 7 à 16 ans et ayant un test de tolérance au glucose normal. Chez la plupart des enfants au moins un des parents ou frères et surs avait le diabète. Une réponse insulinique réduite et retardée, similaire à celle observée chez 15 à 20% des adultes en bonne santé, a été démontrée chez 7 enfants sur les 42. Ces résultats confirment notre suggestion que ce type de réponse insulinique réduite et retardée est probablement déterminée par des facteurs héréditaires.

     

The follow up study of intra-arterial infusion chemotherapy with local vein blocking as a surgical neo-adjuvant treatment for locally advanced breast cancer

Preoperative intra-arterial infusion neo-adjuvant chemotherapy, in combination with local vein blocking, was administered to thirtyone patients with locally advanced stage III breast cancer. The anti-cancer drugs and dosages used were 500 mg of 5-Fluorouracil (5FU), which was infused daily for 7–14 days, and 20 mg of Adriamycin (ADM), which was administered as a bolus dose twice into the subclavian and internal mammary arteries. The response rate of this method on the primary tumor was 48.4 per cent, and, histologically it was found to be as high as 90.3 per cent. The response rate of the clinical effects on the regional lymph nodes was 50.0 per cent, however, histologically, it was found to be lower than that of the primary tumor. In the long-term follow up study the 5-year survival rate was 72.2 per cent. Thus, this method seems to be effective as a combined modality in cases of locally advanced stage III breast cancer.     

The importance of protein content in the Oedema fluid for the resolution of brain Oedema

Summary The infusion model of oedema is developed in the rat. Unilateral, constant volume, intracerebral infusions of oedema fluid of varying protein (bovine albumin) concentrations are performed. Brain tissue is analyzed for water content using the gravimetric technique. The authors find significant differences in the spatial distribution of brain water in the different infusion groups at 48 and 72 hours post infusion. The control infusate (mock cerebrospinal fluid) clears by 72 hours. However, infusates containing protein (32.5 and 65.0mg/ml albumin) are not completely cleared until 5 to 8 days post infusion, with the less concentrated solution clearing more rapidly in the area of infusion at 72 and 96 hours post infusion. The data support the hypothesis that the rate of clearance of vasogenic brain oedema is dependent on the amount of extravasated protein.This work was supported by NIH Grant 5RO1NS19235-03.     

Urea handling by the medullary collecting duct of the rat kidney during hydropenia and urea infusion

Previous micropuncture studies of distal tubule fluid and ureteral urine have indicated a varying degree of urea reabsorption in the collecting duct. In the present experiments the microcatheterization technique was used to directly determine urea, Na, K, total solute and fluid reabsorption along the length of the medullary collecting duct in anaesthetized hydropenic rats and in rats given low dose urea infusion (P_urea 18.9 mM/l). In hydropenic rats, the remaining fraction of filtered urea did not change significantly along the collecting duct, as indicated both by regression analysis of all samples and by comparison of paired samples from the corticomedullary junction and papillary tip. During low dose urea infusion, urine osmolality increased in proportion to the increase in urea concentration and again there was no net urea reabsorption between the beginning and end of the duct. However, during urea infusion, analysis of samples from the beginning, mid-zone, and end of the collecting duct indicated that urea entry occurred in the proximal portion of the duct (beginning to mid-zone,P<0.01) and that urea reabsorption occurred in the distal portion (mid-zone to end,P<0.01). The lack of significant net urea reabsorption along the duct despite the excretion of moderately concentrated urine, has implicatios for the concept of medullary urea recycling and for models of the urinary concentrating mechanism. The finding of functional heterogeneity with respect to urea handling in the collecting duct in vivo, with both reabsorption and secretion being demonstrated, raises the possibility that internal recycling of urea in the medullary collecting duct itself may contribute to maintenance of a high papillary interstitial urea concentration.     

Ventilatory and haemodynamic effects of terbutaline infusion during beta1-selective blockade with metoprolol and acebutolol in asthmatic patients

Summary A double-blind, placebo-controlled study of the haemodynamic and ventilatory effects of two beta₁-selective adrenoceptor blockers and their interaction with the beta₂-adrenoceptor agonist terbutaline was carried out in eight asthmatic patients. One hour after intake of placebo, metoprolol 100 mg or acebutolol 400 mg, increasing doses of terbutaline were infused. Before and one hour after ingestion of the medication and after each infusion of terbutaline, ventilatory and haemodynamic indices were measured. The two beta-blocking agents caused equal changes in basal ventilatory and haemodynamic indices. Terbutaline infusion caused a dose-dependent increase in forced expiratory volume in one second (FEV₁) and peak expiratory flow rate (PEFR), both during placebo and beta-blockade. Metoprolol did not affect the terbutaline-induced bronchodilatation. During acebutolol medication, however, the increase in FEV₁ and PEFR induced by terbutaline was partly inhibited. Terbutaline infusion during placebo caused a dose-dependent increase in heart rate (HR) and systolic blood pressure (BP), and a decrease in diastolic BP. During acebutolol medication, these haemodynamic effects of terbutaline were completely blocked, but during metoprolol medication terbutaline still caused small changes in the same direction as during placebo, presumably because the vasodilator action of terbutaline was not inhibited. A negative correlation was found between the plasma levels of acebutolol and its metabolite N-acetyl acebutolol at the end of the study and changes in FEV₁ and PEFR induced by terbutaline during acebutolol therapy as compared with placebo. The ventilatory and haemodynamic findings suggest a lower degree of beta₁-selectivity after oral administration of acebutolol as compared to metoprolol.     

THE PROTEIN BINDING AND ELIMINATION OF METHOTREXATE AFTER INTRAVENOUS INFUSIONS IN CANCER PATIENTS

Total serum concentrations and protein binding of methotrexate (MTX) have been studied after fifty-eight 6 h MTX infusions in nineteen cancer patients. 1. There was a linear relationship between dose (mg/kg) and serum MTX concentration at termination of infusion. 2. The elimination of total serum and ‘free’ MTX followed similar bi-exponential expressions during the 72 h studied after the infusion. 3. Of the eight occasions when total serum concentrations did not fall below 10^?7 mol/l on the third day, five were associated with toxicity. 4. Mean per cent MTX bound by sera from the nineteen patients was 47.2 (s.d. = 4.4) per cent and appeared to be independent of MTX concentration within the range studied. 5. This study suggests that the very high binding previously reported for MTX should be questioned and that measurement of total serum MTX concentration (bound plus free) is sufficient for the recognition of patients who might be at risk of developing toxicity.     

Should continuous infusion 5-fluorouracil become the standard of care in the USA as it is in Europe?

The mechanism of action of 5-fluorouracil (5-FU) and its pharmacologic behavior are influenced by its mode of administration. Several clinical studies have been conducted with the purpose of evaluating the difference between the continuous (CI 5-FU) and the bolus infusion of 5-FU (BI 5-FU). We focus our review on the studies relevant to the treatment of colorectal cancer, both in the adjuvant and metastatic setting. While individual trials fail to show a survival benefit for CI 5-FU, a meta-analyses of 7 trials shows an improvement in overall survival (OS) over BI 5-FU in metastatic colorectal cancer treatment. All trials in the same setting reveal a different toxicity profile for CI 5-FU that is generally more favorable than BI 5-FU. In the adjuvant setting, CI 5-FU allows the duration of therapy to be shortened by half without compromising the efficacy. CI 5-FU is the regimen of choice when given concurrently with radiation. When given in combination with other cytotoxic agents, CI 5-FU seems to be associated with less toxicity and potentially higher efficacy. Oral fluoropyrimidines, especially capecitabine, appear to behave in similar manner to CI 5-FU and may offer a convenient alternative to the usage of infusion pumps and indwelling catheters. While clinical trials are ongoing to compare capecitabine to CI 5-FU, we believe that CI 5-FU should be offered to patients in the United States given its favorable toxicity profile and higher efficacy in several settings.     

Microinfusion Using Hollow Microneedles

Purpose The aim of the study is to determine the effect of experimental parameters on microinfusion through hollow microneedles into skin to optimize drug delivery protocols and identify rate-limiting barriers to flow. Methods Glass microneedles were inserted to a depth of 720–1080 μm into human cadaver skin to microinfuse sulforhodamine solution at constant pressure. Flow rate was determined as a function of experimental parameters, such as microneedle insertion and retraction distance, infusion pressure, microneedle tip geometry, presence of hyaluronidase, and time. Results Single microneedles inserted into skin without retraction were able to infuse sulforhodamine solution into the skin at flow rates of 15–96 μl/h. Partial retraction of microneedles increased flow rate up to 11.6-fold. Infusion flow rate was also increased by greater insertion depth, larger infusion pressure, use of a beveled microneedle tip, and the presence of hyaluronidase such that flow rates ranging from 21 to 1130 μl/h were achieved. These effects can be explained by removing or overcoming the large flow resistance imposed by dense dermal tissue, compressed during microneedle insertion, which blocks flow from the needle tip. Conclusions By partially retracting microneedles after insertion and other methods to overcome flow resistance of dense dermal tissue, protocols can be designed for hollow microneedles to microinfuse fluid at therapeutically relevant rates.     

Lipid Injectable Emulsions: Pharmacopeial and Safety Issues

Abstract Lipid injectable emulsions have been routinely used in patients worldwide for over 40 years as a nutritional supplement in patients requiring parenteral nutrition. They can be given as a separate infusion or added into total parenteral nutrition admixtures. Despite such broad use, no pharmacopeial standards exist with respect to the optimal pharmaceutical characteristics of the formulation. Several attempts to establish standard physical and chemical attributes have been attempted by various pharmacopeias around the world, but without success largely due to technical issues regarding the creation of globule size limits. Recently, the United States Pharmacopeia has revised its previous efforts and developed two methods and criteria (under Chapter <729>) to measure the mean droplet size (Method I), and the large-diameter tail > 5 μm (Method II) of the globule size distribution to verify the stability of lipid injectable emulsions. Importantly, it is the latter size limits of Method II that have the greatest implications for infusion safety. The major safety issues involving lipid injectable emulsions include impairments in plasma clearance in susceptible patients, and the infusion of an unstable emulsion containing large quantities of potentially embolic fat globules. Recent animal studies investigating the toxicity from the infusion of unstable lipid injectable emulsions have shown evidence of oxidative stress and tissue damage to the liver when recommended globule size limits determined by Method II of the USP are exceeded. Adoption of Chapter <729> of the USP seems appropriate at this time.Dr. Driscoll is a Consultant and/or Researcher in the area of lipids for AstraZeneca, B. Braun, Biolink and Hospira companies.