A Novel,Stable, Aqueous Glucagon Formulation Using Ferulic Acid as an Excipient

Background:Commercial glucagon is unstable due to aggregation and degradation. In closed-loop studies, it must be reconstituted frequently. For use in a portable pump for 3 days, a more stable preparation is required. At alkaline pH, curcumin inhibited glucagon aggregation. However, curcumin is not sufficiently stable for long-term use. Here, we evaluated ferulic acid, a stable breakdown product of curcumin, for its ability to stabilize glucagon.Methods:Ferulic acid-formulated glucagon (FAFG), composed of ferulic acid, glucagon, L-methionine, polysorbate-80, and human serum albumin in glycine buffer at pH 9, was aged for 7 days at 37°C. Glucagon aggregation was assessed by transmission electron microscopy (TEM) and degradation by high-performance liquid chromatography (HPLC). A cell-based protein kinase A (PKA) assay was used to assess in vitro bioactivity. Pharmacodynamics (PD) of unaged FAFG, 7-day aged FAFG, and unaged synthetic glucagon was determined in octreotide-treated swine.Results:No fibrils were observed in TEM images of fresh or aged FAFG. Aged FAFG was 94% intact based on HPLC analysis and there was no loss of bioactivity. In the PD swine analysis, the rise over baseline of glucose with unaged FAFG, aged FAFG, and synthetic native glucagon (unmodified human sequence) was similar.Conclusions:After 7 days of aging at 37°C, an alkaline ferulic acid formulation of glucagon exhibited significantly less aggregation and degradation than that seen with native glucagon and was bioactive in vitro and in vivo. Thus, this formulation may be stable for 3-7 days in a portable pump for bihormonal closed-loop treatment of T1D.     

Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas

Background:A promising approach to treat diabetes is the development of fully automated artificial/bionic pancreas systems that use both insulin and glucagon to maintain euglycemia. A physically and chemically stable liquid formulation of glucagon does not currently exist. Our goal is to develop a glucagon formulation that is stable as a clear and gel-free solution, free of fibrils and that has the requisite long-term shelf life for storage in the supply chain, short-term stability for at least 7 days at 37°C, and pump compatibility for use in a bihormonal pump.Methods:We report the development of two distinct families of stable liquid glucagon formulations which utilize surfactant or surfactant-like excipients (LMPC and DDM) to “immobilize” the glucagon in solution potentially through the formation of micelles and prevention of interaction between glucagon molecules.Results:Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine.Conclusions:These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.     

The Role of Glucagon,Catecholamines and Cortisol in Counterregulation of Insulin-induced Hypoglycemia in Normal Man

ABSTRACT To study the response of glucose counterregulation to insulin-induced hypoglycemia, six normals were given a 4-hour infusion of insulin (2.4 U/h) ± somatostatin (50 μg/h). Supplementary glucagon (1.5 or 3.0 ng/kg/min) was given in additional experiments. In a separate study, glucagon was supplemented for 4 hours as a constant rate infusion (3.25 ng/kg/min) or at rates stepwise increasing from 1.5 to 5.0 ng/kg/min. Insulin decreased blood glucose by 1.5 mmol/1 and simultaneous suppression of glucagon resulted in a more pronounced hypoglycemia enhancing the adrenaline and Cortisol responses. The hyperglycemic effect of glucagon substitution (3 ng/kg/min) faded out after about 2 hours, whereafter exaggerated adrenaline and Cortisol responses to hypoglycemia were seen. A comparison between the effects of steady state hyperglucagonemia and gradually appearing hyperglucagonemia on the counterregulation of hypoglycemia revealed no significant differencies in glucose, adrenaline and Cortisol responses to insulin. It is concluded that the glycemic effect of glucagon is transient in the hypoglycemic state. When the hepatic responsiveness to this hormone is decreased during hypoglycemia, adrenaline becomes the essential protective factor.     

Intranasal Glucagon: A Promising Approach for Treatment of Severe Hypoglycemia

Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia.     

A Feasibility Study of Bihormonal Closed-Loop Blood Glucose Control Using Dual Subcutaneous Infusion of Insulin and Glucagon in Ambulatory Diabetic Swine

Background

We sought to test the feasibility and efficacy of bihormonal closed-loop blood glucose (BG) control that utilizes subcutaneous (SC) infusion of insulin and glucagon, a model-predictive control algorithm for determining insulin dosing, and a proportional-derivative control algorithm for determining glucagon dosing.

Methods

Thirteen closed-loop experiments (∼7–27 h in length) were conducted in six ambulatory diabetic pigs weighing 26–50 kg. In all experiments, venous BG was sampled through a central line in the vena cava. Efficacy was evaluated in terms of the controller''s ability to regulate BG in response to large meal disturbances (∼5 g of carbohydrate per kilogram of body mass per meal) based only on regular frequent venous BG sampling and requiring only the subject''s weight for initialization.

Results

Closed-loop results demonstrated successful BG regulation to normoglycemic range, with average insulin-to-carbohydrate ratios between ∼1:20 and 1:40 U/g. The total insulin bolus doses averaged ∼6 U for a meal containing ∼6 g per kilogram body mass. Mean BG values in two 24 h experiments were ∼142 and ∼155 mg/dl, with the total daily dose (TDD) of insulin being ∼0.8–1.0 U per kilogram of body mass and the TDD of glucagon being ∼0.02–0.05 mg. Results also affirmed the efficacy of SC doses of glucagon in staving off episodic hypoglycemia.

Conclusions

We demonstrate the feasibility of bihormonal closed-loop BG regulation using a control system that employs SC infusion of insulin and glucagon as governed by an algorithm that reacts only to BG without any feed-forward information regarding carbohydrate consumption or physical activity. As such, this study can reasonably be regarded as the first practical implementation of an artificial endocrine pancreas that has a hormonally derived counterregulatory capability.     

Glucagon therapeutics: Dawn of a new era for diabetes care

Although insulin monotherapy prevents death from ketoacidosis, it does not prevent either the hyperglycemic surges or the hypoglycemic plunges of glucose levels that plague the majority of patients with type 1 diabetes. However, significant improvements have occurred with the combination of continuous insulin delivery matched by continuous glucose monitoring, but the technology is not available for all patients, requires extensive education, is expensive and moreover, while much better than standard care, it almost never reduces haemoglobin A_1c (HbA_1c) to below 6%. This may indicate that an improved diabetes therapy involving antagonism of glucagon action will for the first time control glucose levels to normal and eradicate the long‐term complications of diabetes. Although one can never predict that results in animals will be reproduced in humans, the available evidence suggests that patients with type 1 and type 2 diabetes may expect far superior control of the metabolic abnormalities without the need for significant monitoring of glucose, a very important but expensive part of any insulin regimen.     

Use of Personal Continuous Glucose Monitoring Device Is Associated With Reduced Risk of Hypoglycemia in a 16-Week Clinical Trial of People With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion

Aims:Continuous glucose monitoring (CGM) has the potential to promote diabetes self-management at home with a better glycemic control as outcome. Investigation of the effect of CGM has typically been carried out based on randomized controlled trials with prespecified CGM devices on CGM-naïve participants. The aim of this study was to investigate the effect on glycemic control in people using their personal CGM before and during the trial.Materials and Methods:Data from the Onset 5 trial of 472 people with type 1 diabetes using either their personal CGM (n = 117) or no CGM (n = 355) and continuous subcutaneous insulin infusion in a 16-week treatment period were extracted. Change from baseline in glycated hemoglobin A1c (HbA_1c), number of hypoglycemic episodes, and CGM metrics at the end of treatment were analyzed with analysis of variance repeated-measures models.Results:Use of personal CGM compared with no CGM was associated with a reduction in risk of documented symptomatic hypoglycemia (event rate ratio: 0.82; 95% CI: 0.69-0.97) and asymptomatic hypoglycemia (event rate ratio: 0.72; 95% CI: 0.53-0.97), reduced time spent in hypoglycemia (P = .0070), and less glycemic variability (P = .0043) without a statistically significant increase in HbA_1c (P = .2028).Conclusions:Results indicate that use of personal CGM compared with no CGM in a population of type 1 diabetes is associated with a safer glycemic control without a statistically significantly deteriorated effect on HbA_1c, which adds to the evidence about the real-world use of CGM, where device type is not prespecified, and users are not CGM naïve.     

Technology for Hospital Management of Diabetes: Use of Continuous Subcutaneous Insulin Infusion (Insulin Pump) Therapy in the Hospital: A Review of One Institution's Experience

Background

This article reviews the performance of our hospital''s inpatient insulin pump policy.

Methods

Twenty-five hospital admissions of 21 unique patients receiving outpatient insulin pump therapy were reviewed.

Results

Between November 1, 2005, and November 30, 2006, there were 25 hospital admissions involving 21 patients receiving outpatient insulin pump therapy. The average age and duration of diabetes among these 21 patients was 50 and 29 years, respectively; 67% were women, 90% had type 1 diabetes, and all were white. The mean length of hospital stay was 4 days, and the average reported length of insulin pump therapy was 4 years. Patients in 16 of the admissions were identified as candidates for continued use of the insulin pump during the hospital stay. Over 90% of patients remaining on the insulin pump had documentation by nursing of the presence of the pump at the time of admission; 100% of the patients had an admission glucose recorded; 88% had a record of signed patient consent; 81% had evidence of completed preprinted insulin pump orders; 75% received a required endocrine consultation; and 75% of cases had documentation of completed bedside flow sheet. A high frequency of both hypoglycemic and hyperglycemic events occurred in the patients; however, no adverse events were related directly to the insulin pump.

Conclusions

Insulin pump therapy can be safely continued in the hospital setting. While staff compliance with required procedures was high, there was still room for improvement. More data are needed, however, on whether this method of insulin delivery is effective for controlling hyperglycemia in hospitalized patients.     

Formulation Development of a Food-Graded Curcumin-Loaded Medium Chain Triglycerides-Encapsulated Kappa Carrageenan (CUR-MCT-KC) Gel Bead Based Oral Delivery Formulation

In recent years, curcumin has been a major research endeavor in food and biopharmaceutical industries owing to its miscellaneous health benefits. There is an increasing amount of research ongoing in the development of an ideal curcumin delivery system to resolve its limitations and further enhance its solubility, bioavailability and bioactivity. The emergence of food-graded materials and natural polymers has elicited new research interests into enhanced pharmaceutical delivery due to their unique properties as delivery carriers. The current study is to develop a natural and food-graded drug carrier with food-derived MCT oil and a seaweed-extracted polymer called k-carrageenan for oral delivery of curcumin with improved solubility, high gastric resistance, and high encapsulation of curcumin. The application of k-carrageenan as a structuring agent that gelatinizes o/w emulsion is rarely reported and there is so far no MCT-KC system established for the delivery of hydrophobic/lipophilic molecules. This article reports the synthesis and a series of in vitro bio-physicochemical studies to examine the performance of CUR-MCT-KC as an oral delivery system. The solubility of CUR was increased significantly using MCT with a good encapsulation efficiency of 73.98 ± 1.57% and a loading capacity of 1.32 ± 0.03 mg CUR/mL MCT. CUR was successfully loaded in MCT-KC, which was confirmed using FTIR and SEM with good storage and thermal stability. Dissolution study indicated that the solubility of CUR was enhanced two-fold using heated MCT oil as compared to naked or unformulated CUR. In vitro release study revealed that encapsulated CUR was protected from premature burst under simulated gastric environment and released drastically in simulated intestinal condition. The CUR release was active at intestinal pH with the cumulative release of >90% CUR after 5 h incubation, which is the desired outcome for CUR absorption under human intestinal conditions. A similar release profile was also obtained when CUR was replaced with beta-carotene molecules. Hence, the reported findings demonstrate the potencies of MCT-KC as a promising delivery carrier for hydrophobic candidates such as CUR.     

Technology for Hospital Management of Diabetes: Evaluation of Implementation of a Fully Automated Algorithm (Enhanced Model Predictive Control) in an Interacting Infusion Pump System for Establishment of Tight Glycemic Control in Medical Intensive Care Unit Patients

Background

The objective of this study was to investigate the performance of a newly developed decision support system for the establishment of tight glycemic control in medical intensive care unit (ICU) patients for a period of 72 hours.

Methods

This was a single-center, open, non-controlled feasibility trial including 10 mechanically ventilated ICU patients. The CS-1 decision support system (interacting infusion pumps with integrated enhanced model predictive control algorithm and user interface) was used to adjust the infusion rate of administered insulin to normalize blood glucose. Efficacy and safety were assessed by calculating the percentage of values within the target range (80–110 mg/dl), hyperglycemic index, mean glucose, and hypoglycemic episodes (<40 mg/dl).

Results

The percentage of values in time in target was 47.0% (±13.0). The average blood glucose concentration and hyperglycemic index were 109 mg/dl (±13) and 10 mg/dl (±9), respectively. No hypoglycemic episode (<40 mg/dl) was detected. Eleven times (1.5% of all given advice) the nurses did not follow and, thus, overruled the advice of the CS-1 system. Several technical malfunctions of the device (repetitive error messages and missing data in the data log) due to communication problems between the new hardware components are shortcomings of the present version of the device. As a consequence of these technical failures of system integration, treatment had to be stopped ahead of schedule in three patients.

Conclusions

Despite technical malfunctions, the performance of this prototype CS-1 decision support system was, from a clinical point of view, already effective in maintaining tight glycemic control. Accordingly, and with technical improvement required, the CS-1 system has the capacity to serve as a reliable tool for routine establishment of glycemic control in ICU patients.     

Evaluation of Bedoradrine Sulfate (MN-221), a Novel,Highly Selective Beta2-Adrenergic Receptor Agonist for the Treatment of Asthma via Intravenous Infusion

Background. The number of hospitalizations or deaths due to asthma, most of which result from acute exacerbations of asthma, has remained the same for the past 20 years. MN-221 (bedoradrine sulfate) is a novel, highly selective beta₂- (β₂-) adrenergic agonist administered via intravenous (IV) infusion in development for the treatment for acute exacerbation of asthma. Objectives. Trial MN-221-CL-004 assessed the safety profile and preliminary efficacy of MN-221 in escalating doses in patients with stable mild-to-moderate asthma. Study MN-221-CL-005 assessed the safety profile and preliminary efficacy of MN-221 in patients with stable moderate-to-severe asthma when given as a fixed dose over 1- or 2- hr infusion. Methods. Two randomized, placebo-controlled clinical trials (n = 40) were performed to evaluate the pharmacokinetic (PK) and clinical effects of a novel, highly selective β₂-agonist, MN-221, via IV infusion. Safety evaluations included vital signs, adverse events (AEs), clinical laboratory parameters, and electrocardiogram results. Efficacy evaluation included measurement of forced expiratory volume in 1 second (FEV₁) and PK parameters were additionally monitored. The study was reviewed and approved by the Institutional Review Board at each site. Results. Adverse effects were mild or moderate and there were no serious AEs or deaths during the studies. The most frequently reported AEs were tremor, hypokalemia, and headache. There were no consistent dose-dependent effects of MN-221 on any safety parameters, with the exception of heart rate, which was not considered to be clinically significant and did not require any treatment. Moderate hypokalemia occurred once in one subject in the MN-221-CL-004 study and twice in one subject in the MN-221-CL-005 study and were transient and returned to normal range following single oral potassium chloride treatments. PK assessments indicated a linear response in MN-221 plasma concentrations for the doses evaluated. Dose escalation results showed that mean changes in FEV₁ from pre-infusion were significantly greater than placebo and an overall dose response was statistically significant (p < .0001). Post-infusion FEV₁ improvements appeared to plateau at the 30 μg/min dose level despite a higher peak plasma concentration at 60 μg/min. Dose-rate escalation results demonstrated greater mean increases in change in FEV₁ compared to the placebo group with the largest increase associated with the higher MN-221 dose rate and peak plasma concentration. Conclusions. The safety profile of MN-221 and evidence of dose- and plasma-concentration-related bronchodilation supports further clinical development and suggests the potential for clinical benefit without increased clinical risk, particularly for patients where inhaled or nebulized therapy is not adequate or possible. Trial registry name and registration number:Name: MN-221-CL-005Number: NCT00679263     

Performance and Acceptability of a Combined Device for Insulin Infusion and Glucose Sensing in the Home Setting

Background:

The use of sensor-augmented insulin pump (SAP) therapy is increasing. Currently, glucose sensors and insulin infusion cannulas are inserted separately. A new device, MiniMed Duo, combines sensing and infusion capabilities on the same platform and is intended to simplify device insertion and site management. We evaluated the device’s performance with respect to insulin delivery and glucose sensing, and its acceptability with patients.

Methods:

Forty-five patients (mean ± SD age, 45.5 ± 10.9 years, 48% female) with type 1 diabetes and previous use of SAP participated. Each subject was to wear 5 devices connected to insulin pumps over 15 days (3 days/device) and test capillary blood glucose (SMBG) 7 times/day. The primary endpoint was the percentage of sensor-SMBG paired values within 20% of one another. Subject experiences were assessed via questionnaires.

Results:

Overall, 74.8% of sensor-SMBG paired values were within 20%, meeting the primary accuracy endpoint, and the mean absolute relative difference was 15.5 ± 17.1%. Consensus error grid analysis showed that >95% of points were within the A+B zones, exceeding the threshold for adequate clinical accuracy. Insulin dosage and SMBG values did not change significantly compared to prestudy values. The functional survival of the device entering day 3 was 90.5%. There were no serious adverse events. Mean questionnaire results indicated overall satisfaction with the device.

Conclusion:

Duo provided insulin infusion and glucose sensing capabilities in a single device, which provided accurate glucose readings during routine use, was safe to wear, and was acceptable to most patients. It may improve satisfaction and convenience for patients using sensor-augmented insulin pumps.     

Diabetes Technologies and Hospital Care: Comparison of Insulin Pump Therapy (Continuous Subcutaneous Insulin Infusion) to Alternative Methods for Perioperative Glycemic Management in Patients with Planned Postoperative Admissions

Background

Patients with diabetes who use insulin pumps [continuous subcutaneous insulin infusion (CSII)] undergo surgeries that require postoperative hospital admission. There are no defined guidelines for CSII perioperative use.

Methods

This retrospective single-institution study identified type 1 and type 2 diabetes subjects by electronically searching 2005–2010 anesthesia preoperative assessments for “pump.” Surgical cases (n = 92) were grouped according to intraoperative insulin delivery method: (a) CSII continuation of basal rate with/without correctional insulin bolus(es) (n = 53); (b) conversion to intravenous insulin infusion (n = 20); and (c) CSII suspension with/without correctional insulin bolus(es) (n = 19). These groups were compared on mean intraoperative blood glucose (BG) and category of most extreme intraoperative BG.

Results

Differences were found on baseline characteristics of diabetes duration (p = .010), anesthesia time (p = .011), proportions receiving general anesthesia (p = .013), and preoperative BG (p = .033). The conversion group had the longest diabetes duration and anesthesia time; it had a higher proportion of general anesthesia recipients and a higher mean preoperative BG than the continuation group. There was no significant difference in mean BG/surgical case between continuation (163.5 ± 58.5 mg/dl), conversion (152.3 ± 28.9 mg/dl), and suspension groups (188.3 ± 44.9 mg/dl; p = .128). The suspension group experienced a greater percentage of cases (84.2%) with one or more intraoperative BG > 179 mg/dl than continuation (45.3%) and conversion (40%) groups Figure 1 groupings (p = .034).Open in a separate windowFigure 1Comparison of insulin delivery methods to percentage of surgical cases with intraoperative hypoglycemia and hyperglycemia. Chi-square = 13.43, p = .034; continuation group, n = 53; conversion group, n = 20; suspension group, n = 19. All groupings were mutually exclusive. Intraoperative BG is defined as all BG measurements performed in the operating room and the first postoperative anesthesia care unit measurement

Conclusions

In this limited sample, preliminary findings are consistent with similar intraoperative glycemic control between CSII continuation and CSII conversion to intravenous insulin infusions. Continuous subcutaneous insulin infusion suspension had a greater rate of hyperglycemia. Preoperative differences between insulin delivery groups complicate interpretations of findings.     

Single-Dose Daily Infusion of Cyclosporine for Prevention of Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation from HLA Allele-Matched, Unrelated Donors

Peak blood concentration of cyclosporine (CsA) in renal transplantation patients was recently reported to be associated with clinical efficacy. We therefore evaluated the toxicity and efficacy of a regimen of once-daily infusion of CsA plus a short course of methotrexate as prophylaxis of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation from an HLA allele-matched, unrelated donor. Nineteen patients with hematologic malignancies received CsA, 3 mg/kg per day, as a 4-hour intravenous (IV) infusion from day -1. After engraftment, patients received CsA orally at twice the IV dose. The CsA dose was adjusted to maintain the blood trough level between 150 and 200 ng/mL. Methotrexate was administered IV at doses of 10 mg/m(2) on day 1 and 7 mg/m(2) on days 3, 6, and 11. Bone marrow engraftment occurred in all patients. Grade 1 and grade 2 GVHD occurred in 6 (31.6%) and 7 (36.8%) of the 19 patients, respectively. No patient had grade 3 or 4 GVHD. Acute nephrotoxicity developed in 1 (5.3%) of the 19 patients, and hypertension developed in 3 (15.8%) of the 19 patients. We evaluated the pharmacokinetics of 4-hour CsA infusion in 10 patients. The mean trough concentration, mean peak concentration, mean time to peak concentration, and area under the curve (24 hours) were 161 +/- 43 ng/mL, 1498 +/- 387 ng/mL, 3.2 +/- 1.0 hours, and 10,848 +/- 1,991 ng +/- h/mL, respectively. This regimen was well tolerated and did not enhance the risk of severe GVHD in patients undergoing allogeneic bone marrow transplantation from an HLA allele-matched, unrelated donor.     

A 6-hour nocturnal interruption of a continuous subcutaneous insulin infusion: 1. Metabolic and hormonal consequences and scheme for a prompt return to adequate control

Summary Interruption of a continuous subcutaneous insulin infusion, most often due to technical problems occurring during the night, is a not uncommon event whose metabolic consequences have received relatively little attention until now. We have therefore investigated the changes in blood glucose, plasma non-esterified fatty acids, 3-hydroxybutyrate, glucagon and free insulin in eight C-peptide negative Type 1 diabetic patients whose pumps were deliberately stopped between 23.00 h and 05.00 h. A control test with the pump functioning normally was carried out in each patient and the studies were randomized. Considering the values at 23.00 h as reference, interruption of the insulin infusion resulted in (1) a rapid decrease in plasma free insulin significant after 1 h and reaching a nadir of 6±2 mU/l after 6 h; (2) a rise in blood glucose which was significant at hour 3 and reached 17.4±1.9 mmol/l at hour 6; (3) a moderate increase in plasma non-esterified fatty acids which remained in the range of 700–800 mol/l; (4) an early and linear rise in plasma 3-hydroxybutyrate, significant after 1 h and averaging 1290±140 mol/l after 6 h; (5) a late increase (hour 5) in plasma glucagon. The second aim of our study was to provide for the patient a precise scheme of insulin supplements administered via the pump and based on blood glucose monitoring (Dextrostix — Glucometer) and semi-quantitative evaluation of ketonuria (Acetest). Resetting the pump at its basal rate at 05.00h and giving insulin supplements (2–8 U) at 06.45 h (with the usual breakfast dose) and again at 10.00 h have proved efficacious in restoring satisfactory metabolic control by noon the day after starting the experiment. These results form practical recommendations to patients undergoing this type of accident.     

Infusion of peripheral blood stem cells collected at diagnosis,with maintenance of the treatment,resulted in Ph-negative recovery in a chronic myeloid leukaemia patient in persisting aplasia on STI-571 therapy

In advanced chronic myeloid leukaemia patients, STI-571 produces complete haematological response in most cases and cytogenetic response in up to 50%. However, these patients often suffer periods of pancytopenia, which can lead to life-threatening complications, and is probably due to the small number of residual normal stem cells. We have re-infused peripheral blood stem cells collected at diagnosis, in a patient, while maintaining STI-571 treatment. The patient recovered from aplasia, with Philadelphia-negative haematopoiesis. Discontinuing an effective treatment because of persistent aplasia is a major concern; this method circumvents this problem inpatients who have undergone a stem cell harvest at diagnosis.     

A Study on Using the Additive Manufacturing Process for the Development of a Closed Pump Impeller for Mechanically Pumped Fluid Loop Systems

The efficiency of a centrifugal pump for mechanical pump fluid loops, apart from the design, relies on the performance of the closed impeller which is linked to the manufacturing process in terms of dimensional accuracy and the surface quality. Therefore, the activities of this paper were focused on defining the manufacturing process of a closed impeller using the additive manufacturing technology for mechanically pumped fluid loop (MPFL) systems in space applications. Different building orientations were studied to fabricate three closed impellers using selective laser melting technology and were subjected to dimensional accuracy and surface quality evaluations in order to identify the optimal building orientation. The material used for the closed impeller is Inconel 625. The results showed that both geometrical stability and roughness were improved as the building orientation increased, however, the blade thickness presented small deviations, close to imposed values. Finishing processes for inaccessible areas presented significant results in terms of roughness, nevertheless, the process can be further improved. Abrasive flow machining (AFM) post-processing operations have been considered and the results show major improvements in surface quality. Thus, important steps were made towards the development of complex structural components, consequently increasing the technological readiness level of the additive manufacturing process for space applications.