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W D Lougheed

Publications and source records attributed to W D Lougheed.

7 recordsLinked to original sources
PubMed1997

Stability of insulin lispro in insulin infusion systems.

OBJECTIVE: To test stability of insulin lispro in two insulin infusion systems over 48 h. RESEARCH DESIGN AND METHODS: We used reverse-phase and size-exclusion high-performance liquid chromatography (HPLC) to determine the purity, potency, and degree of polymerization of U100 insulin lispro (Humalog) after 24- and 48-h pump cycles conducted at 37 degrees C in five Disetronic H-TRON V100 and five MiniMed 504 pumps. Pumps were set to deliver a basal rate of 0.5 U/h and 6-U boluses at t = 0, 4, 8, 24, 24.5, 28.5, 32.5, and 48 h during each cycle. The effluent was collected into 1-ml vials, pooled at 24 or 48 h, and stored at 4 degrees C until assay. After each 48-h run period of insulin delivery, assays for potency, polymer, and purity were performed on the pooled samples from each individual cycle. m-cresol content and the pooled reservoir content were assayed in the 48-h pooled samples. RESULTS: Insulin lispro retained full HPLC potency (delta < or = 4%) at 48 h, with no degradation of insulin lispro to des-amidoinsulin forms (24 or 48 h). No increase in pumped insulin polymer concentration was observed following 24 h of pump flow. Nonsignificant increases of < or =0.09% (Disetronic) and < or =0.15% (MiniMed) from initial concentrations of 0.18% (polymer divided by total insulin) were detected in three of five pump cycles at 48 h when compared with 37 degrees C paired controls. Nonsignificant decreases (<5 and 10%, Disetronic and MiniMed, respectively) of m-cresol content occurred in both systems following 48 h storage in each device, but sterility was not compromised by this decrease (initial m-cresol concentration, 3.15 mg/ml). Pump performance was without mechanical or electrical fault throughout the study Basal and bolus insulin delivery was evaluated three times daily and remained as expected. Occlusion of catheters by insulin precipitation did not occur, and no change in pH was observed following delivery. CONCLUSIONS: We conclude that insulin lispro is suitable for prolonged infusion in these two medical devices when syringes and catheters are replaced at 48-h intervals.

Chromatography, High Pressure Liquid↗
PubMed1983

Physical stability of insulin formulations.

Insulin aggregation remains a fundamental obstacle to the long-term application of many insulin infusion systems. We here report the effects of physiologic and nonphysiologic compounds on the aggregation behavior of crystalline zinc insulin (CZI) solutions. Under conditions chosen to simulate the most severe that would be encountered in delivery systems (presence of air, continuous motion, and elevated temperature), both highly purified and regular CZI at 5 U/ml formed turbid gels in 5 days. At concentrations of 100 and 500 U/ml stability was increased with turbid gels forming at 12 and 15 days, respectively. Under identical conditions, 5 U/ml CZI formulations containing the physiologic surfactant lysophosphatidylcholine (0.02%) or the synthetic surfactants SDS (1%), Brij 35 (0.1%), Tween (0.01%), or Triton X (0.01%) retained a transmittance at 540 nm of greater than 96% for 67-150 days. These nonionic and ionic surfactants containing the hydrophobic group, CH3(CH2)N, with N = 7-16, remarkably stabilized CZI formulations while those lacking such groups demonstrated little or no effect. The alcohols glycerol (30-50%) and isopropanol (10-50%) were moderately effective stabilizers. Silicone rubber drastically accelerated aggregation in all but one formulation (1% SDS). Emphasis in this study was placed on the properties of 5-U/ml formulations. Controls run at higher concentrations indicated a positive correlation between concentration and stability. It was concluded that the aggregation of insulin into high-molecular-weight polymers may be inhibited by reducing the effective polarity of the solvent. In this regard, anionic and nonionic surfactants containing appropriately long hydrophobic groups demonstrated the greatest degree of stabilization. Finally, of all the medical grade materials likely to be used in pumps, silicone rubber is the most active in promoting insulin aggregation.

Alcohols↗
PubMed1981

A physiological solvent for crystalline insulin.

Insulin is insoluble in water at physiological pH, but dissolves relatively rapidly in plasma. To quantify the ability of various solutions to dissolve crystalline insulin, a simple assay measuring dissolution time was developed. At pH 7.5 and room temperature, distilled water, 0.154 mol/l NaCl, Ringer's lactate solution, and 5% albumin in 0.154 mol/l NaCl did not dissolve insulin crystals within 30 min. Normal postprandial human plasma and a protein-free cell culture medium dissolved insulin crystals within 3 to 8 min. This ability was inhibited by acid titration of the fluids to a stable pH of 6.30, at which point bicarbonate depletion could be implied. Repletion of bicarbonate did restore the ability of these solutions to dissolve insulin crystals, but back-titration to the initial pH with NaOH did not. The effect of sodium bicarbonate alone was strongly concentration dependent above 23 mmol/l. We suggest that the ability of physiological fluids to dissolve insulin crystals at normal pH depends on their bicarbonate content. The ability to dissolve insulin with a physiological solvent which prevents its reaggregation promises to facilitate its use in portable pumping systems.

Adult↗
PubMedDate not supplied

Stabilizing blood glucose with a novel medical expert system.

In health, metabolism is elegantly coordinated. Failure of an underlying process (as occurs in diabetes) disrupts the coordination and impacts on the global status of the affected individual. It takes a medical expert to intervene and restore order. Chaotic processes prevail at all times in biological systems and their behaviour in sickness degenerates between medical interventions. We have explored the use of an expert system to substitute for the physician between interventions and demonstrated its ability to maintain order and thus significantly improve control of blood glucose.

Adolescent↗
PubMedDate not supplied

In vivo bicarbonate deficiency and insulin dissolution.

Exogenous insulin exists primarily as the monomer in human plasma. However, in U100 regular insulin formulations, the concentrations of zinc and peptide are such that the insulin hexamer predominates. The biologic result is further disassociation to the monomer after subcutaneous or i.v. administration. Because of this, human plasma from seven normal controls dissolved 20-30 microm hexagonal insulin crystals in 3-8 min. This ability was inhibited by acid titration to a stable pH of 6.30, at which point bicarbonate depletion could be suggested. Repletion of bicarbonate remarkably restored the solvent effect, while back-titration to the initial pH without repleting bicarbonate had only a moderate result. To establish whether the in vivo reduction of bicarbonate in pathologic states had similar results, plasma from five Type I diabetics in severe acidosis (pH 7.06 +/- 0.04, HCO3 -7.3 +/- 0.6 mmol/l) was similarly studied after stabilization under 5% CO2 (pH, 6.97-7.17). In all cases, the dissolution of insulin crystals was inhibited (dissolution times greater than 25 min). When bicarbonate was replenished (HCO3- 24.1-26.7 mmol/l) and pH accordingly renormalized (pH 7.39-7.43), the dissolution of insulin crystals was completely restored. Because of these observations, we conclude that both plasma bicarbonate and pH markedly affect the dissolution of insulin and that reduced bicarbonate/pH in diabetic ketoacidosis may limit the availability of the biologically active monomer. These influences may play a role in the initial insensitivity to insulin frequently seen in severe insulin deficiency and ketoacidosis.

Adult↗