Insulin Suspension Research Articles

Diabetic ketoacidosis associated with aripiprazole

Atypical antipsychotics have become the mainstay of management of schizophrenia and other psychotic disorders due to low risk of extrapyramidal symptoms. However, postmarketing data has reported atypical antipsychotic agents being associated with hyperglycaemia and diabetic ketoacidosis (DKA). We believe this to be the first published report of hyperglycaemia and DKA with the newest atypical antipsychotic agent, aripiprazole. A 34-year-old African-American female with schizophrenia presented to the emergency department with nausea, vomiting, and malaise for 3-4 days shortly after initiation of aripiprazole therapy. Initial laboratory results revealed significant hyperglycaemia with metabolic acidosis. The patient received treatment for DKA with an intravenous insulin infusion and fluid replacement. Isophane insulin suspension (NPH insulin) was begun immediately following the insulin drip and continued upon discharge from the hospital. Outpatient follow-up information was not available. To our knowledge, this is the first case report of aripiprazole associated with hyperglycaemia and DKA. This case is striking in that DKA occurred 4 days following initiation of aripiprazole and the patient had rapid resolution of symptoms and normalization of laboratory values upon discontinuation of aripiprazole. It is important that health-care providers monitor for hyperglycaemia when prescribing atypical antipsychotics including aripiprazole.

３３ゲージのテーパー型注射針を懸濁インスリン製剤が通過したときのＮＰＨ結晶の形状とインスリンの血糖降下作用への影響について

The Nanopass®33 micro-tapered needle (MT 33 G, Terumo Corp., Tokyo, Japan) is tapered in form : 33 G at the tip end and 28 G at the cartridge end. We examined the structure of insulin crystals in insulin suspensions before and after passing through the MT 33 G needle to determine if there were any changes in it that might adversely affect the pharmacodynamics and action of insulin. We also examined the hypoglycemic effect of insulin in dogs after it had passed through a MT 33 G needle to see if it had been modified by it.No changes were observed in the insulin crystal structure when the insulin preparation in a syringe was discharged at a rate of 10 units/sec through the MT 33 G needle connected to it. Also, when insulin was administered to dogs, there was no significant difference between the MT 33 G and the Micro-FineTM Plus, 31G, Thin Wall needle (Nippon Becton Dickinson Co., Ld., Tokyo, Japan) as regards the blood insulin and blood glucose levels measured.

An assessment of the adequacy of suspension of insulin in pen injectors.

To evaluate the completeness of insulin resuspension by users of neutral Hagedorn (NPH) insulin pens and premixed insulin pens and to relate this to how patients mix insulin before injecting. Patients (n = 180) administering a medium duration or premixed insulin in cartridges in disposable pens were asked questions about mixing insulin, injection technique and storing insulin. They were also asked to demonstrate how they mixed their insulin and to send in a half-used pen. The cloudy component equates to the complexed insulin, while the clear component is the diluting fluid or soluble insulin, depending on the type of insulin used. The optical density, a simple way of measuring cloudiness, was measured in each cartridge or disposable pen and was compared with the range obtained from a series of unused control pens. The results for 146 pens containing the most commonly used insulin were included. The 21 patients whose residual pen insulins showed optical densities > 5 SD from the mean were re-interviewed and their medical records were examined in detail. Insulin in the pens was also measured by immunoassay to confirm the utility of optical density measurements. Only one patient mixed the insulin as the manufacturers recommended. In 58 out of 146 pens or cartridges (40%) the opacity of the insulin varied significantly from the expected value. Most patients in Kirkcaldy do not mix insulin adequately. This may result in their giving different incorrect doses of insulin during the use of each pen. More emphasis should be given to teaching patients to mix correctly.

Diazoxide may improve ??-cell function in patients with type 2 diabetes mellitus receiving metformin and bedtime insulin suspension isophane,

Diazoxide may improve ??-cell function in patients with type 2 diabetes mellitus receiving metformin and bedtime insulin suspension isophane,

Achieving euglycaemia in women with gestational diabetes mellitus: current options for screening, diagnosis and treatment.

Gestational diabetes mellitus is one of the major medical complications of pregnancy. Untreated, the mother and the unborn child may experience morbidity and fetal death may even occur. It is important to diagnose and treat all hyperglycaemia appearing during pregnancy. Ideally, a screening and diagnostic test that identified all women at risk for hyperglycaemia-associated complications would be employed in all pregnant women. Unfortunately, there is no such test available currently. The best alternative is to administer an oral glucose challenge test to all pregnant women and then apply the best strategies for interpretation. This article discusses the limitations of our present diagnostic tools and suggests an option for the clinician until the definitive test has been elucidated. In addition, this article outlines one dietary and management strategy that has been associated with an outcome of pregnancy that is similar to the outcome of pregnancies in healthy women. This strategy includes starting with a "euglycaemic" diet (comprising < 40% carbohydrates and > or =40% fat), which can then be individualised according to the patient's glucose levels. Appropriate exercise, such as arm ergometer training, may enhance the benefits of diet control. For patients who require insulin, if the fasting glucose level is >90 mg/dL or 5 mmol/L (whole blood capillary) then NPH insulin (insulin suspension isophane) should be given before bed, beginning with dosages of 0.2 U/kg/day. If the postprandial glucose level is elevated, pre-meal rapid-acting insulin should be prescribed, beginning with a dose of 1U per 10g of carbohydrates in the meal. If both the fasting and postprandial glucose levels are elevated, or if a woman's postprandial glucose levels can only be blunted if starvation ketosis occurs, a four-injections-per-day regimen should be prescribed. The latter can be based on combinations of NPH insulin and regular human insulin, timed to provide basal and meal-related insulin boluses. The total daily insulin dose for the four-injection regimen should be adjusted according to pregnant bodyweight and gestational week (0.7-1 U/kg/day); doses may need to be increased for the morbidly obese or when there is twin gestation. There is now some evidence that insulin lispro, other insulin analogues and oral antihyperglycaemic drugs may be beneficial in gestational diabetes, and more data on these agents are awaited with interest.

Insulin glargine as effective as insulin suspension isophane

Insulin glargine as effective as insulin suspension isophane

Maximally Utilizing the Available Agents for the Treatment of Type 2 DIabetes

Maximally Utilizing the Available Agents for the Treatment of Type 2 DIabetes

Variability of insulin absorption and insulin action.

Subcutaneous (s.c.) injections of identical insulin doses may lead to considerable intra- and inter-individual differences in the current metabolic control of patients with diabetes mellitus. This well-known variability of the metabolic effect of insulin hampers practical insulin therapy considerably. The aim of this review is to summarize the knowledge about this topic, with a special focus on the variability of insulin action after pulmonary administration of insulin. A number of studies have been published describing the variability of insulin absorption from the s.c. depot. Only in a few published studies has the variability of insulin action after s.c. administration been quantified. Under controlled experimental conditions s.c. injections of regular insulins result in an intra-individual coefficient of variation (CV) of 15-25% of certain pharmacodynamic summary measures--which characterize the metabolic effect of the applied insulin--in healthy subjects. The inter-individual variability was approximately 10% higher than the intra-individual variability. Subcutaneously injected intermediate- and long-acting insulin preparations were described to have an even greater variability (> 50%) than subcutaneously injected regular insulin. However, in a glucose clamp study s.c. application of NPH insulin led to an intra-individual CV in the range of 12-45% in healthy subjects. The reason for this discrepancy might be that the NPH insulin suspension was sufficiently shaken prior to drawing up the dose. Compared with conventional insulin formulations, rapid- and long-acting insulin analogues appear to have a similar variability, which means that, unfortunately, no considerable advantages in terms of variability were achieved by the invention of these novel insulin preparations. There are no appropriate studies available investigating the variability of the metabolic effect after s.c. insulin administration in patients with diabetes. The inhalation of insulin is a novel form of insulin administration that is currently under clinical development. The variability of the metabolic effect induced by the inhalation of insulin has up to now only been investigated in a small number of (published) studies. In a glucose-clamp study with healthy subjects the inhalation of an identical insulin dose on three study days led to an intra-individual variability that was comparable to that after s.c. injection of regular insulin. In a dose-response study with patients with type 1 diabetes the intra-individual CV was 34% for the area under the curve of the glucose infusion rate for 0-10 h. Studies with patients with type 2 diabetes have shown that the intra-individual CVs were within the range seen after s.c. insulin administration or even lower. In summary, the intra-individual variability of the metabolic effect observed after insulin application, be it subcutaneously injected or be it inhaled, is considerable and, therefore, hampers practical diabetes therapy. To date no means have been found that could lead to a clinically relevant reduction in the variable metabolic effect.

Evaluating the Dissolution Behavior of Zinc-Complexed Protein Suspensions by Computer Modeling and Simulation

ABSTRACTIn vitro dissolution of zinc insulin suspensions can be promoted by the complexation of zinc with an ionic species for which the zinc ion has a greater affinity. Studies conducted by our group have previously shown that the rate-limiting steps that govern the dissolution of zinc-complexed insulin suspension may be chemical complexation (surface reaction) and subsequent drug mass transport (diffusion and solubility). The purpose of this work was to use a computer simulation model to predict the dissolution behavior of zinc-complexed insulin suspensions and determine the influence of the above rate-limiting steps on the overall process of dissolution. A quasi-steady-state model was chosen which included the effects of a shrinking particle radius, the drug's solubility, and a convective mass transfer term. Based on this model, the computer simulation program evaluated dissolution behaviors of various model drugs, including zinc insulin suspensions. The experimental data obtained from actual dissolution experiments were superimposed on computer-generated profiles that incorporated quantitative values to key terms, namely the α (diffusion resistance) and β (surface reaction resistance) values. Results demonstrated that the computer simulations could be used to predict the dissolution behavior of zinc-complexed protein suspensions by manipulating the α and β values. Overall, the computer simulations indicated the involvement of both the surface reaction and the diffusion rate-limiting steps in zinc insulin dissolution, which was consistent with the results obtained from actual experimental studies.

A study of factors controlling dissolution kinetics of zinc complexed protein suspensions in various ionic species

The presence of bound and unbound zinc in the crystal matrix of protein suspensions helps physically stabilize the crystal and limits the dissolution of the drug. In case of zinc insulin suspensions, dissolution can be promoted by complexation of zinc with an ionic species for which the zinc has a greater affinity, these complexing ions having either formulation and/or physiological relevance. The purpose of this work was to use ligand-complexed formulations of insulin suspensions to gain an understanding of these products' dissolution performance and to establish a fundamental understanding of the rate-limiting steps in zinc insulin dissolution. Our group has suggested that the critical factors to zinc insulin dissolution are: (1) chemical complexation (zinc with ionic species); and (2) drug transport (insulin diffusion and solubility). Dissolution studies conducted using different ionic species (acetate, phosphate, citrate and EDTA) in a spin-filter device demonstrated a rank order correlation for different sources of zinc insulin; it was observed that human zinc insulin dissolved faster than bovine insulin, these differences attributed to their binding properties and the respective affinities to the various ionic species used. Also, as the amount of crystallinity increased in a formulation, a rank order increase in dissolution times was observed. The project also identified a sensitive and reproducible dissolution testing methodology. Overall, this study demonstrated that: (1) the complexation rate-limiting step was more significant in the dissolution of zinc insulin than the diffusion rate-limiting step; and (2) that dissolution kinetics depended primarily on the source and solid state differences and the binding affinities of the zinc insulin.

Management of Diabetes Mellitus

Abstract Diabetes mellitus is a common metabolic disorder characterized by high blood glucose levels resulting from an insulin deficiency (type 1 diabetes mellitus) or a combination of insulin deficiency and insulin resistance (type 2 diabetes mellitus). The chronic hyperglycemia associated with diabetes mellitus can cause damage to the eyes, kidneys, heart and peripheral circulation, resulting in substantial morbidity, premature mortality and considerable healthcare costs. In both type 1 and type 2 diabetes mellitus, quality of glycemic control has been shown to be a major factor in the prevention of microvascular complications, and tight blood glucose control is the primary goal for all patients with diabetes mellitus. In patients with type 1 diabetes mellitus, multiple daily injections of exogenous insulin and frequent monitoring of blood glucose levels are required to achieve tight glycemic control. Patients with type 2 diabetes mellitus may achieve initial glycemic control with diet and lifestyle interventions alone; however, a large percentage of patients will require pharmacological therapy, first with an oral antidiabetic agent and, ultimately, with insulin. Premixed insulin formulations, consisting of fixed ratios of short- and intermediate-acting insulins, are a convenient and effective treatment option which account for ≈40% of insulin use worldwide. Until recently, the only premixed formulations available contained varying proportions of human regular insulin and human isophane insulin suspension (NPH). However, new premixed formulations containing insulin lispro (a rapid-acting insulin analog) and insulin lispro neutral protamine suspension (NPL) [an intermediate-acting insulin analog] are now available. Insulin lispro mix75/25 (Humalog® Mix75/25™) is a premixed formulation containing 25% insulin lispro and 75% NPL which has been investigated for use in patients with type 1 and with type 2 diabetes mellitus. Administered twice daily immediately before breakfast and dinner, insulin lispro mix75/25 provides better control of postprandial blood glucose, provides similar overall glycemic control, appears to be preferred by patients and may reduce nocturnal hypoglycemia compared with a similar premixed formulation containing 30% human regular insulin and 70% NPH (human insulin 70/30; Humulin® 70/30, Novolin® 70/30). Insulin lispro mix75/25 has a rapid onset of action, allowing for administration immediately before a meal, whereas patients need to administer human insulin 70/30 30 to 60 minutes prior to meals. Insulin lispro mix75/25 also improves glycemic control in patients whose type 2 diabetes mellitus is not well controlled by oral agents.

Five fold increase of insulin concentration delays the absorption of subcutaneously injected human insulin suspensions in pigs

Human NPH U100 (100 IU/ml), given once daily, is often absorbed too fast to cover the basal insulin demand throughout 24 h. The aim of the present study was to examine whether the absorption of human insulin suspensions would be delayed by increasing the insulin concentration from U100 to U500. In each experiment 10 IU of corresponding human Ul00 and U500 preparations, labelled with 125I-insulin, were injected subcutaneously and contralaterally in the neck of a pig followed by monitoring residual radioactivity over the injection sites. The time until 75, 50 and 25% residual radioactivity ( T 75%, T 50% and T 25%) using NPH U500 was compared with NPH U100 in 14 experiments: T 75%: 5.0±0.5 (mean±SEM) vs 3.8±0.3 h ( P=0.007, paired t-test), T 50%: 12.2±0.9 vs 9.0±0.6 h ( P=0.003) and T 25%. 24.2±1.2 vs 17.9±1.2 h ( P=0.001). The corresponding values for semilente U500 compared with semilente U100 in eight experiments were: T 75%: 2.8±0.4 vs 1.6±0.2 h ( P=0.02), T 50%: 5.6±0.6 vs 3.4±0.3 h ( P=0.01) and T 25%: 10.9±1.1 vs 7.2±0.7 h ( P=0.009). Thus, the absorption of a given dose of human NPH or human semilente insulin in pigs is substantially delayed by changing the insulin concentration from Ul00 to U500. Human NPH U500 appears to be more appropriate than human NPH U100 for injection once daily in basal insulin therapy.

Protamine sulfate: Fatal anaphylaxis in a patient receiving insulin suspension isophane: case report

Protamine sulfate: Fatal anaphylaxis in a patient receiving insulin suspension isophane: case report

Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens

Neutral protamine Hagedorn (NPH) insulin is one of the most commonly used insulins in insulin pens. NPH in pen cartridges is in a two-phase solution with either a solvent or a short-acting insulin, and needs adequate mixing for complete resuspension. We assessed whether NPH insulin is accurately resuspended by patients and the association of suspension errors with diabetes control. 109 patients (39 with type 1 diabetes) who had received conventional diabetic education had the NPH content of their cartridges measured by an optical system; a control cartridge was designated as 100%. A questionnaire was used to assess clinical details and insulin suspension habits. After the information about residual insulin error was known, all 109 patients were instructed to resuspend their insulin by rolling and tipping the pen 20 times. 52 patients were randomly selected to have cartridges re-analysed 3 months or 6 months later and to complete another questionnaire. Only 10 (9%) of 109 patients tipped and rolled their pen more than ten times. NPH insulin content ranged from 5% to 214% and varied by more than 20% in 71 (65%) of 109 cartridges. There was no relation between inadequate suspension and the frequency of hypoglycaemic episodes (r=0.2, p=0.08). For all patients, there was a correlation between the absolute error of NPH suspension and cycles of rolling and tipping the pen (r=-0.23, p<0.05). After education on resuspending the pen's contents, data were available from 44 of 52 patients; suspension errors decreased in 35 (80%), were unchanged in three (7%), and increased in six (13%). The 35 patients with improved NPH insulin suspension had fewer mean hypoglycaemic episodes per month compared with the previous period (0.4 [SD 0.1] vs 1.0 [0.3], p<0.05). Mean HbA1c values in patients with improved suspension quality did not differ from baseline (8.4% [0.3] vs 8.9% [0.4], p=0.07). Mixing of NPH insulin by a mechanical device showed that at least 20 cycles were necessary before complete resuspension was obtained. Inadequate NPH insulin suspension is common. We recommended that patients tip pens that contain NPH insulin at least 20 times, since inadequate mixing may impair diabetes control.

Insulin suspension isophane often inadequately resuspended

Insulin suspension isophane often inadequately resuspended

Insulin induces tyrosine dephosphorylation of a 92 kDa protein in suspended monocytes

Monocytes bear insulin receptors similar to those expressed in other tissues, but insulin action in these cells remains unclear. There is evidence that adhesion, by generating a complex array of irreversible transformations, may modify the response of cells to other stimuli, such as hormones. The present study aimed to characterise the pattern of insulin induced tyrosine phosphorylation of monocytes in suspension. Monocytes in suspension were obtained by sequential gradient centrifugation and the tyrosine phosphoproteins were analyzed by immunoblot with antiphosphotyrosine antibodies. The major result of the study is that in suspended monocytes insulin induced a dose and time dependent dephosphorylation of a protein with a molecular mass of about 92 kDa without stimulating the tyrosine phosphorylation of the Insulin Receptor Substrat-1 (IRS-1). In conclusion, we showed that in monocytes in suspension insulin seems to activate a tyrosine phosphatase, which, in turn, dephosphorylates a protein with an apparent molecular weight of 92 kDa.

Preparation and Characterization of a Cocrystalline Suspension of [LysB28,ProB29]-Human Insulin Analogue

□ Soluble preparations of [LysB28,ProB29]-human insulin analogue (LysPro) exhibit more rapid absorption than human insulin upon subcutaneous injection. Biphasic mixtures of LysPro and intermediate-acting insulin suspensions could provide advantages over current preparations for the treatment of diabetes. To prepare biphasic mixtures of LysPro, a suspension formulation of the analogue is required. We have devised a method for crystallizing LysPro with the basic peptide protamine yielding neutral protamine LysPro (NPL) suspension. The crystallization conditions are strongly dependent on the precipitation procedure and temperature. Using various techniques, the crystalline and suspension characteristics of NPL are found to be similar to human insulin (neutral protamine Hagedorn, NPH) (8:1 molar ratio insulin:protamine, rod-shaped crystals, particle size of 4.0–6.0μm, and Point of Zero Charge at 6.0–7.0). Using a dog model with NPL or NPH injected subcutaneously and glucose levels clamped at basal, NPL was found to have kinetic and dynamic responses analogous to human insulin NPH [Cmax (maximal insulin or LysPro concentration, ng/mL) of 2.61±0.22, NPL; 2.58±0.36, NPH, attained at Tmax (min) of 93±22, NPL; 145±33 NPH, and Rmax (maximal rate of glucose infusion, mg/kgmin) of 10.8±1.2, NPL; 13.2±1.9, NPH, attained at TRmax (min) of 277±58, NPL; 265±38, NPH]. There are no statistically significant differences between the insulin curves or the glucose responses. These results provide insight into the mechanism of action of NPH suspensions and the relationship to duration of action. Furthermore, the formulation of a suspension of LysPro having an intermediate time-action makes possible the preparation of stable biphasic mixtures containing LysPro and NPL.

Effect of Chloride Ion on the Sedimentation Volume and Zeta Potential of Zinc Insulin Suspensions in Neutral pH Range

When zinc insulin suspensions of different pH values were prepared in the presence of sodium chloride, an unusually high sedimentation volume was found at about pH 6.9. An experimental investigation was conducted in an effort to understand this phenomenon. The experiments involved measurements of electrophoretic mobilities to calculate zeta potentials and sedimentation volumes of zinc insulin suspensions prepared at different NaCI concentrations (0, 17, and 120 mM) and at various pH values from 5 to 8. The general trend observed was that the magnitude of the zeta potential increased with pH when it was higher than the isoelectric point of 5.3. When the sodium chloride concentration was 120 mM, a very rapid change in zeta potential was observed in the pH range of 6.6 to 7.2, with a maximum magnitude of zeta potential at about pH 6.9, the same pH that was observed to yield the largest sedimentation volume. Our experimental results indicate that the greatest adsorption of chloride ion on the zinc insulin suspension particles occurred in the same pH range, which appeared to be responsible for the rapid change of zeta potential in that pH range. The experimental data were interpreted by DLVO (Derjaguin, Landau, Vervey, and Overbeek) theory, which involves a comparison of the forces of electrostatic repulsion and of the van der Waals attraction.

Slow-release effect of pH-adjusted bupivacaine: In vitro demonstration

Commercial solutions from the same lot of 0.25% bupivacaine (pH = 5.69 ± 0.02) were studied before, and at 3 min and 12 h after alkalinization with 0.4 mEq. sodium bicarbonate/20 ml (final pH = 7.39 ± 0.01). An in vitro dissolution method was modified from a previously described technique used to measure the slow-release effect of insulin suspensions. Alkalinization resulted in a significant increase in the number of crystals of bupivacaine base and in the prolongation of bupivacaine release from the crystals. The results are in agreement with several clinical reports in which prolonged duration of the sensory block was observed. The extent of adsorption on the walls of glass bottles and of plastic syringes increased with the duration of contact after alkalinization. The adsorbed fraction of bupivacaine therefore could not participate in producing the expected clinical effect and might explain several unsuccessful attempts at pH adjustment.

Insulin-induced anestrus in Syrian hamsters

In Syrian hamsters, reproduction is sensitive to the availability of metabolic fuels. Estrous cycles can be interrupted by brief periods of food deprivation, by pharmacological inhibition of glycolysis and fatty acid oxidation, or by increasing energy demands for thermoregulation. We predicted that manipulations that divert an excessive portion of the metabolic fuel supply into storage also should inhibit reproduction. Redirection of metabolic fuels from oxidation to storage was accomplished by treatment with protamine zinc insulin suspension (PZI). Syrian hamsters treated with PZI and fed ad libitum increased their food intake by approximately equal to 40% and body fat stores, but there was no effect on estrous cycles. When PZI-treated hamsters were limited to approximately equal to 110% of their preinjection food intake, they still fattened, and there was a significant inhibition of estrous cyclicity. Thus, in the absence of overeating, PZI-enhanced energy storage may lead to a shortage of oxidizable metabolic fuels with the result that reproduction is inhibited in favor of processes essential for survival (e.g., cellular maintenance, thermoregulation). It is unlikely that insulin-induced anestrus is due to actions of PZI unrelated to metabolic fuel partitioning, because the hormone had no effects on estrous cyclicity in ad libitum-fed hamsters. These findings are inconsistent with the hypothesis that nutritional infertility is due to the failure to maintain a minimum body fat content and raise the possibility that the infertility associated with some types of obesity could be due in part to a disorder of macronutrient partitioning.