Low within- and between-day variability in exposure to new insulin glargine 300 U/ml.

AIMS: To characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM). METHODS: A total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4 U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability. RESULTS: The cumulative exposure and effect of Gla-300 developed linearly over 24 h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was <2, and both the swing and peak-to-trough fluctuation were <1. Day-to-day reproducibility of exposure was high: the between-day within-subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24 h after dosing) and maximum insulin concentration were 17.4% [95% confidence interval (CI) 15-21] and 33.4% (95% CI 28-41), respectively. Reproducibility of the metabolic effect was lower than that of exposure. CONCLUSIONS: Gla-300 provides predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.

Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes.

AIMS: Two single-dose studies were conducted in Japan and Europe to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of new insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) in people with type 1 diabetes mellitus. METHODS: In two double-blind, randomized, crossover studies, 18 Japanese participants (aged 20-65 years) and 24 European participants (aged 18-65 years) with glycated haemoglobin levels ≤9.0% (≤75 mmol/mol) received single subcutaneous doses of Gla-300, 0.4, 0.6 and 0.9 U/kg (0.9 U/kg in the European study only), and Gla-100, 0.4 U/kg. A 36-h euglycaemic clamp procedure was performed after each dosing. RESULTS: The serum insulin glargine concentration (INS) and glucose infusion rate (GIR) developed more gradually into more constant and prolonged profiles with Gla-300 than with Gla-100. In support of this, the times to 50% of glargine exposure and insulin activity were longer for all Gla-300 doses than for Gla-100 during the 36-h clamp period, indicating a more evenly distributed exposure and metabolic effect beyond 24 h. Exposure to insulin glargine and glucose utilization were lower with the 0.4 and 0.6 U/ml Gla-300 doses in both studies compared with the 0.4 U/ml Gla-100 dose. Glucose-lowering activity was detected for up to 36 h with all doses of Gla-300. CONCLUSIONS: Single-dose injections of Gla-300 present more constant and prolonged PK and PD profiles compared with Gla-100, maintaining blood glucose control for up to 36 h in euglycaemic clamp settings in Japanese and European participants with type 1 diabetes.

Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml.

Insulin glargine is processed in vivo into soluble 21(A) -Gly-human insulin (M1), the principal moiety responsible for metabolic effects, and subsequently into M2. This sub-study compared metabolism and metabolite pharmacokinetic (PK) profiles of investigational new insulin glargine U300 (Gla-300) with insulin glargine 100 U/ml (Gla-100, Lantus®, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany) in people with type 1 diabetes. Participants received 0.4 (n = 18) or 0.6 U/kg Gla-300 (n = 12), and 0.4 U/kg Gla-100 (n = 30) once daily in randomized order for 8 days prior to a 36-h euglycaemic clamp. Metabolites were quantified using immunoaffinity enrichment and liquid chromatography tandem mass spectrometry (LC-MS/MS). Glargine metabolism was the same regardless of Gla-100 or Gla-300 administration; M1 was confirmed as the principal active moiety circulating in blood. Steady state concentrations of M1 were achieved after 2 days for Gla-100, and 4 days for Gla-300. Steady state M1 values defined prolonged and even flatter PK profiles after Gla-300 administration compared with M1 profiles after Gla-100.

Lixisenatide resensitizes the insulin-secretory response to intravenous glucose challenge in people with type 2 diabetes--a study in both people with type 2 diabetes and healthy subjects.

AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists improve blood glucose control by enhancing glucose-sensitive insulin release, delaying gastric emptying and reducing postprandial glucagon secretion. The studies reported here investigated the insulin response to an intravenous (iv) glucose challenge after injection of lixisenatide (LIXI) 20 µg or placebo. METHODS: Two single-centre, double-blind, randomized, placebo-controlled, single-dose, crossover studies were performed in healthy subjects (HS) and people with type 2 diabetes mellitus (T2DM). Participants received subcutaneous LIXI or placebo 2 h before an iv glucose challenge. Study endpoints included first- and second-phase insulin response, insulin concentration (INS), glucagon response and glucose disposal rate (K(glucose)). LIXI exposure was measured over 12 h. RESULTS: LIXI 20 µg reached maximum concentration after 2 h and resensitized first-phase insulin secretion by 2.8-fold in T2DM to rates comparable with those in HS on placebo, and raised second-phase insulin secretion by 1.6-fold in T2DM. INS rose correspondingly and glucose disposal was accelerated by 1.8-fold in T2DM. First-phase insulin secretion and glucose disposal were also augmented by LIXI in HS, whereas second-phase insulin secretion reduced blood glucose concentrations to below fasting levels and then ceased, accompanied by a rapid, short-lasting rise in glucagon. Otherwise, suppression of glucagon release subsequent to augmentation of insulin release was unaffected in T2DM and in HS. CONCLUSIONS: LIXI resensitized the insulin response to an iv glucose challenge in people with T2DM, thereby accelerating glucose disposal to nearly physiological intensity, and did not impair counter-regulation to low glucose levels by glucagon.

Planetary science. Nitrogen on the moon.

The nitrogen isotopic compositions seen in lunar soils have long been a mystery to planetary scientists. As Becker discusses in his Perspective, new techniques, such as the depth profiling of mineral grains reported by Hashizume et al., are now shedding some light on the matter, allowing some theories to be excluded. Nevertheless, the relative role of the solar wind and other processes remains hotly debated.

Fluctuation and reproducibility of exposure and effect of insulin glargine in healthy subjects.

AIM: Low diurnal fluctuation and high day-to-day reproducibility in exposure and effect characterize beneficial basal insulin products. Two insulin glargine (LANTUS) formulations [without (R) or with polysorbate-20 (T)], added to minimize unfolding of proteins and subsequent formation of fibril structures, were assessed for equivalence in exposure and effect, and aspects of fluctuation and reproducibility in time-concentration and time-action profiles. METHODS: A dose of 0.4 U/kg was subcutaneously administered to 24 healthy subjects in a two-sequence (R-T-R-T or T-R-T-R), randomized, four-way crossover trial utilizing 30-h Biostator-based euglycaemic glucose clamps. RESULTS: Identical serum insulin glargine concentration and time-action profiles established average, individual and population equivalence in insulin exposure and effect. Point estimates for 24-h area under the curve for insulin (INS-AUC(0-24) (h)) and glucose infusion rates (GIR-AUC(0-24) (h)) were 97% [90% confidence interval (CI): 91-103%] and 100% (88-114%), respectively. Within-subject variability (coefficient of variation) for INS-AUC(0-24) (h) and GIR-AUC(0-24) (h) were 19% (95% CI: 14-25%) and 34% (24-43%), respectively. The diurnal relative fluctuation of the serum insulin glargine concentration was 20% (95% CI: 19-21%). CONCLUSION: Insulin glargine in either formulation presents with a high day-to-day reproducibility of a uniform release after injection enabling an effective basal insulin supplementation.

A pilot study to examine the feasibility of insulin glargine in subjects with impaired fasting glucose, impaired glucose tolerance or new-onset type 2 diabetes.

OBJECTIVE: People with early type 2 diabetes and pre-diabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) are at risk of hyperglycaemia-related complications, including cardiovascular disease. Insulin, traditionally reserved as late treatment in type 2 diabetes, may also be a useful therapy in this population. We examined the short-term efficacy and tolerability of insulin glargine (glargine) in individuals with early or pre-type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicentre, double-blind, placebo-controlled, randomized, parallel group, 12-day study, subjects with IGT/IFG (n=9), newly diagnosed type 2 diabetes (n=9) or normal glucose tolerance (n=3) (confined to a clinical research unit taking a prescribed diet) were randomized to once-daily glargine (n=16) or placebo (saline; n=5) at bedtime. Dose was titrated to achieve target fasting blood glucose (FBG) 80-95 mg/dL. RESULTS: Over the treatment period, mean FBG decreased in glargine-treated subjects (from 100.0+/-18.8 to 85.6+/-18.4 mg/dL), but was unchanged in placebo-treated subjects (from 112.5+/-10.6 to 111.3+/-17.5 mg/dL). Mean eight-point blood glucose value decreased by 9.7 mg/dL in the glargine group, but increased by 8.1 mg/dL in the placebo group. Mean post-exercise blood glucose was similar before and after glargine treatment, but increased after placebo treatment. Five subjects receiving glargine experienced 16 mild symptomatic hypoglycaemia episodes; however, no hypoglycaemia occurred during exercise. Mean body weight decreased in both the glargine (-0.44 kg) and placebo (-0.25 kg) groups, in line with dietary restrictions. CONCLUSIONS: The results of this pilot study suggest that glargine can be used by people with IFG, IGT or new-onset type 2 diabetes for management of hyperglycaemia with low risk of hypoglycaemia. However titration of insulin in people on dietary restrictions should be more cautious as they may be more prone to hypoglycaemia. Further studies are warranted to determine the clinical benefits of this approach.

Insulin glulisine, a new rapid-acting insulin analogue, displays a rapid time-action profile in obese non-diabetic subjects.

AIMS/HYPOTHESIS: This study compared the pharmacokinetics and pharmacodynamics of insulin glulisine, insulin lispro, and regular human insulin in obese subjects. METHODS: In this single-dose, randomized, double-blind, crossover euglycaemic clamp study, 18 non-diabetic subjects (mean body mass index [BMI] 34.7 kg . m (-2)) were randomized to receive subcutaneous injections of each insulin (0.3 U . kg (-1)) in pre-determined sequences. RESULTS: Insulin glulisine and insulin lispro had more rapid-acting profiles than regular human insulin. Fractional glucose infusion rate (GIR)-area under curves (AUC) of the GIR curve and maximum GIR were greater for insulin glulisine and insulin lispro versus regular human insulin. Total glucose disposal was slightly greater with insulin glulisine than with regular human insulin, and was comparable to insulin lispro, although it decreased with increasing insulin resistance (HOMA index) with all insulins. Time to 20 % (early glucose disposal) and 80 % (bulk of activity) of total GIR-AUC were shorter for insulin glulisine and insulin lispro versus regular human insulin. This was corroborated by more rapid and shorter residing pharmacokinetic profiles of insulin glulisine and insulin lispro versus regular human insulin, evidenced by shorter times to 20 % of total INS-AUC, INS-C (max) (INS-t (max)), and mean residence time. Moreover, time to 20 % of total GIR-AUC demonstrated a less rapid-acting profile for insulin lispro versus insulin glulisine, which was consistent with the slightly less rapid pharmacokinetic profile of insulin lispro. There was no significant correlation between BMI or subcutaneous fat thickness and pharmacokinetic or pharmacodynamic profiles for insulin glulisine, unlike insulin lispro and regular human insulin. CONCLUSIONS/INTERPRETATION: Insulin glulisine and insulin lispro demonstrated substantially more rapid time-action profiles than regular human insulin in obese non-diabetic subjects, which prevailed with insulin glulisine irrespective of BMI and subcutaneous fat thickness.

A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp technique.

Insulin glulisine is a new rapid-acting insulin analog. The aim of this study was to assess the glucodynamic efficacy of insulin glulisine compared with regular human insulin (RHI) using a manual euglycemic clamp technique. Steady-state pharmacokinetics of insulin glulisine, and its cardiac safety (ECG) and tolerability after intravenous administration, were also determined. This was a single center, randomized, open-label, two-way crossover study in healthy male subjects (n = 16). At the treatment visits subjects received an intravenous infusion of the study drug at a rate of 0.8 mU kg (-1) . min (-1) for 2 hours. Individual baseline glucose concentrations were targeted for euglycaemia and maintained with a manual adjusted 20 % glucose solution over the clamp period of a maximum 6 hours. A glulisine-specific antibody was used to quantify glulisine concentrations by radioimmunoassay, while a non-specific insulin antibody and C-peptide based correction for endogenous insulin was used to estimate exogenous human insulin (RHI). At steady state (90 - 120 min), insulin glulisine and RHI had equivalent glucose utilization (GIR-AUC (SS), 209 [corrected] mg . kg (-1) for glulisine, 214 [corrected] mg . kg (-1) for RHI) and infusion rates (GIR (SS), 7.0 and 7.2 [corrected] mg . kg (-1) . [corrected] min (-1) . kg (-1)). Both insulins also presented equal total glucose disposal (GIR-AUC (0 - clamp end), 995 and 1050 [corrected] mg . kg (-1)) and onset of activity within 20 min. Insulin glulisine and RHI showed parallel time concentration profiles with similar distribution and elimination, but the different antibodies employed for radioimmunoassay impeded a quantitative comparison. There were no noteworthy individual or within-group changes in cardiac repolarisation parameters measured by 12-lead ECG during insulin glulisine infusion. In conclusion, insulin glulisine and RHI show similar distribution and elimination profiles and equivalent glucodynamic efficacy on a molar, unit-per-unit basis.

Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin.

We studied whether inhibition of angiotensin converting enzyme stimulates the formation of nitric oxide and prostacyclin in cultured human and bovine endothelial cells by an enhanced accumulation of endothelium-derived bradykinin. Nitric oxide formation was assessed in terms of intracellular cyclic GMP accumulation, prostacyclin release by a specific radioimmunoassay. Inhibition of angiotensin converting enzyme by ramiprilat dose- and time-dependently increased the formation of nitric oxide and prostacyclin. These increases, peaking within 10 minutes, were maintained for at least 60 minutes. The ramiprilat-induced cyclic GMP increase was completely abolished by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine. The B2-kinin receptor antagonist, Hoe 140 (0.1 microM), markedly attenuated the cyclic GMP accumulation and abolished the increase in prostacyclin release. The supernatant of endothelial cells, incubated with ramiprilat (0.3 microM) for 15 minutes, elicited a significant nitric oxide release (as assessed by a guanylyl cyclase assay) in untreated endothelial cells used as detector tissue. Preincubation of the detector cells with Hoe 140 completely abolished this nitric oxide release. These data indicate that cultured endothelial cells from different species are capable of producing and releasing bradykinin into the extracellular space in amounts that lead to a sustained stimulation of nitric oxide and prostacyclin formation, provided that bradykinin degradation is prevented by angiotensin converting enzyme inhibition. Thus, the protective effect of angiotensin converting enzyme inhibitors observed on endothelial vasomotor function in hypertension may be explained by the local accumulation of endothelium-derived bradykinin that acts in an autocrine and paracrine manner as potent stimulus for endothelial autacoid formation.

Late treatment with ramipril increases survival in old spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) begin to die from cardiovascular complications at approximately 15 months of age. We tested whether chronic ACE-inhibitor treatment would extend the lifespan of such old animals. We also studied cardiac hypertrophy and function, endothelial function and expression, and activity of NO synthase (eNOS). One hundred 15-month-old SHR were randomized into 3 groups, control (n=10), placebo-treated (n=45), and ramipril-treated with an antihypertensive dose of 1 mg. kg(-1). d(-1) in drinking water (n=45). Ex vivo experiments were performed after 15 months (control) and 21 months, when approximately 80% of the placebo group had died. Late treatment with ramipril significantly extended lifespan of the animals from 21 to 30 months. Fully established cardiac hypertrophy, observed in placebo-treated animals and in controls, was significantly reversed by ramipril treatment. In isolated working hearts, a significantly improved function associated with increased cardiac eNOS expression was seen versus placebo and control hearts. Endothelial dysfunction in isolated aortic rings from control and placebo-treated SHR was significantly improved by ACE inhibition and associated with enhanced NO release. Late treatment of SHR with the ACE inhibitor ramipril extended lifespan from 21 to 30 months, which is comparable to the lifespan of untreated normotensive Wistar-Kyoto rats. This lifespan extension, probably due to blood pressure reduction, correlated with increased eNOS expression and activity followed by a regression of left ventricular hypertrophy and cardiac and vascular dysfunction.

A microsphere study on the effects of somatostatin and secretin on regional blood flow in anesthetized dogs.

The endogenous peptides somatostatin and secretin are effective in the therapy of upper gastrointestinal tract bleeding and acute pancreatitis. The clinical effects may be partly brought about by changes in the regional blood flow. To evaluate the effects of somatostatin (50 and 100 micrograms/min over 6-8 min) and secretin (0.1 and 0.5 U X kg-1 X min-1 over 3-5 min) on tissue blood flow, particularly of the gastrointestinal tract, the tracer microsphere reference sample method was used in anesthetized dogs. Infusion of somatostatin significantly diminished gastric and pancreatic blood flow whereas no changes of duodenal and ileal blood flow could be obtained. Blood flow through spleen, kidneys and adrenal glands was increased but no changes were observed in the blood flow of other tissues. Cardiac hemodynamics remained unchanged. Secretin increased the blood flow of the duodenum, the kidneys and the adrenal glands and diminished gastric blood flow without changing pancreatic, ileal, hepatic, pulmonary and muscle blood flow. Cerebral, pituitary and myocardial blood flow was increased by a higher dose of secretin. It also evoked a slight but significant positive ino- and chronotropic effect. Since secretin and somatostatin differ in their respective effects on gastrointestinal blood flow it is suggested that the previously reported beneficial effects of both peptides on upper gastrointestinal bleeding cannot solely be attributed to changes in regional blood flow.

Equipotency of insulin glargine and regular human insulin on glucose disposal in healthy subjects following intravenous infusion.

The absolute glucose disposal of insulin glargine (Lantus) was compared to that of regular human insulin in healthy subjects (n=20) using the euglycaemic clamp technique in a single-dose, double-blind, randomized, two-way crossover design. Subjects received 30-minute intravenous infusions of insulin glargine (0.1 IU/kg) or human insulin (0.1 IU/kg) and a 20% glucose solution infused at a variable rate to maintain euglycaemia at the subject's baseline glucose level. At equal baseline blood glucose levels (4.42 mmol/l [range, 4.00-5.16 mmol/l] and 4.42 mmol/l [range, 4.01-4.94 mmol/l], respectively), the area under the glucose infusion rate (GIR) time curves from 0-6 hours (AUC(0-6h)) was within the bioequivalence range (insulin glargine, 663.92 mg/kg; human insulin, 734.85 mg/kg). Both the time to maximum GIR and the suppression of serum C-peptide were similar with insulin glargine and human insulin. The resulting maximum serum insulin concentrations (Cmax) were 151.16 microIU/ml and 202.23 microIU/ml, and the time to Cmax (Tmax) was 30 minutes (the duration of the infusion). The observed differences in the Cmax (the mean value for insulin glargine was about 25% lower than that of human insulin) could be explained by lower cross-reactivity of insulin glargine in the human insulin radioimmunoassay. The employed intravenous route, though definitely not the intended clinical use of insulin glargine, provided the clinical evidence in healthy subjects that on a molar basis insulin glargine is equipotent to regular human insulin regarding glucose disposal.

Preliminary report: examination of young children with Lea symbols.

BACKGROUND: Lea symbols are highly sensitive for detection of amblyopia in cooperative patients. They are favorable for visual acuity assessment in childhood. Therefore, we assessed age-related normal values and interocular differences of Lea symbol visual acuity. METHODS/PATIENTS: We reexamined 50 out of 193 children aged 21 months to 7 years who came for a routine pediatric examination between January and November 1999. Lea symbol acuity (Lea Symbols Single Symbol Book (LS) and Lea 15-Line Folding Distance Chart (CLS)) and Landolt-C acuity (single (LC) and crowded with 2.6' inter-optotype distance (LC(2.6))) were measured. A three out of four criterion was used. Strabismus and any organic eye disease were excluded by orthoptic and ophthalmologic examination, consisting of biomicroscopy, ophthalmoscopy, retinoscopy or refractometry, cover test or Hirschberg test and Lang Stereotest. RESULTS: Only 26% of the parents (50 out of 193) accepted an examination in our hospital. In 35 (32) of the 50 children, visual acuity could be measured in both eyes separately with single (crowded) Lea symbols, while 26 (25) children could be examined in both eyes monocularly with the Landolt-C with single (crowded) optotypes. Except for one 3-year-old boy, all of the children older than 30 months could be tested with single Lea symbols. Lea acuity surpassed Landolt acuity. The difference was about 1.5 lines (1.5 dB) for both the single and the crowded optotypes. In 63% (69%) of the children who could be tested monocularly, LS acuity (CLS acuity) was higher than 0.8 (0.63). 89% (83%) of the children had an interocular difference of maximum 1 line for single (crowded) Lea symbols. CONCLUSIONS: The youngest child whose visual acuity could be assessed with Lea symbols was 23 months old. Almost every child older than 30 months could be tested with Lea symbols. Lea acuity higher than 1 and an interocular difference less than 2 lines is not suspect for amblyopia. Children with a difference of more than one line should be reexamined.

Insulin glulisine: a faster onset of action compared with insulin lispro.

AIM: This randomized, single-centre, double-blind, crossover study compared the pharmacodynamic and pharmacokinetic properties of two different doses of insulin glulisine (glulisine) and insulin lispro (lispro) in lean to obese subjects. METHODS: Eighty subjects without diabetes, stratified into four body mass index (BMI) classes (<25, >or=25 to <30, >or=30 to <35 and >or=35 kg/m(2)), were randomized to receive single injections of glulisine and lispro (0.2 and 0.4 U/kg) on four study days under glucose clamp conditions. Glucose infusion rates (GIR) and insulin (INS) concentrations were assessed for 10 h postdose. RESULTS: Glulisine showed a greater early metabolic action than lispro [GIR-area under the curve (GIR-AUC) between 0 and 1 h (0.2 U/kg: 102.3 +/- 75.1 vs. 83.1 +/- 72.8 mg/kg, p < 0.05; 0.4 U/kg: 158.0 +/- 100.0 vs. 112.3 +/- 70.8 mg/kg, p < 0.001)], with an earlier time to 10% of total GIR-AUC (0.2 U/kg: 1.4 +/- 0.4 vs. 1.5 +/- 0.4 h; 0.4 U/kg: 1.4 +/- 0.3 vs. 1.5 +/- 0.3 h, p < 0.05). The total metabolic effect was not different between the two insulins. In accordance with these findings, the time to 10% of total INS-AUC was faster with glulisine compared with lispro at either dose (0.2 U/kg: 0.7 +/- 0.2 vs. 0.8 +/- 0.2 h; 0.4 U/kg: 0.8 +/- 0.2 vs. 0.9 +/- 0.2 h, p < 0.001). The faster rise in insulin concentrations and the earlier onset of activity of glulisine vs. lispro was consistently observed in each individual BMI class. CONCLUSIONS: Glulisine shows a faster onset of action than lispro, independent of BMI and dose.

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique.

AIMS/HYPOTHESIS: This single-dose, double-blind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique. METHODS: In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments. RESULTS: In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC0-24 h) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported. CONCLUSIONS/INTERPRETATION: Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.

[ACE inhibition and atherosclerosis in the animal model]. / ACE-Hemmung und Atherosklerose im Tiermodell.

The goals of rational antihypertensive medication should embrace the alleviation of atherosclerosis, the clinical consequences of which pose a major health problem and hence socio-economic concern for industrialized countries. Angiotensin converting enzyme (ACE) inhibitors are endowed with pharmacodynamic features which may help to attain this aim. Various animal experiments with cholesterol-fed rabbits, pigs and monkeys, as well as with rabbits with inherent disorder of lipid metabolism (WHHL-rabbit), demonstrated endothelial protection against loss of function due to hyperlipidemia and attenuation of lipid deposition in conduit blood vessels with ACE-inhibition. The alleviation of progressive atherosclerosis, which is a common feature of restenosis development following angioplasty, was shown in hypercholesterolemic rabbits and normal rats, but did not occur in clinically more relevant porcine models nor in large clinical trials. Circumstantial evidence from miscellaneous experiments is in line with the view that it is enhancement of bradykinin activity which causes the endothelial protection against the consequences of hypercholesterolemia. Furthermore, loss of relaxation of coronary resistance vessels without overt atherosclerosis despite hypercholesterolemia can be restored by augmentation of the EDRF-pathway as has been demonstrated with ramiprilat in vitro. This is being substantiated in preliminary clinical reports with different ACE-inhibitors. The possible association between improvement in both insulin sensitivity and endothelial function requires further investigation. The critical analysis of present experimental findings on a beneficial influence on both the spontaneous and the progressive development of atherosclerosis indicates ACE-inhibition to be more likely to preserve or restore the function of an intact endothelium than to interfere with the complex reaction occurring after injury of an already affected blood vessel.

Physical performance during sustained converting enzyme inhibition with Hoe 498 in conscious dogs.

The effect of sustained converting enzyme (CE) inhibition on modest levels of exercise performance was investigated using German Shepherds. The dogs were trained to run on an inclined treadmill and to tolerate repeated jugular venous puncture. The effects of exercise were assessed by monitoring heart rate and respiratory rate and plasma catecholamine- and serum electrolyte concentrations on each of two control runs. Plasma CE- and renin activity were also determined. Inhibition of CE-activity was established thereafter by high dose treatment with 10 mg/kg Hoe 498 p.o. once daily for one week and the run repeated. These large doses of Hoe 498 were well tolerated. Neither running performance nor cardiorespiratory responses were altered by CE-inhibition. Plasma K+ and catecholamines were taken as measures of peripheral sympathetic activity, and CE-inhibition did not alter the increase in either of these in response to exercise. It is concluded that converting enzyme inhibition with Hoe 498 does not impair exercise performance despite any direct effects the loss of angiotensin II may have on reflex sympathetic functions.