Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites.

OBJECTIVE: To determine the subcutaneous absorption rates and the appearance in plasma of 3 formulations of the long-acting human insulin analog insulin glargine (HOE 901) differing only in zinc content (15, 30, and 80 microg/ml). RESEARCH DESIGN AND METHODS: We conducted 2 studies. Study 1 compared the subcutaneous abdominal injection of 0.15 U/kg of 125I-labeled insulin glargine[15], insulin glargine[80], NPH insulin, and placebo. In study 2, 0.2 U/kg of insulin glargine[30] was injected into the arm, leg, and abdominal regions. Both studies had a randomized crossover design; each enrolled 12 healthy men, aged 18-50 years. RESULTS: In study 1, the time in hours for 25% of the administered radioactivity to disappear after bolus subcutaneous injection (T75%) for NPH insulin indicated a significantly faster absorption rate compared with the 2 insulin glargine formulations (3.2 vs. 8.8 and 11.0 h, respectively P < 0.0001). Mean residual radioactivity with NPH insulin was also significantly lower at 24 h (21.9 vs. 43.8 and 52.2%, P < 0.0001). The calculated plasma exogenous insulin concentrations after NPH insulin were substantially higher than those with insulin glargine, reaching a peak within the first 6 h after administration before declining. Insulin glargine, however, did not exhibit a distinct peak. Weighted average plasma glucose concentration between 0 and 6 h was significantly lower after NPH compared with insulin glargine (P < 0.001). In study 2, there were no significant differences in the absorption characteristics of insulin glargine between the 3 injection sites (T75% = 11.9, 15.3, and 13.2 h for arm, leg, and abdomen, respectively) or in residual radioactivity at 24 h. CONCLUSIONS: Subcutaneous absorption of insulin glargine is delayed compared with NPH insulin. There is little or no difference in the absorption rate of insulin glargine between the main subcutaneous injection sites.

Probes for imidazoline binding sites: synthesis and evaluation of a selective, irreversible I2 ligand.

An irreversible ligand (7) has been prepared based on the selective I2 ligand 2-BFI. Compound 7 displayed high affinity and selectivity for I2-sites and has been shown to irreversibly bind to these sites in rat brain. Compound 7 should, therefore, prove an invaluable tool for the further elucidation of I2-site function.

Estimation of glomerular filtration rate in type II (non-insulin dependent) diabetes mellitus patients.

The aim of this research was to develop an estimation of glomerular filtration rates (GFRs) from a combination of simple parameters in a large group of type II diabetic patients. We selected 122 newly presenting, previously untreated, type II patients whose GFR was determined from the plasma clearance of 51Cr-ethylenediamine tetraacetic acid (51Cr-EDTA) and simultaneous measurements of demographic variables, including fasting plasma glucose concentration, HbA1c, blood pressure, lipids, age, weight, body-mass index, body surface area, urea, and plasma creatinine concentration. The actual GFR values were compared with estimated values obtained from multiple regression and the Cockroft-Gault equations. Out of all the demographic variables, only plasma creatinine concentration (r = -0.56, p < 0.001), age (r = -0.50, p < 0.001), urea (r = -0.28, p < 0.01), and systolic blood pressure (r = -0.21, p < 0.05) showed significant correlations with the actual GFR values, for which the mean and standard deviation were 117.5 +/- 22.0 ml min-1 x 1.73 m-2. The estimated values are highly correlated with the actual values (r = 0.70), having an identical mean value of 117 +/- 15.3 and an unbiased regression relation (y = 0.000 + 1.000x). As standard measurements of the GFR are very time consuming and expensive, the use of the simple equation GFR1 = 218.1 - 0.916 x Age - 0.635 x Creatinine is recommended. The classification of GFR values into three ranges has also revealed the nonlinear characteristics of GFR in relation to other demographic variables: age and creatinine are the dominant variables in the middle GFR range, while the body-mass index and urea are dominant in the high and low ranges, respectively.

Insulin secretion and sensitivity in newly diagnosed NIDDM Caucasians in the UK.

Beta-cell secretion and insulin sensitivity was studied in healthy subjects and newly diagnosed Caucasian (Welsh) NIDDM patients. A standardized meal tolerance test (MTT) and frequent sampled intravenous glucose tolerance tests (FSIVGTT) were employed and the patients stratified according to fasting plasma glucose (FPG). A deficient early (first hour) post-prandial (MTT) insulin secretion was demonstrated in all NIDDM patients, deteriorating with increasing fasting hyperglycaemia. For the patient group fasting and post-prandial hyperproinsulinaemia was evident with diminishing post-prandial excursions as fasting hyperglycaemia increased. The early phase (0-10 min) insulin secretion to intravenous glucose (300 mg kg-1) was severely impaired in NIDDM patients. A shortlived paradoxical fall in plasma insulin concentrations was observed in those with FPG > 9 mmol l-1. Insulin sensitivity utilizing the insulin modified FSIVGTT demonstrated that all NIDDM patients had marked insulin insensitivity. Characteristic of the newly diagnosed previously untreated Caucasian NIDDM is a dysfunctional beta cell, resulting in a deficit in insulin secretion with relative hyperproinsulinaemia. The quantitative and qualitative secretory status of the beta cell decreases with increasing fasting hyperglycaemia. Insulin sensitivity is markedly reduced when FPG exceeds 7.0 mmol l-1 with little or no further discernible fall with deteriorating glycaemic control.

Dominant risk factors for retinopathy at clinical diagnosis in patients with type II diabetes mellitus.

A study of 270 newly presenting, previously untreated, type II diabetic patents revealed that 38 patients (14%) had already developed diabetic retinopathy (DR). Among this group, 26 patients had lesions of background diabetic retinopathy and 12 patients already had maculopathy or preproliferative changes. The aim of this study was to determine the risk factors influencing susceptibility to retinopathy, and to provide an accurate predictive value for diabetic retinopathy from a detailed multiple regression analysis that involved 27 demographic variables and the metabolic and hormonal responses during a meal tolerance test (MTT) at presentation. Compared to the nonretinopaths, the retinopaths had higher fasting plasma glucose levels (FPG) (mean +/- SD) (13.9 +/- 3.1 versus 11.6 +/- 3.2 mmol/L, p < 0.001), lower body-mass index values (BMI) (26.1 +/- 3.8 versus 29.3 +/- 5.0 kg/m2, p < 0.001) and higher plasma urea concentrations (6.0 +/- 1.9 versus 5.3 +/- 1.2 mmol/L, p 0.05). In contrast, gender and levels of blood pressure and other lipid levels did not influence the prevalence of diabetic retinopathy. A multiple regression formula for the prediction of diabetic retinopathy was derived and then used to categorize patients into high-risk and low-risk groups. The retinopaths also had higher HbA1c (p < 0.001), higher plasma glucose are under curve (0-2 h, p < 0.001), lower plasma insulin area under curve (0-22 h, p < 0.001), lower C-peptide area under curve (0-2 h, p < 0.01). They were also leaner (p < 0.001) and older (p < 0.05). However, these variables did not feature significantly in the multiple regression formula. The retinopaths were found to have higher risk probability values (25.1 +/- 11.5 versus 13.1 +/- 10.4%, p < 0.001). In the high risk group, 81.6% of retinopaths were identified. In the low-risk group, 63.8% of nonretinopaths were found. The incidence of diabetic retinopathy in type II diabetic patients at clinical diagnosis was found to be highly related to the degree of hyperglycemia, body-mass index, and to a lesser extent, renal impairment.

Chemistry of pseudomonic acid. Part 16. Aryl and heteroaryl ketone derivatives of monic acid.

The synthesis, antibacterial activities, murine pharmacokinetic and infection model data for a range of aryl and heteroaryl ketone derivatives of monic acid (2a) are reported. The best results were found for the 3-furyl and 2-methoxy thiazol-5-yl analogues.

Preliminary synthetic studies of methyllycaconitine, a potent nicotinic acetylcholine receptor antagonist: rapid syntheses of AE-bicyclic analogues.

A series of bicyclic analogues incorporating the homocholine motif of methyllycaconitine has been prepared to test the hypothesis that this is the essential pharmacophore of this potent, selective nicotinic receptor antagonist. A double Mannich reaction has been employed to construct the 3-azabicyclo[3.3.1]-nonane ring system, containing an N-ethylpiperidine moiety. The neopentyl-like alcohol was then esterified, using isatoic anhydride under basic conditions, to afford the corresponding anthranilate.

An HPLC assay for the norditerpenoid alkaloid methyllycaconitine, a potent nicotinic acetylcholine receptor antagonist.

The extremely potent and selective nicotinic acetylcholine receptor antagonist methyllycaconitine, MLA, and related norditerpene alkaloids are finding increasing use as neurochemical probes and as targets for structure-activity relationship studies. In this work, an assay procedure for MLA which utilises ion suppression reverse-phase HPLC with UV absorbance detection at 270 nm is described. The method detected 280 ng MLA on column.

Comparison of estimates of insulin sensitivity from minimal model analysis of the insulin-modified frequently sampled intravenous glucose tolerance test and the isoglycemic hyperinsulinemic clamp in subjects with NIDDM.

Minimal model (MINMOD) analysis of the frequently sampled intravenous glucose tolerance test (FSIVGTT) is dependent on an adequate insulin response to the glucose load. As this is characteristically deficient in subjects with non-insulin-dependent diabetes mellitus (NIDDM), the technique has been modified by the use of an intravenous bolus of insulin. Previous validation of this modification in humans has relied on agreement between insulin sensitivity indexes (SI) estimated from tolbutamide- and insulin-modified tests and not on direct comparison with estimates derived from the isoglycemic glucose clamp. We have compared estimates of insulin sensitivity derived from minimal modeling of a 4-h insulin-modified FSIVGTT and the glucose clamp in subjects with NIDDM. Twelve subjects underwent an insulin-modified FSIVGTT and an isoglycemic hyperinsulinemic clamp in random order 2-4 weeks apart. Fasting plasma glucose (8.4 vs. 9.0 mmol/l) and immunoreactive insulin (IRI) concentrations (104.5 vs. 101.5 pmol/l) were not different between the 2 study days. SI(clamp) was derived from the steady-state glucose infusion rate during the 3rd h of the clamp, corrected for the ambient insulin and glucose concentrations. SI(ivgtt) was derived using MINMOD. SI(ivgtt) was 1.06 +/- 0.18 min-1.mU-1.ml x 10(4), and mean SI(clamp) was 4.97 +/- 0.69 l.min-1/pmol.l-1 x 10(4) (mean +/- SE). SI(ivgtt) was positively correlated with SI(clamp) (r = 0.73, P = 0.004) and negatively correlated with body mass index (r = -0.7, P = 0.005) and fasting IRI(ivgtt) (r = -0.64, P = 0.008). In summary, MINMOD analysis of the insulin-modified FSIVGTT provides a valid measure of insulin sensitivity in subjects with NIDDM.

Intranasal insulin: the effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects.

In both fasting normal and diabetic subjects, nasally administered insulin achieves significant falls in plasma glucose concentrations. Repeated administration before and during a meal has been necessary to lower postprandial glycaemic excursion in subjects with NIDDM. We have studied the use of Novolin Nasal which employs a non-irritant, lecithin-based enhancer as a vehicle for human insulin, on postprandial glucose profiles in NIDDM subjects to determine efficacy, optimal dose frequency, and tolerability. Seventeen NIDDM subjects (15 men, 2 women) participated in a randomized, partially blinded, placebo-controlled, crossover trial of three active treatment regimens (nasal insulin, 120 U at 0 min, 60 U at 0 and +20 min or 120 U at +20 min) in relation to a standardized mixed meal given at 0 min. All active treatments significantly reduced postprandial glucose concentrations compared to placebo. Intranasal insulin given at 0 min at a dose of 60 U or 120 U resulted in a 50% reduction in postprandial incremental glucose compared to placebo over the first 2 h, whereas treatment with 60 U both at 0 and 20 min lead to a 70% reduction over the 240 min postprandial period. Post-prandial intravenous insulin was the least effective. There were no episodes of symptomatic hypoglycaemia. Local tolerability was excellent with only four reports of transient nasal irritation out of a total of 68 doses. The delivery device was accurate with intra-device CV of delivered dose of 4.8%.(ABSTRACT TRUNCATED AT 250 WORDS)

A glimpse of the 'natural history' of established type 2 (non-insulin dependent) diabetes mellitus from the spectrum of metabolic and hormonal responses to a mixed meal at the time of diagnosis.

The reported glucose and immunoreactive insulin (IRI) responses to oral and intravenous glucose in subjects with Type 2 diabetes have not always been consistent. This may have resulted from variations in the method of glucose administration, the ethnic backgrounds of subjects, the diagnostic criteria applied, the duration of the disease or IRI assay methods. The use of a mixed meal rather than glucose has been shown to provide a more physiological stimulus to the pancreatic beta-cell due to both glucose and non-glucose secretagogues. We have analysed the metabolic and hormonal responses of 188 newly diagnosed Caucasian subjects with Type 2 diabetes and 38 non-diabetic subjects to a 500 kcal mixed meal. The diabetic subjects were stratified according to fasting plasma glucose (FPG) (< 9, 9-12, 12-15 and > or = 15 mmol/l) and body mass index (BMI) (< 26.5, 26.5-30 and > or = 30 kg/m2). Increasing FPG was associated with higher peak glucose concentrations and increasing failure to achieve basal glucose levels by 4 h. Median fasting IRI concentrations were similar to those of normal subjects, but all diabetic subjects had reduced early-phase insulin secretion. Diabetic subjects with FPG < 9 mmol/l showed augmented IRI area under the curve (AUC) at 2 and 4 h, whereas those with FPG > 9 mmol/l had progressive falls in IRI AUC to below that of the normal subjects (P < 0.0001 for the trend). Peak IRI concentrations declined progressively with increasing FPG. Despite equivalent glucose exposure simple trends of increasing AUC, IRI with increasing BMI were statistically significant (P < 0.001, P < 0.02, P < 0.001 and P < 0.01, respectively for each FPG group). Both fasting and AUC non-esterified fatty acid concentrations increased significantly with FPG regardless of BMI (P < 0.001 for the trends). These results using a more physiological mixed meal challenge in a large number of recently diagnosed Type 2 diabetic subjects demonstrate a marked and increasing loss of beta-cell secretory function with increasing fasting hyperglycaemia aggravated by insulin resistance with increasing obesity.

Reduced sampling protocols in estimation of insulin sensitivity and glucose effectiveness using the minimal model in NIDDM.

Recent work in healthy subjects, the aged, and subjects with gestational diabetes or drug-induced insulin resistance using minimal model analysis of the tolbutamide-modified frequently sampled intravenous glucose tolerance test suggested that a reduced sampling regimen of 12 time points produced unbiased and generally acceptable estimates of insulin sensitivity (SI) and glucose effectiveness (SG) compared with a full sampling schedule of 30 time points. We have used data from 26 insulin-modified frequently sampled intravenous glucose tolerance tests in 21 subjects with NIDDM to derive and compare estimates of SI and SG from the full sampling schedule (SI(30), SG(30)) with those estimated from the suggested 12 time points (SI(12), SG(12)) and those estimated with the addition of a 25-min time point (SI(13), SG(13)). Percentage relative errors were calculated relative to the corresponding 30 time-point values. A statistically significant bias of 15% (97% confidence interval from 7.4 to 25.6%, interquartile range 25%) was introduced by the estimation of SI(12) but not SI(13) (1%, 97% confidence interval from -9.4 to 9.3%, interquartile range 21%). Results for SG(12) (-12%, 97% confidence interval from -46.7 to 1.2%, interquartile range 49%) and SG(13) (-5%, 97% confidence interval from -27.8 to 6.8%, interquartile range 37%) were statistically equivocal. The precision of estimation of SI(12), SG(12), and SG(13) measured by the interquartile range of the percentage relative errors was poor. The precision of determination measured by the median minimal model coefficient of variation was 18, 29, and 27% for SI(30), SI(12), and SI(13) and 9, 11, and 11% for SG(30), SG(12), and SG(13), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of five pre-mixed combinations of 'short-' and 'intermediate-acting' (NPH) insulins in healthy subjects following subcutaneous administration.

The pharmacokinetics of five pre-mixed insulin preparations in the ratio of soluble to NPH insulin of 10:90, 20:80, 30:70, 40:60 and 50:50, were examined in a two part study in fasting healthy subjects. Each received by bolus subcutaneous injection into the anterior abdominal wall, on separate occasions one to two weeks apart, 20U of each of three pre-mixed insulin preparations in random order. In Part 1, nine subjects received Penmix 10:90, Penmix 20:80 and Penmix 30:70 and were observed over a period of 24 hours. In Part 2, eight subjects received Penmix 30:70, Penmix 40:60 and Penmix 50:50 and were observed over an 8 hr post-injection period. Three subjects were common to both parts of the study. Plasma glucose, C-peptide and insulin levels were measured frequently throughout both study periods. Increasing soluble insulin content in the pre-mixtures was reflected in increasing peak plasma insulin concentrations and a greater hypoglycaemic response. There were highly significant differences between the five premixtures and preparations in the 0-4 and 0-8 hours area under the curve (AUC) values for plasma glucose, C-peptide and immunoreactive insulin concentration (p < 0.01). Whereas a gradual difference between the premixtures was seen no two adjacent ones were significantly different, however an overall highly significant difference between the five preparations tested was observed.

Neurological complications of systemic sclerosis--a report of three cases and review of the literature.

We report three cases of systemic sclerosis demonstrating four different neurological complications: trigeminal neuropathy, peripheral neuropathy, carpal-tunnel syndrome and prolonged response to local anaesthesia. A review of the literature reveals a wide range of neurological abnormalities associated with systemic sclerosis. When they occur, these are often presenting features.