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Method of obtaining drug-macromolecule binding parameters directly from dynamic dialysis data.

A new method of treating dynamic dialysis data to obtain binding parameters for drug-macromolecule interactions is presented. This method allows the determination of binding parameters directly from dialysis data according to a theoretical model. It is not necessary to determine the dialysis rate constant accurately in a separate experiment, and bias is not introduced due to differentiation. The proposed method should be applicable where the drug is substantially bound to the dialysis membrane.

Albumins↗

LC/MS/MS method for the analysis of acrylamide and glycidamide hemoglobin adducts.

Hemoglobin adducts of acrylamide and its primary metabolite, glycidamide are used as biomarkers of acrylamide exposure. Several methods for analyzing these biomarkers in blood have been described previously. These methods were developed to analyze small numbers of samples, not the high sample throughput that is needed in population screening. Obtaining data on exposure of the US population to acrylamide through food and other sources is important to initiate appropriate public health activities. As part of the Centers for Disease Control and Prevention biomonitoring activities, we developed a high throughput liquid chromatography tandem mass spectrometry (LC/MS/MS) method for hemoglobin adducts of acrylamide. The LC/MS/MS method consists of using the Edman reaction and isolating the reaction products by protein precipitation and solid-phase extraction (SPE). Quantitation is achieved by using stable-isotope labeled peptides as internal standards. The method is performed on an automated liquid handling and SPE system. It provides good sensitivity in the low-exposure range as assessed in pooled samples and enables differentiation between smokers and non smokers.

Acrylamide↗

Improvement of metabolic control in diabetic patients during mebendazole administration: preliminary studies.

After the observation of decreasing insulin resistance in a diabetic patient during treatment with mebendazole for nematosis, we investigated the effect of mebendazole on metabolic control in six Type 1 (insulin-dependent) and six Type 2 (non-insulin-dependent) diabetic patients, eight of whom were chronically resistant to conventional treatment. Before and after mebendazole treatment for 1 month, plasma glucose and serum C-peptide concentrations were determined both fasting and 4 h after a mixed breakfast. Improvements in fasting blood glucose concentrations occurred in Type 1 (12.83 +/- 1.11 versus 6.56 +/- 0.56 mmol/l; p less than 0.05) and Type 2 (10.22 +/- 0.56 versus 7.56 +/- 0.67 mmol/l; p less than 0.05) diabetic patients and were associated with increases in post-cibal C-peptide responses in Type 1 and Type 2 diabetic patients. Following discontinuation of mebendazole, metabolic control deteriorated in five out of the six Type 1 diabetic patients and in all the Type 2 diabetic patients. We conclude that mebendazole increases insulin secretion, and decreases plasma glucose concentration in Type 1 and Type 2 diabetic patients. However, these beneficial effects may be transient.

Adult↗

Sulphonylurea therapy doubles B-cell response to glucose in type 2 diabetic patients.

The effect of sulphonylurea therapy for 3 weeks on glucose-stimulated insulin secretion and insulin resistance was studied in Type 2 diabetic patients. The fasting plasma insulin and C-peptide concentrations on diet alone were compared with each subject's fasting concentrations on sulphonylurea treatment at a lower fasting plasma glucose and at the original diet-alone glycaemic level obtained by the hyperglycaemic clamp technique. At this isoglycaemic level (mean 11 mmol/l), plasma insulin levels increased from 6.9 mU/l on diet alone to 12.1 mU/l on sulphonylurea treatment (p less than 0.01). The subjects were also studied by the hyperglycaemic clamp technique at mean glycaemic levels of 13 mmol/l before and after sulphonylurea treatment; the incremental insulin response was similarly enhanced from 7.6 +/- 3.5 to 13.7 +/- 6.9 mU/l (p less than 0.02) respectively. Sulphonylureas appear to reduce glycaemia by enhancing B-cell function two-fold. In the patients studied this was from approximately 21% to 37% of a normal response. Insulin resistance assessed by the same hyperglycaemic clamps as endogenous plasma insulin concentrations divided by glucose infusion rates was unchanged by sulphonylurea therapy (mean 4.37 compared to 4.40 mU X 1(-1) X mg-1 X kg X min on diet alone).

Aged↗

Neuroleptic properties of cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (YM-09151-2) with selective antidopaminergic activity.

A new benzamide, cis-N-(1-benzyl-2-methylpyrrolidin - 3 - yl) - 5 - chloro - 2 - methoxy - 4 - methylaminobenzamide (YM-09151-2) exhibited more potent and longer-lasting inhibitory effects on apomorphine-induced behaviours (stereotyped behaviour, emesis and hypothermia), and methamphetamine-induced stereotyped behaviour, conditioned avoidance response and open field behaviour, conditioned avoidance response and open field behaviour than either structurally similar benzamides (YM-0850 and sulpiride) or classical neuroleptics [chlorpromazine (CPZ) and haloperidol(HPD)]. Such inhibitory effects of YM-09151-2 relative to cataleptogenicity were greater than those of CPz and HPD. In contrast, sulpiride elicited few of the neuroleptic effects described above. YM-09151-2, a potent inhibitor for dopamine-sensitive adenylate cyclase (Ki: 3.0 nM) reduced, in a selective manner, the binding of [3H]dopamine to the dopamine D1 receptor (Ki:4.8 nm) associated with adenylate cyclase rather than to the dopamine D2 receptor (Ki: 0.98 microM) independent of adenylate cyclase. Sulpiride, on the contrary, inhibited only the binding to the dopamine D2 receptor, CPZ and HPD antagonized [3H]dopamine nonselectively at the two distinct dopaminergic receptors. These results suggest that YM-09151-2 is a potent and long-lasting neuroleptic with a highly selective blocking action on the dopamine D1 receptor.

Animals↗

Improved metabolic control does not reverse left ventricular filling abnormalities in newly diagnosed non-insulin-dependent diabetes patients.

In this study left ventricular diastolic function at rest was evaluated in ten newly diagnosed, non-insulin-dependent diabetic patients by Doppler echocardiography, performed at the onset of disease and after 6 and 12 months of adequate glycaemic control. Glycosylated haemoglobin A1C, total cholesterol and triglyceride levels were assessed at the same time. The control group consisted of ten healthy subjects of matching age and body mass index. The following parameters of left ventricular function were evaluated: ejection fraction (EF), peak velocity of the early (E) and late atrial (A) mitral flow, A/E ratio, duration of the early (Ei) and of the atrial (Ai) filling phase, and heart rate. The diabetic patients had significantly higher total cholesterol and triglyceride levels compared with healthy subjects. These remained elevated throughout the follow-up period, in spite of improved glycaemic control. A significantly shorter duration of Ei (0.15 +/- 0.008 vs 0.18 +/- 0.004, P < 0.01) and a higher value of A (0.51 +/- 0.02 vs 0.39 +/- 0.01, P < 0.001) and A/E (1.06 +/- 0.05 vs 0.73 +/- 0.02, P < 0.001) were found in the diabetic patients before treatment. The parameters did not significantly change after 1 year of adequate glycaemic control. These results indicate a left ventricular filling abnormality which is present in newly diagnosed non-insulin-dependent diabetic patients and does not reverse with improved glycaemic control.

Adult↗