Effect of a Suicide Prevention Centre for young people with suicidal behaviour in Copenhagen.

BACKGROUND: In the 1980s, suicide rates in Denmark were among the highest in the world. In 1992, a Suicide Prevention Centre was opened in Copenhagen with a 2-week programme of social and psychological treatment. The aim of the study was to evaluate the effect of the Suicide Prevention Centre. METHODS: In a quasi-experimental study, 362 patients in the Suicide Prevention Centre and a parallel comparison group of 39 patients were interviewed with European Parasuicide Study Interviewer Schedule I (EPSIS I), which is a comprehensive interview including several validated scales. All patients were invited to follow-up interviews with EPSIS II and followed in the National Patients Register and the Cause of Death Register. RESULTS: At the 1-year follow-up, 59% of patients in the intervention group and 53% of patients in the comparison groups were interviewed with EPSIS II. The intervention group obtained a significantly greater improvement in Beck's Depression Inventory, Hopelessness Scale, Rosenberg's Self-Esteem Scale and CAGE-score and a significantly lower repetition rate. DISCUSSION: Although the design cannot exclude selection bias, it seems likely that the improvement in the intervention group was facilitated by the treatment.

Sustained signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency.

The metabolic and mitogenic potencies of six different insulin analogues were determined by measuring glucose transport in primary adipocytes and DNA synthesis in CHO cells respectively. Three analogues showed a disproportionately high mitogenic potency compared with their metabolic potency, and were up to 7 times more mitogenically than metabolically potent when compared with human insulin. The mitogenic/metabolic potency ratio of the analogues was found to be inversely correlated with the insulin receptor dissociation rate constant (Kd) in an exponential fashion (r=0.99), with a disproportionately greater increase in mitogenic potential compared with metabolic potential for analogues with Kd values of less than 40% of that of human insulin. To investigate the molecular mechanisms behind the correlation between the increased half-life of the receptor-ligand complex (low Kd) and mitogenicity, 3 h time-course experiments were performed. Slow ligand dissociation from the insulin receptor induced a parallel sustained activation of the insulin receptor tyrosine kinase. A similar pattern was observed for insulin receptor autophosphorylation and Shc phosphorylation, whereas the duration of insulin receptor substrate-1 phosphorylation with low-Kd analogues and with insulin was similar Thus the increased half-life of the ligand-receptor complex induces sustained activation of the insulin receptor tyrosine kinase and sustained phosphorylation of Shc, which may be the cause of the disproportionately high mitogenic potency seen for some insulin analogues.

Intranasal administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects.

The pharmacokinetics of intranasal insulin containing a medium-chain phospholipid (didecanoyl-L-alpha-phosphatidylcholine) as absorption enhancer, was studied in normal volunteers by measuring plasma glucose, insulin, C-peptide, and glucagon. Eleven fasting subjects received 4 U insulin intravenously, 6 U subcutaneously, or three doses intranasally (approximately 0.3 U kg-1, 0.6 U kg-1, 0.8 U kg-1) in random order on five separate days. Intranasal insulin was absorbed in a dose-dependent manner with a mean plasma insulin peak 23 +/- 7 (+/- SE) min after administration. Mean plasma glucose nadir was seen after 44 +/- 6 min, 20 min later than following intravenous injection. Furthermore, intranasal administration of insulin resulted in a faster time-course of absorption than subcutaneous injection, with significantly reduced intersubject variation (p less than 0.001). Bioavailability for the nasal formulation was 8.3% relative to an intravenous bolus injection when plasma insulin was corrected for endogenous insulin production estimated by C-peptide. A dose-dependent suppression of C-peptide and stimulation of glucagon secretion occurred after intranasal administration of insulin. Nasal irritation from spraying was absent or slight.

In vitro and in vivo potency of insulin analogues designed for clinical use.

Analogues of human insulin designed to have improved absorption properties after subcutaneous injection have been prepared by recombinant DNA technology. Five rapidly absorbed analogues, being predominantly in mono- or di-meric states in the pharmaceutical preparation, and a hexameric analogue with very low solubility at neutral pH and slow absorption, were studied. Receptor binding assays with HEP-G2 cells showed overall agreement with mouse free adipocyte assays. Two analogues, B28Asp and A21Gly + B27Arg + B30Thr-NH2, had nearly the same molar in vitro potency as human insulin. Another two showed increased adipocyte potency and receptor binding, B10Asp 194% and 333% and A8His + B4His + B10Glu + B27His 575% and 511%, while B9Asp + B27Glu showed 29% and 18% and the B25Asp analogue only 0.12% and 0.05% potency. Bioassays in mice or rabbits of the analogues except B25Asp showed that they had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation in in vivo potency reflects the differences in receptor binding affinity. Relative to human insulin a low concentration is sufficient for a high affinity analogue to produce a given receptor complex formation and metabolic response. In conclusion, human insulin and analogues with markedly different in vitro potencies were equipotent in terms of hypoglycaemic effect. This is in agreement with the concept that elimination of insulin from blood and its subsequent degradation is mediated by insulin receptors.

Receptor binding and tyrosine kinase activation by insulin analogues with extreme affinities studied in human hepatoma HepG2 cells.

The insulin-receptor affinity of five human insulin analogues with one to four amino acid substitutions was measured with human hepatoma cells (HepG2). The binding affinities ranged from 0.05% for AspB25 insulin, 18% for AspB9, GluB27 insulin, 80% for AspB28 insulin, and 327% for AspB10 insulin to 687% for HisA8, HisB4, GluB10, HisB27 insulin relative to human insulin. Binding constants obtained by competition experiments at steady state with [125I]TyrA14-labeled insulin and unlabeled analogues and by kinetic studies with [125I]TyrA14-labeled analogues and insulin gave essentially the same values. The kinetic studies showed that differences in affinity between analogues were due to differences in both dissociation and association rate constants. The affinity for insulinlike growth factor I receptor was low, ranging from less than 0.005% for AspB25 insulin to 0.6% for HisA8, HisB4, GluB10, HisB27 insulin. The potencies of insulin analogues in activation of the tyrosine kinase of solubilized and partially purified insulin receptors from HepG2 cells, measured with the exogenous substrate poly(Glu80-Tyr20), ranked in the same order as the binding affinities, the actual values being somewhat elevated for the high-affinity analogues, however. We conclude that these human insulin analogues are active in insulin-receptor binding and tyrosine kinase stimulation but show wide variation in affinity.

Equivalent in vivo biological activity of insulin analogues and human insulin despite different in vitro potencies.

In vivo biological potency of two human insulin analogues, AspB9,GluB27 insulin and AspB10 insulin with low and high affinity to the insulin receptor, respectively, was assessed by intravenous infusion of equimolar amounts in pigs, with the euglycemic clamp technique. Human insulin and the low- and high-affinity analogues showed equivalent glucose utilization rates in the steady state (mean +/- SE 14.7 +/- 1.4, 12.7 +/- 1.5, and 12.2 +/- 1.2 mg.kg-1.min-1, respectively; n = 7). The corresponding plasma insulin levels, however, were markedly different (329 +/- 25 and 856 +/- 46 pM, P less than 0.05; 197 +/- 19 pM, P less than 0.05). There was an inverse relationship between the insulin levels and the in vitro activities measured by binding to human hepatoma cells (HepG2; 100, 20, and 308%) or by incorporation of glucose into lipids in mouse free fat cells (100, 31, and 207%). The total amount of glucose infused during and after insulin infusion was equal for the three insulins, whereas glucose utilization as a function of time was somewhat different. By describing the individual plasma concentration courses with an open two-compartment model with elimination from the receptor compartment, the time courses for binding and elimination of the three insulins in the receptor compartment were estimated. The effect seems closely linked to the elimination of insulin from the receptors rather than to the amount of insulin bound to the receptors. In conclusion, the total effect of equimolar amounts of human insulin and the two insulin analogues on glucose utilization is equal regardless of the different receptor affinities of the insulins.

A prospective study of young men at high risk for alcoholism: neuropsychological assessment.

As part of the first phase of a prospective longitudinal study on alcoholism, a battery of neuropsychological tests covering general intelligence, memory, attention, field-dependence, categorizing ability, and organizing and planning, was administered to 204 18-19-year-old males. Of these, 134 subjects are the sons of alcoholic fathers and are thereby themselves at high risk for becoming alcoholic. The remaining 70 subjects comprise a control group matched for several social and familial variables. The high risk group was found to have a relatively poorer vocabulary and to perform worse on tests of categorizing ability and organization and planning. All of these findings concur with other results from this study. The anticipated future alcoholics from among the high risk subjects may prove to be those who differed most on these tests.