Insulin formulations--a review.

Although the improvement on insulin therapy since it was first conceived, it is still far from mimicking physiological secretion of pancreatic b-cells and research to find new insulin formulations and new routes of administration continues. Human biosynthetic insulin (rapid-acting, intermediate-acting and long-acting), produced by recombinant DNA technique, is currently available. The pharmacokinetic profile of rapid-acting insulin (regular) does not adequately reproduce the physiological post-prandial insulin response. This has led to the development of molecular analogues with slight modifications that prevent the spontaneous polymerisation underlying delayed absorption. Fast-acting analogues such as Lyspro and Aspart can be injected immediately before the meal, inducing a very fast and substantial peak of insulin, similar to that produced by b-cells, but have the disadvantage of short duration of action. For this reason, and because of the difficulty of obtaining sufficient basal insulin concentrations to control preprandial blood glucose levels with current long-acting insulins, analogues known as Glargine and Detemir have been synthesized. They have virtually no plasma peak and acts for about 24 h. These characteristics make it ideal to cover basal insulin requirement. With insulin analogues, it also seems possible to overcome the problem of intra- and inter-individual variability in absorption after subcutaneous injection. This variability is directly proportional to the duration of insulin action. Research into new routes of administration has led to production of inhaled insulin powder, soon to become commercially available. Insulin is absorbed through the lung alveoli. Trials to evaluate efficacy and toleration have shown that inhaled insulin has a similar kinetic profile to the fast-acting injected analogue and can therefore be used for mealtime requirement, combined with a single daily injection of long-acting insulin. Oral insulin is currently being studied in type 1 diabetes prevention with promising results.

[Clinical study of the therapeutic effect of Mefoxine]. / Osservazioni cliniche sull'azione terapeutica del Mefoxin.

The therapeutic efficacy of cefoxitin was studied in 15 patients with pulmonary or urinary infections, after other unsuccessful antibiotic treatment. The drug determined a total regression of clinical picture within 10 days of therapy. Our results show that brief periods of treatment are sufficient in order to obtain recovery and to avoid selection of resistant germs. Patients treated with cefoxitin did not present any intolerance. The conclusion is drawn that "Mefoxin" is useful in patients affected by infections resistant to common antibiotics.

[Effects of ticlopidine on the plasma levels of beta-thromboglobulin and thromboxane B2 in types 1 and 2 diabetics]. / Effetti della ticlopidina sui valori plasmatici della beta-tromboglobulina e del trombossano B2 rilevati in diabetici tipo 1 e 2.

11 insulin-dependent and 19 non insulin-dependent diabetics with varying degrees of metabolic compensation and with high plasma levels of beta-thromboglobulin and thromboxane B2 were selected. Depending on the type of diabetes and the degree of glycaemia, control plasma levels of beta-thromboglobulin and thromboxane B2 were progressively lower after 14, 28 and 42 days of treatment with ticlopidine (500 mg/per day orally), than those encountered at the start of the study. It is concluded that ticlopidine influences plasma levels of beta-thromboglobulin and thromboxane B2 independently of the type and degree of metabolic compensation in diabetes mellitus.

[Prolactin secretion in patients with essential obesity]. / Aspetti della secrezione prolattinica in pazienti affete da obesità essenziale.

17 women affected by essential obesity were examined, 9 of whom had become obese as adults (group A) and 8 had been obese since childhood (group B). In group A, fasting and after TRH, the PRL presented higher plasmatic levels than those found in the controls. In group B the hormone showed basal values and global secretory areas higher than those observed in the controls and in group A, while incremental areas did not result different from those found in the other groups examined. In no case did IRI, GH and glycaemia undergo changes in relation to TRH. In conclusion we think that the behaviour of prolactin can be an important physiopathological characteristic, expression of the different neuroendocrine hypothalamic homeostasis existent in the heterogeneous obese population.

[Thromboxane, beta-thromboglobulin and the degree of blood sugar control in type 1 diabetes mellitus]. / Trombossano, beta-tromboglobulina e grado di controllo glicemico nel diabete mellito tipo 1.

Plasma concentrations of beta-thromboglobulin (B-TG) and of Thromboxane B2 (TxB2) were found to be increased in diabetics but their values didn't result in relation to simultaneous fasting glycemia. The aim of this study was to elucidate if the B-TG and TxB2 levels were correlated with the indexes of medium and long-term diabetes control, namely non-enzymatic glycosylation of serum proteins (GSP) and irreversibly glycosylated hemoglobin, stable (S) HbA1. Therefore the behaviour of B-TG, TxB2, glycemia, GSP, T-HbA1 (stable and labile) and S-HbA1 were determined in 37 type 1 diabetics without any apparent vascular complication. All these parameters, except S-HbA1, were studied also in 8 ketoacidotic diabetic out patients before and during the recovery of metabolic control. Glycemia was assayed by the method of Trinder; B-TG and TxB2 were determined by radio-immunoassay. GSP was measured by chemical procedure using thiobarbituric acid (TBA test). The concentration of HbA1 was performed before and after incubation of erythrocytes for 6 h at 37 degrees C in saline to evaluate T and S-HbA1. In the out-patients B-TG and TxB2 were found to be correlated only with GSP. During the recovery of glycemic control a progressive decrease in the levels of T-BG and TxB2 was observed. We conclude that in vitro platelet activation i.e. B-TG and TxB2 levels, stable metabolite of proaggregatory TxA2, are deranged in relation to medium term glycemic disturbance rather than to short-term glucose fluctuations.

[Glycolipid pattern and glycosilated hemoglobin (HbA 1) in a group of arteriosclerotic subjects]. / Assetto glico-lipidico ed emoglobina glicosilata (HbA1) in un gruppo di soggetti arteriosclerotici.

Total glycosilated haemoglobin (HbA1) concentration, serum triglyceride and cholesterol levels were measured in 55 arterio sclerotic patients classified in three groups: (A) normal, (B) borderline and (C) chemical diabetics according to their OGTT results. HbA1 values were high only in group C. In these patients the HbA1 concentrations correlated to the serum glucose peaks and serum triglyceride levels. Therefore we believe that the HbA1 concentration can be considered an index of the degree of carbohydrate imbalance in arteriosclerotic patients who frequently have high triglyceride levels and carbohydrate intolerance.

[Prolactin response to TRH in insulin-dependent diabetes mellitus]. / Risposta prolattinica al TRH nel diabete mellito insulino-indipendente.

17 obese women were examined, 8 of which were diabetic and 9 affected only by essential obesity. These patients, all of whom had become obese during adult life and 8 control subjects were tested for IRI, GH and PRL levels in basal conditions and after infusion of TRH. In the obese and diabetic women fasting GH values were normal while IRI levels were higher than those of the control subjects. In all cases neither IRI nor GH variations during TRH stimulation test. There was no difference in the plasma levels of PRL between the 3 groups when examined in basal conditions. After TRH the hormone increased considerably in all the subjects. In the obese and diabetic obese women the incremental area did not present different values from those observed in the control subjects. In conclusion in insulin-independent diabetes, as in essential obesity, the pharmacological stimulus did not show any evident alteration of the specific hypofisary receptorial system that regulates the secretion of PRL and GH.

Comparative study of chromatographic and non-chromatographic procedures in the assay of serum 25-hydroxyvitamin D.

Chromatographic and non-chromatographic procedures in the assay of serum 25-hydroxyvitamin D are compared. Samples extracted with chloroform/methanol were analysed using a competitive protein binding assay, with or without prior chromatography. Non-chromatographic methods constantly gave higher values than chromatographic methods. It is concluded that chromatography is an essential step in the preparation of extracts for the assay of 25-hydroxyvitamin D.

[Behavior of plasma insulin, C-peptide and glucagon in normal subjects and in patients with liver cirrhosis]. / Comportamento dell'insulina, del C-peptide e del glucagone plasmatici in soggetti normali e in pazienti affetti da cirrosi epatica.

Plasma levels of IRI, C-peptide and glucagon were determinated in 19 patients with liver cirrhosis and 9 control subjects after an oral glucose load (OGTT). 9 of the cirrhotics showed chemical diabetes, the remaining 7 cases showed ascites and a normal OGTT. Both groups of cirrhotics showed high IRI and C-peptide values in basal conditions, peaks of these parameters, higher than those observed in the control subjects, were found during the OGTT. The C-peptide/IRI ratio, which was lower than normal both during fasting and after glucose load, presented the lowest value in patients with ascites. In the conditions adopted for this study, glucagon showed higher plasma levels in all the cirrhotics studied than those found in the controls, but the highest levels were found in patients with ascites and with a normal OGTT. It can be concluded that the high levels of insulin found in liver cirrhosis are due to a B-pancreatic hypersecretion (high C-peptide levels) but are also maintained by a decreased hepatic degradation of the hormone (C-peptide/IRI ratio below normal). Hyperglucagonemia is not the chief factor in determining the insulin-resistance observed in liver cirrhosis.

Evaluation of sera of various origin as sources of binding protein for the assay of 25-hydroxyvitamin D.

The affinity for 25-hydroxycholecalciferol (25OHD3) of transport proteins present in sera of various origin was estimated by means of Scatchard plots, using tritiated 25OHD3 as the tracer. Normal and rachitic rat sera showed the highest affinities, human sera showing lower association constants. Serum from normal rats is therefore to be considered the most suitable source of binding protein for the assay of 25-hydroxyvitamin D.

Prevalence of dermatophytic skin and nail infections in diabetic patients.

To determine whether there is a higher frequency of mycotic infections due to dermatophytes in diabetics, 171 diabetic outpatients and 276 controls were recruited in the period 1997-98. Patients with suspicious lesions underwent mycological examination which was positive in seven diabetics and 17 controls. In diabetics the most frequent infection was tinea pedis, followed by distal subungual onychomycosis; the most frequently isolated fungus was Trichophyton mentagrophytes. The results of the study did not show a prevalence of dermatophyte infections in diabetics. No correlation was found between dermatophytosis and duration or type of diabetes and its complications, blood sugar levels or levels of glycosylated haemoglobin. None of the diabetic patients with dermatophytosis had complications related to diabetes and basal blood sugar and glycosylated haemoglobin levels indicated good metabolic control.

Effects of somatostatin on the behaviour of thromboxane B2 and beta-thromboglobulin in type I diabetes.

Pharmacological studies have shown that the addition of somatostatin to insulin promotes a more rapid recovery from diabetic ketoacidosis. However, contradictory results have been reported concerning the action of somatostatin on platelet function, frequently deranged in diabetes. Therefore the plasma levels of thromboxane B2, a stable metabolite of proaggregatory thromboxane A2 and of beta-thromboglobulin, a marker of platelet activation, were studied in 9 control subjects and in 13 insulin-dependent diabetic patients before and during somatostatin injection, administered as an initial 250 micrograms iv bolus followed by infusion of 300 micrograms over 3 h. In both groups, after somatostatin infusion thromboxane B2 and beta-thromboglobulin levels showed, respectively, a progressive fall and an increase up to the second hour. Over the next hour thromboxane B2 increased and beta-thromboglobulin decreased but their levels did not return to basal values. During this experiment beta-thromboglobulin plasma values in diabetic patients did not differ from those of control subjects. In contrast, thromboxane B2, decreased in relation to pharmacological treatment, maintained elevated levels. Our data, however, demonstrate that the dose of somatostatin used, produced in the diabetic patients a normal fall of thromboxane B2 in terms of percentage of base-line values, but increases of beta-thromboglobulin lower than in control subjects. It is suggested that platelet function should be evaluated when somatostatin is used in the treatment of poorly controlled type I diabetes.

[Behavior of C-peptide and immunoreactive insulin in essential obesity]. / Comportamento del C-peptide e dell'insulina immunoreattiva nell'obesita' essenziale.

The levels of glucose, immunoreactive insulin and C-peptide were studied in 13 obese patients and 10 control subjects, in basal conditions and after an oral glucose load (OGTT). The IRI and C-peptide levels were higher in the obese patients than in the controls either during fasting or during the OGTT. The C-peptide/IRI ratio decreased after the oral glucose load in both groups studied. However in the obese subjects the values for the C-peptide/IRI ratio were lower than those found in the controls during the same observation period. These results suggest the hypothesis that in the obese patients the high IRI levels which reflect an increased insulin secretion, are, at least in part, due to an early saturation of the hepatic degradation of insulin and/or to a decrease in the specific receptor sites normally present in the cell membranes.

Plasma levels of insulin, C-peptide and glucagon in liver cirrhosis.

Plasma levels of immunoreactive insulin (IRI), C-peptide and glucagon were assayed in 16 patients with liver cirrhosis and 9 control subjects after an oral glucose load (OGTT). Nine of the cirrhotics showed glucose intolerance, the remaining 7 cases showed normal OGTT. Both groups of cirrhotics showed high IRI and C-peptide values in basal conditions; peaks of these parameters, higher than those observed in the control subjects, were found during the OGTT. The C-peptide/IRI ratio, which was lower than normal both during fasting and after glucose load, presented the lowest values in patients with normal OGTT. In the conditions adopted for this study, glucagon showed higher plasma levels in all the cirrhotics studied than those found in the controls, but the highest levels were found in patients with normal OGTT. It can be concluded that the high levels of insulin found in liver cirrhosis are due to a beta-pancreatic hypersecretion (high C-peptide levels) but are also maintained by a decreased hepatic degradation of the hormone (C-peptide/IRI ratio below normal). Hyperglucagonemia is not the chief factor in determining the insulin-resistance observed in liver cirrhosis.

[Correlation between beta-thromboglobulin and metabolic compensation in diabetes type I]. / Correlazione fra beta-tromboglobulina e compenso metabolico del diabete tipo I.

In 37 type I diabetic out-patients without any apparent vascular complication and in 9 diabetics with ketoacidosis we have studied the behavior of beta-TG and of glycemia, GSP and HbA1 which are indexes of the short, medium and long-term glycemic control, respectively. In the out-patients beta-TG was found to be correlated only with the GSP. During the recovery of glycemic control, a progressive decrease in the level of beta-TG was found. Therefore, we conclude that also the metabolic derangement of diabetes takes part in the platelet activation.

Non-enzymatic glycosylation of urinary proteins in type 1 (insulin-dependent) diabetes: correlation with metabolic control and the degree of proteinuria.

In 18 control subjects and in 41 Type 1 (insulin-dependent) diabetic patients (13 with normal proteinuria, group A; 15 with microproteinuria, group B; and 13 with clinical proteinuria, group C), mean blood glucose, glycosylated haemoglobin and non-enzymatic glycosylated serum and urinary proteins, expressed as 5-hydroxymethylfurfural (5-HMF), were measured. In each group of diabetic patients, the levels of mean daily blood glucose, glycosylated haemoglobin and serum 5-HMF/mg protein were higher than in the control subjects. The urinary 5-HMF/mg proteinuria and the urinary/serum 5-HMF concentration ratio values were raised in group A and reduced in groups B and C. Moreover, they showed a negative correlation with 24-h urinary protein excretion in the control subjects and in each group of diabetic patients. The urinary 5-HMF/day in groups A, B and C was greater than in the control subjects. The urinary 5-HMF/day did not correlate with the mean daily blood glucose levels and, only in group A, did it correlate with serum 5-HMF and glycosylated haemoglobin. This suggests that, in this group, functional factors result in the increased renal elimination of 5-HMF and, therefore, of non-enzymatically glycosylated proteins. However, in the other groups of patients, this elimination depends on the degree of proteinuria.

Effects of somatostatin on the behavior of thromboxane B2 and B-thromboglobulin in type 1 diabetes.

Somatostatin, as an adjunct to insulin in the treatment of poorly controlled type 1 diabetes, has been recently suggested. However, some authors, after injection of the polypeptide, detected a reduction in number and aggregation of platelets, others instead, reported a proaggregatory effect of the drug. To answer these questions, the plasma levels of proaggregatory thromboxane A2 and of B-thromboglobulin, marker of the platelet activation, were studied in nine control subjects and in thirteen insulin dependent diabetic patients before and during the endovenous injection, for three hours, of somatostatin (250 micrograms in bolus followed by infusion of 100 micrograms/h). In both groups, 30 min after the infusion of somatostatin, a fall of thromboxane B2, stable metabolite of thromboxane A2 and an increase of B-thromboglobulin were respectively observed. Their greatest figure was reached after 120 min and their levels did not return to basal values within the end of the observation. In diabetics, during the infusion of somatostatin, thromboxane B2 presented normal percentual falls while B-thromboglobulin showed increases which were lower than controls. In conclusion, the effect of somatostatin implied in the relative lower increase of B-thromboglobulin, seems connected to the precedent continuous activation of circulating platelets, the one, responsible for the decrease of thromboxane B2, instead, seems linked to a direct action of somatostatin, independently on the deranged metabolic conditions found in diabetic patients.