Influence of lactation on morphometric and secretory variables in pancreatic beta-cell of mildly diabetic rats.

In nondiabetic rats, lactation accelerates the restoration of pancreatic beta-cell function after the period of increased secretory activity associated with pregnancy. To investigate whether a comparable situation prevails in mildly diabetic animals, streptozocin (22.5 mg/kg body wt) was administered to female rats at the onset of pregnancy. Plasma glucose and insulin concentrations, content and release of insulin in isolated islets, total mass and volume density of both the endocrine pancreas and granulated beta-cells, and ultrastructural prevalence of light and dark secretory granules were measured on the 20th day of pregnancy and in lactating and nonlactating animals 20 days after delivery. In the mildly diabetic animals, the changes in endocrine pancreatic function normally associated with pregnancy and lactation were greatly attenuated, albeit not completely eliminated. We propose that the increased biosynthetic and secretory activity imposed on surviving beta-cells after streptozocin administration tends to mask the adaptative changes in beta-cell function otherwise seen during the postpartum and lactation period.

Possible role of glycogen accumulation in B-cell glucotoxicity.

Rat pancreatic islets cultured for 1 to 5 days in the presence of 20 to 80 mmol/L D-glucose accumulate glycogen in a time- and concentration-dependent manner. When the glycogen-rich islets are incubated for 6 to 10 minutes in the absence of D-glucose, the rate of glycogenolysis is grossly proportional to the glycogen content. Exogenous D-glucose (7 to 20 mmol/L) inhibits glycogenolysis. This inhibitory effect opposes the increase in glycolytic flux attributable to the utilization of exogenous glucose. Both the inhibitory effect of D-glucose on glycogenolysis and the utilization of exogenous hexose tend to be higher with alpha- than with beta-D-glucose. In light of these findings, it is proposed that the interference of D-glucose with glycogenolysis might play a role in the paradoxical changes in insulin output and its altered anomeric specificity in response to D-glucose administration, as is often encountered in non-insulin-dependent diabetic subjects and experimental models of B-cell glucotoxicity.

Perturbation of pancreatic islet function in glucose-infused rats.

The secretory behavior of insulin- and glucagon-producing cells was found to be perturbed in isolated perfused pancreases removed from rats infused with hypertonic solutions of glucose for 48 hours. The anomalies included a high basal release of insulin and a paradoxical increase in insulin output and decrease in glucagon release in response to a fall in D-glucose concentration. Likewise, in isolated islets prepared from the glucose-infused rats, L-arginine or theophylline stimulated insulin release at a low ambient concentration of D-glucose, at variance with the situation found in islets removed from normal rats. These secretory perturbations could not be attributed to any obvious defect in either the transport of D-glucose into islet cells or its further utilization and oxidation, but coincided with the abnormal accumulation of glycogen in the B-cell. It is proposed that the latter anomaly may play a role in the altered dynamics of insulin release found in animals or patients with long-term hyperglycemia.

Neonatal streptozotocin injection: a model of glucotoxicity?

Adult rats injected with streptozotocin during the neonatal period displayed in the fed state moderate hyperglycemia. However, the percentages of glycated hemoglobin in erythrocytes and glycated lactate dehydrogenase in liver and pancreatic islets, as well as the sorbitol and glycogen content of the islets, were not significantly increased. Likewise, in intact islets, the ouabain-sensitive inflow of 86Rb+, and the ratio between 3H2O production from D-[2-3H]glucose and D-[5-3H]glucose were not different in control and streptozotocin-injected rats. These findings suggest that the alteration in both the mitochondrial catabolism of D-glucose and secretory response to the hexose previously documented in the islets of the latter animals are not attributable to factors such as the excessive nonenzymatic glycation of cytosolic proteins, sorbitol or glycogen accumulation, or impaired Na+, K(+)-adenosine triphosphatase (ATPase) activity. Although a contributive role of glucotoxicity in the impaired function of beta cell in this model of non-insulin-dependent diabetes should not be ruled out, it is speculated that streptozotocin might also cause a long-term damage of key mitochondrial dehydrogenases in the pancreatic beta cells and, possibly, their precursor cells.

Safety of itraconazole pulse therapy for onychomycosis. An update.

After experience with more than 34 million patients over 10 years, the safety of itraconazole and its potential drug-drug interactions are well known. In clinical trials, the average incidence of adverse events with a 1-week pulse regimen was 18% in pooled safety data (n = 2,867); only 2.2% of patients dropped out. In direct comparative trials, the incidence of mild and reversible adverse effects was comparable for itraconazole and terbinafine (31% and 28%, respectively) during treatment. The rate of permanent withdrawal because of adverse events was 3.6% for itraconazole and 7.5% for terbinafine (P < .05). Itraconazole was significantly better tolerated as evaluated by the investigator and patients. The analysis of the elderly subpopulation showed that patients 65 and older tolerated itraconazole pulse well, with only 20% experiencing mild and reversible side effects (total group). In direct comparative trials, itraconazole also produced fewer adverse effects than terbinafine (13% vs 32%, respectively). As newer oral antifungal agents gain widespread use, clinicians need to be aware of their potential drug-drug interactions and their possibly serious adverse events. However, pooled data from the 1-week itraconazole pulse regimen indicated a favorable safety profile, and a dose increase to 400 mg had no impact on safety.

The effects of foot disease on quality of life: results of the Achilles Project.

BACKGROUND: Foot diseases have a high prevalence in the general population, but their impact on quality of life has not been assessed in large-scale studies. The Achilles Project surveyed foot disease in patients visiting their primary care physician or dermatologist. METHODS: A total of 43 593 patients were asked about the impact of their condition on their quality of life: pain, discomfort in walking, limitations in daily activities, and embarrassment. RESULTS: Overall, 52.5% of patients had some aspect of their quality of life affected by their foot disease. More specifically, 30.7% of patients experienced pain, 40.3% had discomfort in walking, 19.6% had their daily activities limited, and 27.3% were embarrassed. The survey indicated a larger impact of foot disease on the quality of life of women vs. men in all categories, except for daily activities. Similarly, the elderly (> or = 65 years) were more affected by their foot disease, although they suffered no more embarrassment than other age groups. Participation in sports seemed to lower the proportion of patients who had their quality of life adversely affected. Non-fungal foot diseases, particularly ulcer and gangrene, are more likely to cause pain, discomfort in walking and limit daily activities, than fungal diseases. CONCLUSIONS: In general, non-fungal foot diseases caused pain, discomfort in walking and limitations in daily activities in more patients than fungal foot diseases, but a higher proportion of patients with fungal foot diseases were embarrassed by their condition than patients with non-fungal foot diseases. The study found that the impact of foot disease on quality of life may be greater than previously suggested. Given that effective treatments are available, routine examination of patients' feet by dermatologists and primary care physicians may help to reduce the burden of these foot conditions.

Activity and kinetics of liver 6-phosphofructokinase in normal and diabetic rats.

The activity and kinetics of phosphofructokinase were measured in the postmicrosomal supernatant of livers removed from either normal or streptozotocin-induced diabetic rats. The activity of the enzyme was lower in diabetic than normal rats. However, the relative magnitude of changes in reaction velocity evoked by different concentrations of D-fructose 6-phosphate, ATP, D-glucose 1,6-bisphosphate and/or D-fructose 2,6-bisphosphate were comparable in normal and diabetic rats. Such was also the case after separation of cytosolic proteins from low molecular weight metabolites by gel filtration chromatography. These findings suggest that a sustained increase in intracellular D-glucose concentration, as presumably occurring in hepatocytes of diabetic animals, does not result in any obvious alteration of the intrinsic kinetic properties of phosphofructokinase.

Anomeric specificity and kinetics of glucokinase: theoretical unsuitability of the Hill equation.

The kinetics of the low-Km hexokinase isoenzymes, which obey the Michaelis-Menten equation, can be established from the Km (Michaelis constant) and Vmax (maximal velocity) values for either equilibrated D-glucose or its alpha- and beta-anomers. In the case of the high-Km glucokinase isoenzyme, however, the sigmoidal substrate dependency and the competition between the two anomers of D-glucose do not allow, theoretically, to assign any meaningful value to either the Km, Vmax or n (Hill number) constants for equilibrated D-glucose. Thus, with equilibrated D-glucose, the concentration dependency fails to display a rectilinear relationship in the Hill plot. These observations illustrate the shortcomings of current biochemical studies in which the anomeric heterogeneity of D-glucose is ignored.

Oscillations in glycolysis: multifactorial quantitative analysis in muscle extract.

A multifactorial quantitative analysis of oscillations in glycolysis was conducted in the postmicrosomal supernatant of rat muscle homogenates incubated in the presence of yeast hexokinase. Oscillations in adenine nucleotides, D-fructose 1,6-bisphosphate, triose phosphates, L-glycerol 3-phosphate, 3HOH generation from D-[5-3H]glucose, NADH and L-lactate production were documented. The occurrence of such oscillations were found to depend mainly on the balance between the consumption of ATP associated with the phosphorylation of D-glucose, as catalyzed by both yeast and muscle hexokinase, and the net production of ATP resulting from the further catabolism of D-fructose 6-phosphate, as initiated by activation of phosphofructokinase. The oscillatory pattern was suppressed in the presence of D-fructose 2,6-bisphosphate. It is proposed that the quantitative information gathered in this study may set the scene for further studies in extracts of cells other than myocytes, e.g. hepatocytes and pancreatic islet cells, in which no oscillation of glycolysis was so far observed.

Occurrence of the purine nucleotide cycle in rat pancreatic islets.

The presence of the purine nucleotide cycle is investigated in rat pancreatic islets. Adenylosuccinase, adenylate deaminase, and adenylosuccinate synthetase activities are characterized in islet homogenates. In the assay of the latter enzyme, evidence is obtained for operation of the full cycle in islet extracts. The activities of the three enzymes are not vastly different in islet and brain. These findings are discussed in the light of the role currently ascribed to the purine nucleotide cycle in producing ammonia from amino acids, in adjusting the concentration of Krebs cycle intermediates, in regulating the relative concentrations of ATP, ADP, and AMP, and in controlling the activity of phosphofructokinase.

The endocrine pancreas during pregnancy and lactation in the rat.

The percentage of endocrine tissue in the whole pancreas, the volume density of the insulin producing beta-cells, the non-fasting plasma glucose level and the plasma insulin level were studied in pregnant rats and in puerperal lactating and non-lactating rats. During pregnancy there was a progressive rise in the percentage of endocrine tissue, in the volume density of the beta-cells and in the insulin level in peripheral blood. Plasma glucose levels declined during pregnancy. A lower plasma glucose level, a lower plasma insulin level, a lower percentage of endocrine tissue and a lower volume density of the beta-cells was found in lactating compared to non-lactating rats.

Ultrastructural changes of the pancreatic beta-cell and the insulin secretion by islets from lactating and non-lactating rats.

Islets isolated from lactating rats, as compared to islets from non-lactating rats, release less insulin when incubated in the absence of exogenous nutrient or presence of either D-glucose (11.1 mM) or the association of L-leucine and L-glutamine (10.0 mM each). The insulin content of the islets is not different in lactating and non-lactating rats. The volume density of the dark granules in the beta-cells is not at variance in both groups. However the volume density of the light (pale) granules is significantly lower in the lactating rats. The reduced amount of light granules is in keeping with the reduced secretory capacity of the beta-cells from lactating rats.

Anomeric specificity of D-glucose phosphorylation by rat liver glucose-6-phosphatase.

The anomeric specificity of D-glucose phosphorylation by hepatic glucose-6-phosphatase was examined in rat liver microsomes incubated in the presence of carbamoyl phosphate. At 10 degrees C, the Km for the equilibrated hexose and phosphate donor was close to 56 mM and 11 mM, respectively. The enzymic activity, which was increased in diabetic rats, was about 40% lower in untreated than in sonicated microsomes. No anomeric difference in affinity was found in sonicated microsomes. In untreated microsomes, however, the Km for beta-D-glucose was slightly lower than that for alpha-D-glucose. The maximal velocity was higher with beta- than alpha-D-glucose in both untreated and sonicated microsomes. These data indicate that the phosphotransferase activity of glucose-6-phosphatase cannot account for the higher rate of glycolysis and glycogen synthesis found in hepatocytes exposed to alpha- rather than beta-D-glucose.

Itraconazole pulse therapy for onychomycosis and dermatomycoses: an overview.

BACKGROUND: Itraconazole is a broad-spectrum antifungal agent that has been used to treat dermatomycosis and onychomycosis using continuous therapy. More recently the drug has been used as pulse dosing. OBJECTIVE: Our purpose was to review the studies in which itraconazole pulse therapy (PT) has been administered in the management of dermatomycoses. RESULTS: For tinea pedis and manuum, the recommended dosage is itraconazole 200 mg twice daily for 1 week (n = 220). A clinical response and mycologic cure rate of 90% +/- 4% and 76% +/- 6%, respectively, has been obtained. For tinea corporis/cruris, itraconazole 200 mg/day for 1 week (n = 354) resulted in a clinical response and mycologic cure rate of 90% +/- 4% and 77% +/- 6%, respectively. When three pulses of itraconazole are used to treat toenail onychomycosis (n = 1389), the clinical cure rate, clinical response, and mycologic cure rate at follow-up 12 months after the start of therapy were 58% +/- 10%, 82% +/- 3%, and 77% +/- 5%, respectively. With two pulses for onychomycosis of the fingernails, the clinical cure rate, clinical response, and mycologic cure rate at follow-up, 9 months after the start of therapy, were 78% +/- 10%, 89% +/- 6%, and 87% +/- 8%, respectively. CONCLUSION: Itraconazole PT is effective and safe in the treatment of tinea pedis/manuum, tinea corporis/cruris, and onychomycosis.

Safety of itraconazole in diabetic patients.

BACKGROUND: Onychomycosis and dermatomycoses can result in serious complications in patients with underlying chronic diseases such as diabetes. To avoid these complications, these dermatological disorders need to be treated efficiently, for example with the triazole antifungal itraconazole. Itraconazole can inhibit the metabolism of drugs by CYP 3A4 and therefore might affect the efficacy of antidiabetic agents. OBJECTIVE: To investigate this, we assessed the safety of itraconazole in diabetic patients with onychomycosis or dermatomycoses. METHODS: We reviewed pharmacokinetic and safety data from clinical trials and postmarketing surveillance over the past 10 years. RESULTS: Postmarketing surveillance (a review of all adverse-event reports in patients receiving itraconazole concomitantly with insulin or an oral antidiabetic agent) revealed 15 reports suggestive of hyperglycemia and 9 reports suggestive of hypoglycemia; in most patients, no change in antidiabetic effect was reported. From clinical trials including a total of 189 diabetic patients treated with itraconazole for various infections (mainly systemic infections and vaginal candidiasis), only one itraconazole-related adverse event was recorded; this was a case of aggravated diabetes in a renal transplant recipient who was also receiving cyclosporine. Adverse effects due to drug-drug interactions are not expected in diabetic patients receiving oral antidiabetic agents that are not metabolized through the CYP 3A4 system (e.g. tolbutamide, gliclazide, glibenclamide, glipizide and metformin). CONCLUSION: Itraconazole can be used safely and efficiently for the treatment of dermatological disorders in diabetic patients.

The use of itraconazole to treat cutaneous fungal infections in children.

BACKGROUND: Cutaneous mycoses such as tinea capitis, onychomycosis and some cases of tinea corporis/cruris, and tinea pedis/manus require oral antifungal therapy. There is relatively limited data regarding the use of the newer oral antifungal agents, e.g. itraconazole, in the treatment of these mycoses in children. OBJECTIVE: We wished to determine the efficacy and safety of itraconazole continuous therapy in the management of cutaneous fungal infections in children. METHODS: Children with cutaneous mycoses were treated with itraconazole in an open-label manner in 4 studies. For tinea capitis, the treatment regimens using itraconazole continuous therapy were: study 1, 3 mg/kg/day for 4 or 8 weeks; study 2, 5 mg/kg/day for 6 weeks, and study 3, 5 mg/kg/ day for 4 weeks. In a different trial, study 4, itraconazole continuous therapy 5 mg/kg/day was used to treat toenail onychomycosis (duration: 12 weeks), tinea corporis/ cruris (duration: 1 week) and tinea pedis/manus (duration: 2 weeks). RESULTS: The efficacy rates at follow-up 12 weeks from the start of therapy in children with tinea capitis treated using the itraconazole continuous regimen were: clinical cure (CC) and mycological cure (MC) in study 1 (n = 10, Trichophyton violaceum all patients), CC 50%, MC 86%; in study 2 (n = 35, Microsporum canis 22 patients, Trichophyton sp. 12 patients), CC 82.8%, MC 80%, and in study 3 (n = 16, M. canis 11 patients, Trichophyton sp. 5 patients), (CC 66.7%, MC 78.5%. Itraconazole was also effective in the treatment of dermatomycoses in 24 children (study 4). The CC and MC rates at the follow-up 8 weeks from the start of therapy in children with dermatomycoses and 12 months in children treated for onychomycosis were: onychomycosis (n = 1, T. rubrum), CC 100%, MC 100%; tinea corporis (n = 12, M. canis 10 patients), CC 100%, MC 90%; tinea cruris (n = 3, Trichophyton sp. 2 patients), CC 100%, MC 100%; tinea manus (n = 1, T. rubrum), CC 100%, MC 100%, and tinea pedis (n = 7, T. rubrum), CC 100%, MC 100%). Adverse effects consisted of a cutaneous eruption in 1 (1.2%) of the 85 children, with mild, transient, asymptomatic elevation of liver function tests (less than twice the upper limit of normal) in 2 (3.4%) of 58 children in whom monitoring was performed. CONCLUSIONS: Itraconazole is effective and safe in the treatment of tinea capitis and other cutaneous fungal infections in children.

High prevalence of foot diseases in Europe: results of the Achilles Project.

OBJECTIVE: To provide an insight into the prevalence of foot disease in Europe, and to include an assessment of the prevalence of predisposing factors and their correlation with foot disease. DESIGN: Large population-based survey conducted in 16 European countries. SETTING: The project consisted of two parts (study I and study II), in which all patients presenting to general practitioners and dermatologists over a defined time period were invited to participate. Patients. In study I, 70,497 patients presenting to dermatologists or general practitioners were recruited, and in study II 19,588 patients presenting to dermatologists were recruited. MAIN OUTCOME MEASURE: The feet of all participants were examined for signs of foot disease. The assessors also recorded relevant details such as the age and sex of patients, and the presence of predisposing factors for foot disease. In addition, patients in study II were offered a free mycological examination of the toenails and skin on the feet. RESULTS: In study I, 57.0% of patients had at least one foot disease. In study II, 61.3% had at least one foot disease. The proportions of patients with fungal foot disease and non-fungal foot disease in study I were 34.9% and 38.4%, respectively, and in study II were 40.6% and 41.7%, respectively. Orthopedic conditions and metatarsal corns were the most frequently reported non-fungal foot diseases, and onychomycosis and tinea pedis were the most frequently observed fungal infections. CONCLUSIONS: This large-scale survey suggests that the prevalence of fungal and non-fungal foot disease is higher than previously estimated.