Croatian guidelines for the pharmacotherapy of type 2 diabetes

INTRODUCTION: The Croatian Association for Diabetes and Metabolic Disorders of the Croatian Medical Association has issued in 2011 the first national guidelines for the nutrition, education, self-control, and pharmacotherapy of diabetes type 2. According to the increased number of available medicines and new evidence related to the effectiveness and safety of medicines already involved in the therapy there was a need for update of the existing guidelines for the pharmacotherapy of type 2 diabetes in the Republic of Croatia. PARTICIPANTS: as co-authors of the Guidelines there are listed all members of the Croatian Association for Diabetes and Metabolic Diseases, as well as other representatives of professional societies within the Croatian Medical Association, who have contributed with comments and suggestions to the development of the Guidelines. EVIDENCE: These guidelines are evidence-based, according to the GRADE system (eng. Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendations. CONCLUSIONS: An individual patient approach based on physiological principles in blood glucose control is essential for diabetes' patients management. Glycemic targets and selection of the pharmacological agents should be tailored to the patient, taking into account the age, duration of disease, life expectancy, risk of hypoglyce- mia, comorbidities, developed vascular and other complications as well as other factors. Because of all this, is of national interest to have a practical, rational and applicable guidelines for the pharmacotherapy of type 2 diabetes.

Effect of flavonoids and hyperthermal intraperitoneal chemotherapy on tumour growth and micronucleus induction in mouse tumour model.

Hyperthermia enhanced the clastogenicity of alkylating agents. We investigated whether quercetin (QU; 3,3',4',5,7-pentahydroxy flavone) or naringenin (NAR) can sensitize Ehrlich ascites tumour (EAT) to cisplatin (CP) hyperthermal intraperitoneal chemotherapy treatment and whether these flavonoids in combination with CP can ameliorate CP-induced micronuclei (MNs) in peripheral blood reticulocytes of mice. QU or NAR were administered to mice 7 and 3 days before implantation of EAT cells, while CP (5 or 10 mg kg-1) was injected intraperitoneally to normothermic or hyperthermic-treated mice 3 days after implantation of EAT cells (2 106). Our study supports the claim that the QU or NAR in combined treatment with CP has the potential to inhibit tumour growth in both normothermic and hyperthermic conditions and attenuate number of MNs in the peripheral blood reticulocytes of mice at normothermic condition but enhanced the clastogenicity of CP agents in hyperthermal condition.

Effect of two starting insulin regimens in patients with type II diabetes not controlled on a combination of oral antihyperglycemic medications.

In an open-label, 24-week, parallel-group study, 135 patients inadequately controlled with oral antihyperglycemic medications (OAMs) were treated with maximally tolerated doses of metformin and glibenclamide for at least 8 weeks and then randomized to bedtime neutral protamine Hagedorn (NPH) insulin plus maximally tolerated dose of glibenclamide BID (glib/NPH group) or insulin lispro mix 50 (50% lispro, 50% insulin lispro protamine suspension [ILPS]) pre-breakfast and lispro mix 25 (25% lispro, 75% ILPS) pre-dinner (LM50/LM25 group) (both OAMs discontinued). The LM50/LM25 group had significantly lower 2-hour postprandial BG (both meals combined) compared with glib/NPH after 12 (11.70+/-3.40 mmol/L vs. 13.15+/-2.44 mmol/L, p=0.010) and 24 weeks (11.13+/-3.31 mmol/L vs. 14.46+/-2.93 mmol/L, p =0.0001). Both regimens significantly decreased HbA1c. The reduction was greater with LM50/LM25 (-1.31+/-2% vs. -0.5+/-1.6%; P=0.01). At endpoint, the overall hypoglycemia rate increased with LM50/LM25 and decreased with glib/NPH compared with baseline (0.22+/-0.9 vs. -0.08+/-0.72 episodes/patient/30 days; p =0.037). Treatment with LM50/LM25 compared with glib/NPH in patients with inadequate control on combined OAMs yielded better postprandial and overall glycemic control with a higher rate of hypoglycemia.

Elevated level of methylglyoxal during diabetic ketoacidosis and its recovery phase.

Carbonyl stress is hypothesized to be an associated complication of diabetic ketoacidosis. The production of the glycolytic intermediate methylglyoxal (MG) was followed up in 7 diabetic patients treated for ketoacidosis during pretreatment and recovery phase. Blood samples for methylglyoxal analysis were collected upon patient arrival in emergency department (0 h), and during ketoacidosis treatment between 12-24 h and at 168 h. The study also included 10 normoglycaemic healthy volunteers and 31 type 1 diabetic patients (control diabetes group). The methylglyoxal assay, based on methylglyoxal derivation with 1,2-diamino-4,5-dimethoxybenzene (DDB), was performed by HPLC, only assessing the level of free methylglyoxal. The baseline level of methylglyoxal recorded in normoglycemic healthy controls was 338 +/- 62 nmol/l versus 374 +/- 89 nmol/l in control diabetes group (P = 0.0407). A consistent feature of diabetic ketoacidosis before and during treatment was striking elevation of methylglyoxal as compared with control diabetes group (median test chi(2) = 14.6, df = 3, P = 0.0021). Friedman's ANOVA indicated differences (P = 0.04) among the three sampling times with a peak value (601 +/- 95 nmol/l) at 12-24 h following therapy initiation. However, fasting treatment values at 168 h were still significantly higher than the mean fasting methylglyoxal level in control diabetes group (P = 0.008). The study indicated that diabetic ketoacidosis results in an increase in methylglyoxal level. Excessive production of toxic intermediates such are alpha-dicarbonyls may be a link connecting an acute metabolic event with accelerated tissue damage, a feature characteristic of long-term complications of diabetes.

Predictors of house-dust-mite allergen concentrations in dry regions in Australia.

BACKGROUND: House-dust-mite allergen content differs between houses and is thought to be a function of the housing characteristics and furnishing choices that affect indoor microclimate and mite proliferation. The importance of these features may differ with regional climates. METHODS: Concentrations of mite allergen were analysed as a function of housing features. Information on housing features was collected by questionnaire in 50 houses in two towns in a dry inland region of Australia. Mite allergen (Der p 1) was measured by ELISA in dust samples collected on five occasions over 2 years from beds and floors. RESULTS: Der p 1 was detected in all houses. Many housing features did not influence mite allergen concentrations. However, the presence of evaporative cooling increased mite allergen by 3.34-fold in beds (P=0.007) and 3.94-fold in floors (P=0.003). Mite allergen was threefold higher in mattresses >5 years old, and synthetic and feather duvets tended to have higher and lower levels of mite allergen, respectively. CONCLUSIONS: In houses in dry, inland regions of Australia, evaporative cooling and older mattresses are associated with higher concentrations of mite allergen. Alternative forms of air conditioning to evaporative cooling may be useful for control of mite allergen in dry regions.

Relationship between autonomic function, 24-h blood pressure, and albuminuria in normotensive, normoalbuminuric patients with Type 1 diabetes.

We performed a battery of cardiovascular reflex tests, 24-h ambulatory blood pressure (AMBP) and 24-h urinary albumin excretion (UAE) in 116 normoalbuminuric and normotensive patients with Type 1 diabetes. Tests of heart rate variation (HRV) included the coefficient of variation (CV) and the low-frequency (LF), mid-frequency (MF), and high-frequency (HF) bands of spectral analysis at rest, HRV during deep breathing (CV, mean circular resultant--MCR), Valsalva ratio, and maximum/minimum 30:15 ratio. Autonomic neuropathy, characterized as an abnormality of more than two tests, was found in 33 patients. Patients with neuropathy compared to those without neuropathy showed significantly higher mean day and night diastolic blood pressure (dBP), mean systolic night blood pressure (sBP), and mean day and night heart rate (HR). Mean night dBP was inversely related to MF, HF, and HRV during deep breathing; mean day dBP and mean night sBP to HF; mean night HR to CV at rest, MF, HF, HRV during deep breathing, 30:15 ratio; mean day HR to HF, HRV during deep breathing, Valsalva, and 30:15 ratio. Mean 24-h UAE was not significantly different in neuropathic than in nonneuropathic patients. UAE was inversely related to CV at rest and HF. In the stepwise multiple regression analysis, reduced MF, HF, HRV during deep breathing, and high levels of UAE and HbA1c were associated with high night dBP. Autonomic neuropathy is already present in normotensive Type 1 diabetic patients at the normoalbuminuric stage and related to BP and albuminuria.

Clinical importance of Alternaria exposure in children.

The fungus Alternaria is known to be allergenic and is one of the most common fungi worldwide. We investigated the extent to which exposure to Alternaria increases the severity of asthma. We undertook a prospective cohort study in Australia of 399 school children who had positive skin tests to one or more aeroallergens. Airway responsiveness to histamine, wheeze, and bronchodilator use in 1 mo was measured five times between 1997 and 1999. Airway hyperresponsiveness was defined as PD(20)FEV(1) = 3.9 micromol histamine. Airborne concentrations of Alternaria spores were measured throughout the study, and mean daily concentrations over 1 mo ranged from 2.2 to 307.7 spores/m(3) of ambient air. Using generalized estimating equations, we found that airway responsiveness, wheeze, and bronchodilator use increased significantly in association with increased spore concentrations and that the increase in airway responsiveness was greater in children sensitized to Alternaria than in other children (p = 0.01). The odds ratio for airway hyperresponsiveness in children sensitized to Alternaria was 1.26 (95% CI, 1.14 to 1.39) after an increase in mean exposure of 100 spore/m(3)/d over 1 mo. These results suggest that Alternaria allergens contribute to severe asthma in regions where exposure to the fungus is high.

Having lived on a farm and protection against allergic diseases in Australia.

BACKGROUND: Farmers' children in northern Europe have a lower prevalence of atopy, hay fever and asthma than other children. Farms in Australia differ in scale and operation from those in Europe and the prevalence of allergic diseases in children is higher. OBJECTIVE: To investigate whether having lived on a farm as a child in Australia is associated with a lower risk of allergic diseases. METHODS: Cross-sectional study of children (n = 1500) aged 7-12 years from two rural towns: Wagga Wagga in a mixed farming region, and Moree in a crop farming region. Parents answered a questionnaire and children had a skin prick test for atopy. RESULTS: Twenty percent of children had lived on a farm for at least 1 year. The effect of having lived on a farm differed between the towns (P < 0.001). It was associated with a lower risk of atopy in Wagga (adjusted odds ratio (aOR) 0.47, 95% confidence interval (CI) 0.32-0.72) but not in Moree (aOR 0.97, 95% CI 0.62-1.53). Children from Wagga were more likely to have lived on a livestock farm than children from Moree (26.1% vs. 9.1%, 95% CI for the difference 8.9-25.4). CONCLUSION: Having lived on a farm in Australia can confer protection against atopy in children. Further studies are needed to identify possible protective mechanisms associated with farm animals or to establish whether the protective effect is explained by other related exposures.

Thunderstorm outflows preceding epidemics of asthma during spring and summer.

BACKGROUND: A study was undertaken to assess the importance of thunderstorms as a cause of epidemics of asthma exacerbations and to investigate the underlying mechanism. METHODS: A case control study was performed in six towns in south eastern Australia. Epidemic case days (n = 48) and a random sample of control days (n = 191) were identified by reference to the difference between the observed and expected number of emergency department attendances for asthma. The occurrence of thunderstorms, their associated outflows and cold fronts were ascertained, blind to case status, for each of these days. In addition, the relation of hourly pollen counts to automatic weather station data was examined in detail for the period around one severe epidemic of asthma exacerbations. The main outcome measure was the number of epidemics of asthma exacerbations. RESULTS: Thunderstorm outflows were detected on 33% of epidemic days and only 3% of control days (odds ratio 15.0, 95% confidence interval 6.0 to 37.6). The association was strongest in late spring and summer. Detailed examination of one severe epidemic showed that its onset coincided with the arrival of the thunderstorm outflow and a 4-12 fold increase in the ambient concentration of grass pollen grains. CONCLUSIONS: These findings are consistent with the hypothesis that some epidemics of exacerbations of asthma are caused by high concentrations of allergenic particles produced by an outflow of colder air, associated with the downdraught from a thunderstorm, sweeping up pollen grains and particles and then concentrating them in a shallow band of air at ground level. This is a common cause of exacerbations of asthma during the pollen season.

Continued increase in the prevalence of asthma and atopy.

AIMS: To describe the change in the prevalence of wheeze, diagnosed asthma, and atopy in Wagga Wagga, NSW, Australia, between 1992 and 1997, and to compare this to the increase in prevalence reported between 1982 and 1992. METHODS: A cross sectional study of the prevalence of respiratory symptoms and atopy in schoolchildren aged 8-11 years (n = 1016, response rate 71%) in 1997 compared with studies of similar design in 1992 (response rate 83%, n = 850) and 1982 (response rate 88%, n = 769). Main outcome measures were respiratory symptoms measured by parent completed questionnaire and atopy measured by skin prick tests. RESULTS: Between 1992 and 1997, the prevalence of wheeze increased by 5.1% (95% CI 1.2 to 9.0), asthma diagnosis by 8.1% (95% CI 3.8 to 12.4), and atopy by 6.7% (95% CI 2.2 to 11.2). Similar increases in prevalence had been found between 1982 and 1992. CONCLUSIONS: The prevalence of wheeze, asthma diagnosis, and atopy in Wagga Wagga has continued to increase.

[The diabetic foot. The Croatian model--national consensus (clinical recommendations for diagnosis, prevention and therapy)]. / Dijabeticko stopalo. Hrvatski model--nacionalno usuglaseno misljenje (klinicke preporuke za dijagnostiku, prevenciju i lijecenje).

Diabetic foot occurs due to the loss of protective sense and circulation disorder and a marked proneness to infections. Mechanical stress of bone growths frequently leads to ulcerations. The prevention and timely treatment of diabetic foot requires the participation of both patients and all health care levels. This consensus is given for the purpose of procedure standardization. Education is the basis of prevention and should be carried out with every patient suffering from diabetes mellitus and those with a sensory defect in particular. Appropriate footwear significantly contributes to prevention and treatment of ulcers. As regards the treatment, the necessity of surgical approach with a long term and often manifold antibiotic therapy should be pointed out. Infections are usually mixed. The deeper the ulceration, the more likely the infection with anaerobes and Gram-negative bacteria occurs in addition to Gram-positive ones which are normally present in surface lesions. Strict metabolic control is a precondition for successful treatment. In conclusion, diabetic foot is a major health problem which requires multidisciplinary approach with permanent patient education as its essential part, and a specific cooperation of all levels and different health care specialties.

Reduction of diffusion capacity for carbon monoxide in diabetic patients.

Diabetes can cause the development of pulmonary complications due to collagen and elastin changes, as well as microangiopathy. This study demonstrates the relationship between pulmonary complications and other chronic complications in diabetes. Twenty-seven patients with diabetes, aged 21 to 62 years, who had had the disease from 3 to 32 years, were included in this study. The protein excretion rate (PER) and the diffusion capacity of the lung for carbon monoxide (DLCO) were included as parameters of the severity of complications. PER was determined by the Biuret method. DLCO was measured by the single-breath method and was corrected by the measurement of alveolar volume (VA). The values of DLCO as corrected by VA (DLCO/VA) were included in the statistical evaluation of the results. The variables of age, duration of diabetes, and complication parameters were included in a multiple regression model with forward, stepwise selection to assess their value in predicting DLCO/VA. The variables were found to be significant predictors of DLCO/VA (R2 = 0.46, adjusted R2 = 0.32, p < 0.022). However, proteinuria was the only significant independent predictor of DLCO/VA. This finding indicates that both renal and pulmonary complications of diabetes share a similar microangiopathic background.

Zinc and copper in the serum of diabetic patients.

The Zn/Cu ratio was examined in the serum of three groups of persons: healthy volunteers, diabetic patients on diabetic diet (NIDDM), and diabetic patients on diabetic diet and insulin (IDDM). Zinc, copper, the Zn/Cu serum ratio, and the blood glucose level were determined during fasting and 2 h after breakfast. Zn and Cu serum levels in NIDDM and IDDM patients were decreased. The Zn/Cu ratio was higher in both groups of diabetic patients. These changes in the Zn and Cu levels as well as in the Zn/Cu ratio were not related to chronic diabetic complications.

[The femoral hypoplasia syndrome and unusual facies in an infant of a diabetic mother]. / Sindrom hipoplasticnih femura i neobicnog lica u djeteta majke dijabeticarke.

One-month-old female infant of diabetic mother with the femoral hypoplasia--unusual facies syndrome is presented. At birth the characteristic facial pattern of long philtrum with thin upper lip, micrognathia and cleft palate was present. Both legs showed extreme shortening of the upper segments. X-rays showed numerous skeletal abberations including radioulnar synostosis of the right elbow, dysplastic sacrum and hypoplasia of the femurs, the right one more severe. Radiological findings also revealed abnormal left kidney's collecting system and absence of the right kidney. Possible contributing factors to the pathogenetic mechanism underlying the skeletal defects in infants of diabetic mothers are considered.

Quantification and assessment of viability of Pneumocystis carinii organisms by flow cytometry.

Analysis of drug efficacy in animal models of Pneumocystis carinii pneumonia requires an accurate method of quantification of organisms, as well as a means of assessing viability. Lung homogenates were prepared from a colony of athymic nude F344 rats experiencing a spontaneous outbreak of P. carinii pneumonia. With the fluorescent nucleic acid stain propidium iodide, flow cytometric analysis was able to quantify P. carinii cysts and trophozoites reproducibly. As this stain is excluded by living cells, this method was also used to assess the viability of organisms. Application of this technique to analysis of bronchoalveolar lavage specimens was demonstrated.

Protein turnover in exponential and stationary phase Vibrio cells.

Vibrio strain 14 supports phage alpha 3a growth in standing stationary phase cells but not in shaking (aerated) stationary phase cells. In exponential cells, protein was turned over at 1.8% h-1, and the rate was increased by starvation or inhibition of protein synthesis. In shaking stationary phase cells the rate of protein turnover was low (1.0% h-1) for proteins synthesised during growth but high (20% h-1) for recently synthesised proteins. In contrast recently synthesised proteins in standing stationary phase cells were stable over 60 min and proteins synthesised during growth were turned over at 2.9% h-1. ppGpp and pppGpp were detected in exponential cells, but were not detected in stationary phase cells.

Ascorbic acid prevents the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption.

The effects of maize-bran phytate and of a polyphenol (tannic acid) on iron absorption from a white-bread meal were tested in 199 subjects. The phytate content was varied by adding different concentrations of phytate-free and ordinary maize bran. Iron absorption decreased progressively when maize bran containing increasing amounts of phytate phosphorous (phytate P) (from 10 to 58 mg) was given. The inhibitory effect was overcome by 30 mg ascorbic acid. The inhibitory effects of tannic acid (from 12 to 55 mg) were also dose dependent. Studies suggested that greater than or equal to 50 mg ascorbic acid would be required to overcome the inhibitory effects on iron absorption of any meal containing greater than 100 mg tannic acid. Our findings indicate that it may be possible to predict the bioavailability of iron in a diet if due account is taken of the relative content in the diet of the major promoters and inhibitors of iron absorption.

The effects of piretanide in patients with congestive heart failure and diabetes mellitus: a double-blind comparison with furosemide.

A double-blind parallel group study was carried out to compare the effects of piretanide on daily glucose profiles, symptoms of congestive heart failure and serum electrolytes with those of furosemide in 24 diabetic in-patients suffering from congestive heart failure. After a 3-day run-in period on placebo, patients were allocated at random to receive 10-days' treatment with either 6 mg piretanide or 40 mg furosemide once daily. The results showed that there were no differences between the glucose profiles between the first and the last day of treatment, nor were there any differences between the two treatments. Piretanide and furosemide both produced a significant reduction in the number of symptoms of congestive heart failure. There were no significant changes in biochemical variables within the groups, nor were there any differences between the groups, except for an increase in uric acid and decrease in total protein values after furosemide. Mean triglyceride values decreased significantly after piretanide treatment, and SGOT values decreased after both treatments, the latter change being of no clinical relevance. Side-effects were generally mild in both groups and did not require any counter-measures.