Influence of immediate release tablet formulation on dissolution profile of paracetamol

Introduction: Paracetamol is analgesic and antipyretic, which is usually in the form of an immediate release tablet formulations. Therapeutic effects in terms of the speed and intensity of the analgesic effect is dependent on speed of liberation from formulation. Aim: The aim of this work was to determine and compare dissolution profiles of 4 paracetamol immediate release tablet formulations and to determine influence of excipients on kinetic of paracetamol dissolution. Materials and Methods: Dissolution profiles of paracetamol tablets were determined using method with paddles and phosphate buffer pH 6.8 as a medium. Release of paracetamol was followed 60 minutes (using 6 time points). Concentration of paracetamol was measured using UV/Vis spectrophotometric method (243 nm). Dissolution profiles were compared using model-independent method (difference factor and similarity factor), statistic method (ANOVA-based method and pair Student's T-test, p<0.05) and model dependent methods (to determinate the release kinetics of paracetamol). Results: All formulations in the first 45 minutes liberated more than 85 % of the labled content. Formulation D, which contained superdesintegrator, released 90% of the content in the first 5 minutes. Though based on values of difference and similarity factors formulations are, not significantly different, ANOVA-based method showed that formulation A and B, B and C, as well as formulation B and D do statistically differ in all 6 time points, meaning they have parallel profiles. The release of paracetamol from formulations A and D is best described by the first order kinetic model, while the release of formulations B and C by the logistic model. Conclusions: The release kinetic of paracetamol is mostly influenced by the type of superdisintegrants and lubricants. Formulation with superdisintegrant technology OptiZorb® demonstrated fastes release rate and thus it is expected to produce the fastest pharmacodynamic effect.

Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis

Aims/hypothesis: Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or ‘lipokine’) to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans. Methods: Plasma NEFA concentration and composition were determined in non-diabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort at baseline (n = 1234) and after a 3 year follow-up (n = 924). Glucose tolerance, insulin secretion and beta cell function were assessed during an OGTT. Whole-body insulin sensitivity was measured by a hyperinsulinaemic–euglycaemic clamp (M/I) and OGTT (oral glucose insulin sensitivity index [OGIS]). The liver insulin resistance index was calculated using clinical and biochemical data. Body composition including fat mass was determined by bioelectrical impedance. Results: Circulating palmitoleate was proportional to fat mass (r = 0.21, p &lt; 0.0001) and total NEFA levels (r = 0.19, p &lt; 0.0001). It correlated with whole-body insulin sensitivity (M/I: standardised regression coefficient [std. β] = 0.16, p &lt; 0.0001), liver insulin resistance (std. β = −0.14, p &lt; 0.0001), beta cell function (potentiation: std. β = 0.08, p = 0.045) and glucose tolerance (2 h glucose: std. β = −0.24, p &lt; 0.0001) after adjustment for age, sex, BMI, adiposity and other NEFA. High palmitoleate concentrations prevented the decrease in insulin sensitivity associated with excess palmitate (p = 0.0001). In a longitudinal analysis, a positive independent relationship was observed between changes in palmitoleate and insulin sensitivity over time (std. β = 0.07, p = 0.04). Conclusions/interpretation: We demonstrated that plasma palmitoleate is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals. These results support the role of palmitoleate as a beneficial lipokine released by adipose tissue to prevent the negative effects of adiposity and excess NEFA on systemic glucose metabolism

Risk factors for the development of diabetic nephropathy

Introduction. Results of epidemiological analysis show that one third of patients with diabetes mellitus develop diabetic nephropathy (DN). Strategies used until now to slow down the progression of DN were initiated when the symptoms of DN were already present. Objective. Our objective was to analyze the prevalence and characteristics of DN and to determine the factors leading to DN. Methods. Fifty-two patients with diabetes mellitus (DM) - 32 with type 1 aged 32 years and 20 with type 2 aged 59 years - were referred from the Institute of Endocrinology, Diabetes and Metabolic Diseases to the Department of Nephrology for kidney function evaluation. Apart from routine laboratory analyses, glomerular filtration rate was calculated using the MDRD formula (modification of diet in renal disease), the size of the kidney was measured by ultrasound, and kidney volume was calculated using the ellipsoid formula. Results Thirty percent of the patients revealed normal (eight patients with DM type 1) or satisfactory kidney function (eight patients with DM type 1) with physiological proteinuria. Micro-albuminuria (MAU) or pathological proteinuria (PRT) were found in 10 and 9 patients, respectively, with DM type 1, while decreased kidney function was found in one patient without proteinuria. MAU or PRT were found in four and eight patients, respectively, with DM type 2 and decreased kidney function in four patients without proteinuria. Kidney function was significantly lower in patients with DM type 2 in comparison to DM type 1, while the patients with decreased kidney function had a higher PRT. Compared to DM type 2, in DM type 1 patients, the kidney was longer, and parenchymal artery resistance index was lower in DM type 1 patients compared to DM type 2. Factors associated with DN were patient's age, duration of diabetes, systolic blood pressure, HbA1c and kidney volume. Conclusion. The prevalence of DN among the studied patients was 70%. Treatable factors associated with the development of DN are strict control of blood pressure and glycaemia control

Structural myocardial alterations in diabetes and hypertension: the role of galectin-3.

Background: Galectin-3 is a protein widely distributed in the heart, brain and blood vessels, and has a regulatory role in inflammation, immunology and cancer. Many studies demonstrated that the increased level of galectin-3 is associated with progressive fibrosis and stiffening of the myocardium. The aim of this study was to investigate the role of galectin-3 in patients with type 2 diabetes (T2D) and/or arterial hypertension (HT). Methods: Study population included 189 patients, with no coronary artery disease, divided into three groups: group 1 (T2D), group 2 (T2D+HT), and group 3 (HT). All subjects underwent routine laboratory tests, as well as specific biomarkers assessment [galectin-3, glycosylated hemoglobin (HbA1c), N- terminal fragment B-type natriuretic peptide (NT-proBNP)]. Cardiological evaluation included physical examination, transthoracic tissue Doppler echocardiography and stress echocardiography. Results: The results of this study demonstrated significantly increased levels of galectin-3, blood glucose, and HbA1c in group 2. Also, echocardiographicaly, left ventricular (LV) diameters and IVS thickness were increased in this group of patients. Furthermore, in the same cohort a positive correlation between galectin-3 and NT-pro BNP, and galectin-3 and LV mass were demonstrated. In addition, a negative correlation between galectin-3 and LV end-diastolic diameter was revealed. Conclusions: This study revealed that levels of galectin-3 were higher in patients with both T2D and HT, and correlated with LV mass, indicating the potential role of this biomarker for early detection of myocardial structural and functional alteration

Altered Daytime Fluctuation Pattern of Plasminogen Activator Inhibitor 1 in Type 2 Diabetes Patients with Coronary Artery Disease: A Strong Association with Persistently Elevated Plasma Insulin, Increased Insulin Resistance, and Abdominal Obesity

This study was aimed at investigating daily fluctuation of PAI-1 levels in relation to insulin resistance (IR) and daily profile of plasma insulin and glucose levels in 26 type 2 diabetic (T2D) patients with coronary artery disease (CAD) (group A), 10 T2D patients without CAD (group B), 12 nondiabetics with CAD (group C), and 12 healthy controls (group D). The percentage of PAI-1 decrease was lower in group A versus group B (4.4 ± 2.7 versus 35.0 ± 5.4%; P<0.05) and in C versus D (14.0 ± 5.8 versus 44.7 ± 3.1%; P<0.001). HOMA-IR was higher in group A versus group B (P<0.05) and in C versus D (P<0.01). Simultaneously, AUCs of PAI-1 and insulin were higher in group A versus group B (P<0.05) and in C versus D (P<0.01), while AUC of glucose did not differ between groups. In multiple regression analysis waist-to-hip ratio and AUC of insulin were independent determinants of decrease in PAI-1. The altered diurnal fluctuation of PAI-1, especially in T2D with CAD, might be strongly influenced by a prolonged exposure to hyperinsulinemia in the settings of increased IR and abdominal obesity, facilitating altogether an accelerated atherosclerosis

Asymptomatic cardiovascular manifestations in diabetes mellitus: Left ventricular diastolic dysfunction and silent myocardial ischemia

Introduction. Several cardiovascular manifestations in patients with diabetes may be asymptomatic. Left ventricular diastolic dysfunction (LVDD) is considered to be the earliest metabolic myocardial lesion in these patients, and can be diagnosed with tissue Doppler echocardiography. Silent myocardial ischemia (SMI) is a characteristic and frequently described form of ischemic heart disease in patients with diabetes. Objective. The aim of the study was to assess the prevalence of LVDD and SMI in patients with type 2 diabetes, as well as to compare demographic, clinical, and metabolic data among defined groups (patients with LVDD, patients with SMI and patients with type 2 diabetes, without LVDD and SMI). Methods. We investigated 104 type 2 diabetic patients (mean age 55.4±9.1 years, 64.4% males) with normal blood pressure, prehypertension and arterial hypertension stage I. Study design included basic laboratory assessment and cardiological workup (transthoracic echocardiography and tissue Doppler, as well as the exercise stress echocardiography). Results. LVDD was diagnosed in twelve patients (11.5%), while SMI was revealed in six patients (5.8%). Less patients with LVDD were using metformin, in comparison to other two groups (χ2 =12.152; p=0.002). Values of HDL cholesterol (F=4.515; p=0.013) and apolipoprotein A1 (F=5.128; p= 0.008) were significantly higher in patients with LVDD. Conclusion. The study confirmed asymptomatic cardiovascular complications in 17.3% patients with type 2 diabetes

Ischemic stroke in patients with type 2 diabetes: Relationship between decreased insulin sensitivity and fibrinolysis impairment

The role of insulin sensitivity (IS), as well as the association of IS with fibrinolysis impairment, in the occurrence of ischemic stroke, has not been clarified. The study was aimed to analyze IS, plasma insulin (PI) and plasminogen activator inhibitor (PAI)-1 levels in 34 type 2 diabetics (T2D) with ischemic stroke (group A), 30 T2D without ischemic stroke (group B), 33 nondiabetics with ischemic stroke (group C) and 33 healthy controls (group D). Ischemic stroke was confirmed by clinical and neuroimaging criteria. IS levels were determined by the minimal model analysis (Si index). Plasma insulin levels were measured by radioimmunoassay and PAI-1 activity was performed by the plasminogen chromogenic plasmin substrate assay. We found that Silevels were significantly lower in group A vs. B (1.17+/-0.66 vs. 2.79+/-0.62 min-1/mU/Lx104; p<0.001) and in C vs. D (3.25+/-0.84 vs. 6.03+/-1.69 min-1/mU/Lx104; p<0.001), while PI levels were higher in group A vs. B (19.46+/-4.11 vs. 14.79+/-1.75 mU/L; p<0.001) and in C vs. D (15.16+/-2.23 vs. 7.54+/-2.03 mU/L; p <0.001). Also, PAI-1 activity was significantly higher in group A vs. B (7.78+/-1.05 i 4.56+/-0.71 mU/L; p<0.001) and in C vs D (4.65+/-0.69 i 3.48+/-1.29 mU/L; p<0.001). Moreover, Silevels correlated with PAI-1, both in T2D and nondiabetics. Our results indicate that appearance of ischemic stroke was associated with decreased insulin sensitivity, together with compensatory hyperinsulinemia, both in T2D and nondiabetics. Our results imply that impaired insulin sensitivity exerts its atherogenic influence, at least in part, by decreased fibrinolysis

Morphometric study of uninvolved rectal mucosa 10 cm and 20 cm away from the malignant tumor

Recently, many details of the interplay between tumor cells and tumor-associated stromal elements leading to the progression of malignant disease were elucidated. In contrast, little is known about the role of uninvolved stromal tissue in the remote surrounding of the malignant tumor. Therefore, we performed a computer-aided morphometric study of rectal mucosa in samples taken 10 cm and 20 cm away from the malignant tumor during endoscopic examination of 23 patients older than 60 years. The samples of rectal mucosa from 10 healthy persons of corresponding age subjected to diagnostic rectoscopy during active screening for asymptomatic cancer were used as control. All structural elements of the rectal mucosa were studied and the number of nucleated cells in the lamina propria per 0.1 mm2 of tissue was assessed. Our study revealed a reduced number of cells in the lamina propria of the rectal mucosa 10 cm and 20 cm away from the tumor lesion in both male and female patients. The decreased mucosal height and increased crypt number were registered in female patients 10 cm away from the tumor. The connective tissue of lamina propria showed a disorderly organization: the collagen fibers were frail, loosely arranged and signs of tissue edema were present. Small blood vessels and capillaries were much more frequently seen than in healthy tissue. Our results demonstrate the complex interactions between the cancer and remote mucosal tissue of the affected organ

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D