Telmisartan and irbesartan therapy in type 2 diabetic patients treated with rosiglitazone: effects on insulin-resistance, leptin and tumor necrosis factor-alpha.

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.     

In vivo measurements of fibrin formation and degradation in nephrotic patients

Summary Intraglomerular fibrin deposition has been implicated as an important pathogenetic mechanism in patients with glomerular diseases and the nephrotic syndrome. To investigate fibrin formation and degradation in nephrosis, we measured fibrinopeptide A by radio-immunoassay and D-dimer by enzyme-linked immunosorbent assay in the plasma of 30 consecutive adult patients with the nephrotic syndrome; in 10 the serum creatinine was more than 2 mg/dl. Both fibrinopeptide A and D-dimer were abnormally elevated in the majority of nephrotics (P<0.001 vs. healthy controls), providing evidence of increased fibrin generation and lysis “in vivo.” A positive correlation was found between fibrinopeptide A and D-dimer (correlation coefficient 0.64,P<0.001), suggesting a close relationship between fibrin formation and degradation. Calcium heparin, administered to 12 nephrotics, caused a marked decrease in plasma fibrinopeptide A, due to a reduction of in vivo thrombin activity. As enhanced thrombin activity can favor fibrin deposition within the renal parenchyma, as well as vascular complications, it is reasonable to assume that an antithrombotic treatment aimed at controlling thrombin generation may ameliorate the natural history of nephrosis.     

Caries experience in Icelandic 12-year-old urban children between 1984 and 1991

Abstract – In order to evaluate trends in caries experience, a 20% random sample of 12-yr-old residents of Reykjavik, Iceland (252 children) was examined clinically and radiographically in 1991 under conditions consistent with those of the survey conducted in 1984. In addition to caries data, frequency of toothbrushing and use of fluoride dentifrice were recorded. The mean DFT and DPS were 3.0 and 4.1, respectively. The decrease in caries experience reached 60% with an annual fall in DPS of nearly 10%. During the 7-yr period between examinations the decline in DFT and DFS scores averaged 5.2 and 8, respectively, the annual reduction amounting to 0.7 DF teeth or 1.1 DF surfaces per child. The ratio of approximal/occlusal caries and the proportion of approximal caries were similar in both surveys. Fourteen percent of the children were free from manifest caries in 1991, but only 2% in 1984. Polarization between low and high prevalence individuals had intensified. Ninety-five percent of the children brushed their teeth regularly and 97% reported using a fluoride dentifrice.     

Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension.

There are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase (MMP) system and their inhibitors (TIMPs) in human hypertension. The authors hypothesized that MMP-2, MMP-9, and TIMP-1 would be abnormal in hypertension, reflecting alterations in extracellular matrix (ECM) turnover. The authors measured plasma levels and activities of MMP-2, MMP-9, and TIMP-1 in 44 hypertensive patients and 44 controls. MMP-2 levels and activity were significantly higher in hypertensive group (p < .0001). Significant increase was also observed for MMP-9 level and activity (p < .0001) and for TIMP-1 (p < .0001) in hypertensive patients. Plasma levels and activities of MMP-2, MMP-9, and TIMP-1 are increased in hypertensive patients, which may reflect abnormal ECM metabolism.     

Primary headaches in patients with temporomandibular disorders: Diagnosis and treatment of central sensitization pain

Objectives: Central sensitization (CS) has been found in patients with temporomandibular disorders (TMD), craniofacial pain (CP) and primary headaches, but its clinical implications remain uncertain. The first aim was to provide a synthesis of the current state of knowledge about the link between CS and TMD associated with primary headaches; the second goal was to find methodologies to assess and treat CS in this subgroup of patients.

Methods: A narrative review of the literature was conducted.

Results: CS is described in literature as an aggravating factor in patients with TMD-related primary headaches. Further studies are required to support this assertion.

Conclusions: The importance of excluding chronic neuropathic pain and recognizing CS as the main component using a top-down approach to target the best pharmacological and non-pharmacological treatments is evident. Some useful tools to discriminate patients with CS from others have become available, but more research is required to enable an appropriate diagnosis.     

α1-Adrenergic receptor antagonists and gynecomastia. A case series from the Italian spontaneous reporting system and VigiBase™

Purpose

The aim of this study was to analyze the cases of gynecomastia associated with α_1A-adrenergic receptor antagonists (α₁-ARAs) in the Italian spontaneous reporting system database (Rete Nazionale di Farmacovigilanza or RNF) and in the World Health Organization ICSRs database (VigiBase^?), focusing on tamsulosin use.

Methods

We analyzed the spontaneous reports of gynecomastia related to the use of α₁-ARAs and collected from the RNF and from VigiBase^? up to December 2012. Cases of gynecomastia have been defined as reports associated with gynecomastia according with Medical Dictionary for Regulatory Activities (MedDRA). Reporting odds ratio (ROR) and Information Component (IC) were calculated as measures of disproportionality in RNF and VigiBase^?, respectively.

Results

Up to December 2012, about 186,000 reports were recorded in the RNF. Among these, 902 reports of adverse drug reaction (ADR) have been associated with the use of at least one α₁-ARAs. Of these, in 15 cases, gynecomastia was a listed ADR: in 10, the suspected drug was tamsulosin (in eight, it was the sole suspect); in two, doxazosin and alfuzosin, respectively; and in one, terazosin. ROR for tamsulosin was 5.3 (95 % CI 1.8, 15.7). In VigiBase^?, 84 reports of gynecomastia indicated tamsulosin as suspected drug. Tamsulosin-associated gynecomastia showed the highest IC value within this class of drugs (IC 95 % 2.43).

Conclusion

In this study, we highlight a possible association between gynecomastia and tamsulosin use. To our knowledge, this association has not been described before and could represent a potential signal.     

Effect of tryptophan on the early tri-iodothyronine uptake in mouse thymocytes

OBJECTIVE: We have studied the effect of tryptophan on cellular [(125)I]tri-iodothyronine (T3) uptake by mouse thymocytes. MATERIALS AND METHODS: Mouse thymocytes (20 x 10(6 )cells/ml) were suspended in Krebs-Ringer solution buffered by Tris-HCl and incubation (23 degrees C at pH7.45+/-0.6), in the presence or absence of 1mM tryptophan, was started by adding 25 pM [(125)I]T3. At the end of incubation, samples were cooled in ice, centrifuged over a 30% sucrose cushion and the cell-associated radioactivity was measured in the pellet. RESULTS: Tryptophan reduced both the total and the saturable fraction of [(125)I]T3 uptake by 44% (P=0.0009) and 60% (P=0.0006) respectively, following 1 min of incubation. This effect was specific and dose-dependent, being maximal at 5mM concentration (-82%). In contrast, the pre-exposure of cells to tryptophan for up to 2h had no effect on the subsequent uptake of [(125)I]T3, in the absence of tryptophan. The effect of D-tryptophan on saturable T3 uptake was not different from that obtained using the L-stereoisomer. Tryptophan reduced the V(max) of the initial rate of saturable [(125)I]T3 uptake by two-thirds without affecting the apparent K(m) (2.2 nM) of the process, thus indicating the non-competitive nature of the inhibition. In sodium-free medium the saturable [(125)I]T3 uptake was reduced by 43%. The inhibitory effect of tryptophan on [(125)I]T3 uptake was exerted in both the presence and the absence of sodium. In fact, the inhibitory effect of tryptophan on T3 transport was greater and significantly different (P=0.0046) from that obtained by sodium depletion alone. CONCLUSIONS: Tryptophan interferes with both the sodium-dependent and -independent components of [(125)I]T3 uptake by a dose-dependent, non-competitive mechanism which operates in cis-modality at the plasma membrane level of mouse thymocytes.     

DNA single- and double-strand breaks produced by ferric nitrilotriacetate in relation to renal tubular carcinogenesis

Fe(III) bound to a chelator, nitrilotriacetate (NTA), has beenreported to induce a high frequency of adenocarcinoma localizedto the proximal tubules of the kidney in rodents. In order toexamine possible mechanisms for the carcinogenic activity, weinvestigated the in vitro production of single- and double-strandbreaks in DNA mediated by iron alone or Fe-NTA chelate usingsupercoiled plasmid pZ189. Neither Fe(III) nor NTA alone brokeDNA. Fe(III) plus NTA together mediated the efficient oxidativeproduction of DNA single-and double-strand breaks in the presenceof reducing agents (ascorbate » H₂O₂ > cysteine). TheFe(III): NTA ratio (1:4) that was found to be optimal for DNAstrand breakage was similar to the ratio that produced adenocarcinomasin rodents. Maximal Fe-NTA-mediated DNA damage in vitro wasinduced under conditions of neutral pH, low ionic strength,presence of reducing agent and absence of albumin. These conditionsare present exclusively in the cortical proximal tubules ofthe kidney, the only location where toxicity and carcinogenicityof Fe-NTA has been observed. Thus, localized DNA damage mayexplain the anatomic site preferred by Fe-NTA-induced carcinogenesis.     

Comprehensive study of haemostasis in nephrotic syndrome

A comprehensive study of haemostasis has been performed in a homogeneous group of 20 patients with nephrotic syndrome without renal failure. We have found unchanged number of platelets and a significant increase of platelet adhesiveness and aggregation; increased levels of activity and related antigen of fibrinogen, of factor VIII, of activity of factors II, VII and X and of antigens of factors XIII. Antithrombin III was unchanged in plasma and was detected in the urine. Euglobulin lysis times were decreased, and levels of plasminogen and its activators were increased after a venous occlusion test. At the same time urokinase inhibitors and antiplasmins were increased not only after, but also before a venous occlusion test. Fibrinogen degradation products have been found in the urine of all our patients but not in their sera.     

Method for improving accuracy of virus titration: standardization of plaque assay for Junin virus.

Titrating infective virus is one of the most important and common techniques in virology. However, after many years of widespread use, the parameters governing the accuracy of titration values are still not well understood. It was found that under conditions currently used for virus titration, only a small percentage of virus in the inoculum is adsorbed onto the cells and thereby detected in the titration assay. The objective of our work was to establish the conditions for a plaque assay which could estimate more accurately the titer of Junin virus. Two different stain methods were compared and several parameters governing plaque formation were studied. The volume of the inoculum appeared as the most important factor affecting observed titer. A linear relationship between the volume of inoculum and the reciprocal apparent titer allowed us to estimate an absolute titer by extrapolation. The approach described here is likely to be applicable to the more accurate estimation of the titer of a wide range of virus.