Katalin Biro

Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models.

Abstract: Bimoclomol (BML), a symptomatic antidiabetic agent, has been developed by Biorex R & D Co. to treat diabetic neuropathy and retinopathy. BRX‐220, an orally active member of the BRX family, has been developed to treat diabetic complications and insulin resistance (IR) as a follow‐up compound. The effect of BRX‐220 on peripheral neuropathy was examined in rats with diabetes (type 1) induced by administration of a β‐cell toxin, streptozotocin (STZ, 45 mg/kg iv). Nerve functions were evaluated by electrophysiological measurements of muscle motor and sensory nerve conduction velocities (MNCV and SNCV, respectively). MNCV and SNCV decreased in diabetic rats by 25% (p < 0.001). A 1‐month preventive treatment with BRX‐220 (2.5, 5, 10, and 20 mg/kg po) dose‐dependently improved diabetes‐related deficits in MNCV (51.3%, 71.3%, 86.1%, and 91.3%) and SNCV (48.9%, 68.5%, 86.1%, and 93.2%). Insulin sensitivity was measured using the insulin tolerance test (ITT), both in STZ diabetic and in Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). Severe IR was detected in STZ diabetic and ZDF rats. This resistance was significantly (p < 0.05) reduced by BRX‐220 treatment.

Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats

A silent process involving both neural and vascular structures in diabetic retina persists for several years before clinically detectable retinopathy. Recordings of the electroretinogram (ERG) and visual evoked potential (VEP) provide early warning of abnormalities in the visual pathway of diabetic patients and animal models. Treatment of streptozotocin-diabetic rats for 1 or 2 months with the heat-shock protein coinducer bimoclomol, a drug ameliorating experimental neuropathy, prevented and corrected the abnormal increase in latency and reduction of amplitude of ERG and VEP waves both in acute and chronic experiments. Improvements may be explained by cytoprotective effect of bimoclomol on retinal glia and/or neurons against diabetes-related ischemic cell damages. These findings suggest that bimoclomol may have future therapeutic use in diabetic retinopathy.

The relationship between hemorheological parameters and mortality in critically ill patients with and without sepsis

PURPOSE The prognostic scoring systems for mortality of intensive care patients estimate clinical outcome using several physiological and biochemical parameters. In altered hemodynamic conditions of critically ill patients, hemorheological variables may play a significant role in appropriate tissue perfusion. We investigated if hemorheological parameters are altered in critical status and if they could be markers of mortality. METHODS 112 patients (67.8 ± 12 years, 58 males, 54 females) treated in intensive care unit with different non-surgical diseases were investigated. Routine laboratory parameters and prognostic scores were determined and hemorheological variables (hematocrit, plasma and whole blood viscosity, red blood cell aggregation and deformability) were measured on the 1st and the 2nd day after admission. RESULTS ICU scores predicted 35.2-41.3% mortality rate, real mortality in intensive care unit was 37.5%, while 30-day mortality was 46.6%. Whole blood viscosity (WBV) and red blood cell (RBC) deformability were lower, red blood cell aggregation was higher in septic than in nonseptic patients (p < 0.05). In septic patients calcium was increased, osmolality was decreased, while in nonseptic patients WBV and RBC aggregation were higher in nonsurvivors compared to survivors (p < 0.05). Worsening of RBC deformability from day 1 to day 2 predicted higher mortality (p < 0.05). CONCLUSION Calcium and osmolality level were associated with outcome in sepsis. Whole blood viscosity, red blood cell aggregation and change in red blood cell deformability could predict mortality in nonseptic patients and they may add prognostic information over the ICU scores. Further investigations are needed to evaluate the benefit of our findings in clinical practice.

Toe-brachial index and exercise test can improve the exploration of peripheral artery disease

BACKGROUND AND AIMS We assumed that hand-held Doppler ultrasound (DUS) at rest was insufficient to assess the severity of peripheral artery disease (PAD). Toe pressure and transcutaneous tissue oxygen pressure were studied to prove whether these could identify more patients with severe lower limb ischemia; exercise was applied to provoke ischemia. METHODS 120 patients with PAD and 30 volunteers without PAD were recruited. DUS, transcutaneous tissue oxygen pressure (tcpO2) and toe pressure measurements were performed at rest and after exercise. The differential power of these examinations for severe limb ischemia (SLI) was determined by receiver-operating curves (ROCs) and pattern recognition by independent multicategory analysis (PRIMA). RESULTS There was an obvious significant difference between the patient and control groups at rest; after exercise; the ratio of severely impaired values (ankle-brachial index - ABI, toe-brachial index - TBI, tcpO2 measured on index forefoot) increased significantly in the patient group (p < 0.05). TBI, tcpO2, ABI measured after exercise could differentiate SLI better than the values of these tests at rest (p < 0.001). In ROC analysis, the largest area under the curve (AUC) was covered by post- (AUC: 0.860) and pre-exercise TBI (AUC: 0.785), and post-exercise tcpO2 (AUC: 0.720) (p < 0.001). Post-exercise TBI gained the best discriminant score in PRIMA. CONCLUSIONS Pre- and post-exercise non-invasive vascular tests could reveal severe limb ischemia. Toe pressure measurement and TBI should become a basic part of the vascular workup.

Hemorheological alterations in carotid artery stenosis

BACKGROUND Carotid artery stenosis (CAS) is not only an important risk factor of cerebrovascular events but it can also indicate generalized atherosclerosis. Hemorheological parameters are altered in CAS and in chronic cerebrovascular disorders as well, but it is controversial if hemorheological parameters could be markers of stenosis or atherosclerosis. METHODS 107 patients were investigated, 40% of them had stroke or TIA in case history and 48% had CAS. Routine lab parameters were determined and hemorheological variables were measured: hematocrit, plasma viscosity, whole blood viscosity, red blood cell aggregation, and deformability. RESULTS In the stenotic group whole blood viscosity and red blood cell aggregation were deteriorated (p < 0.05). Whole blood and plasma viscosity were higher and red blood cell deformability was lower in the symptomatic group (p < 0.05). Plasma viscosity and red blood cell deformability were altered in the evolving atherosclerosis group and the CAS groups compared to patients having no signs of stenosis (p < 0.05), but there was no difference among the CAS groups. CONCLUSION Although hemorheological parameters are impaired both in CAS and chronic cerebrovascular disorders, the severity of stenosis cannot be detected based on hemorheological parameters. Our investigation suggests that alteration of hemorheological parameters could indicate carotid atherosclerosis.

Lower limb ischemia and microrheological alterations in patients with diabetic retinopathy

BACKGROUND Diabetes mellitus is frequently associated with vascular pathologies and hemorheological disorders. METHODS 105 patients with diabetic retinopathy (DRP) (mean age 64.64±9.01 years, 56 males, 49 females), 35 age-matched non-diabetic (mean age 61.65±7.6 years, 14 males and 21 females) and 42 young healthy volunteers (mean age 25.52±3.32 years, 22 males, 20 females) were recruited. Lower extremity artery disease (LEAD) and microcirculatory alterations were screened by hand-held Doppler, transcutaneous partial tissue oxygen tension (tcpO2), tuning fork test, 6-minute walk test, erythrocyte aggregation and deformability. RESULTS High prevalence of LEAD was detected in diabetic population: 55.3% fulfilled the criteria of LEAD based on ankle-brachial index; severely impaired tcpO2 was measured in 18.6%. The results of non-invasive measurements of the diabetic patients were significantly worse than those of the control groups (p < 0.05). Hemorheological disturbances could be characterized by the significantly higher erythrocyte aggregation (p < 0.05) and lower erythrocyte deformability (p < 0.05) in the diabetic population. CONCLUSION Macro- and microcirculatory lower limb disorders could be revealed at high prevalence in diabetic patients with retinopathy. Measurement of tcpO2 and hemorheological variables could be useful to discover patients at higher risk for diabetic foot complications.

Altered microrheological parameters in Raynaud's phenomenon

Raynauds phenomenon is an episodic, painful attack of the acral parts caused by local diminished blood supply. The aim of our study was to examine hemorheological parameters, cold agglutinins, cryoglobulins and their relationship in patients suffering from Raynauds phenomenon.Blood was taken from 74 patients (mean age: 48 years, female/male: 56/18). Cold agglutinins and cryoglobulins were determined. Hemorheological parameters were also measured such as hematocrit, plasma and whole blood viscosity, red blood cell aggregation and deformability. Results were compared to a group of 58 healthy controls (mean age: 31.5 years, female/male: 24/34).Cold agglutinins were positive in 70%, cryoglobulins in 43% of patients. When compared to healthy controls, increased red blood cell aggregation (64.54  ±  8.93 vs. 61.11  ±  7.05) and decreased red blood cell deformability (0.669  ±  0.002 vs. 0.681  ±  0.001) was observed in Raynauds patients (p < 0.05), but there were no differences in hematocrit (43.27% ± 3.85 vs. 44.10% ± 3.70), plasma (1.27 mPas ± 0.08 vs. 1.24 mPas ± 0.09) and whole blood viscosity (4.12 mPas ± 0.52 vs. 4.26 mPas ± 0.46). No differences were found between the hemorheological profile of cold agglutinin/cryoglobulin positive and negative patients. Also primary and secondary Raynauds patients had similar rheological profile.Erythrocyte aggregation and deformability seems to be unfavorable in Raynauds patients that can play a role in the disturbance of the microcirculation.

In vitro hemorheological effects of parenteral agents used in peripheral arterial disease

Peripheral arterial disease (PAD) is a frequent manifestation of systemic atherosclerosis. In PAD hemorheological parameters were defined as risk factors in a number of studies and several therapeutic agents were tried in these conditions. Our study aims to investigate and compare the in vitro hemorheological effects of various drugs generally used in the parenteral treatment of intermittent claudication and critical limb ischemia. Blood samples of healthy male volunteers were incubated with iloprost, alprostadil, pentoxifylline, sulodexide or pentosan polysulfate at calculated therapeutic serum concentration. Hematocrit (Hct) was determined by microhematocrit centrifuge. Plasma and apparent whole blood viscosities (WBV) were evaluated by capillary viscometer. Red blood cell aggregation was measured by LORCA (laserassisted optical rotational cell analyzer) aggregometer, and LORCA ektacytometer was used for measuring erythrocyte deformability at 37°C. Iloprost, alprostadil, and pentoxifylline incubation did not have any significant effect on plasma and apparent WBV. Elongation index increased in samples incubated with alprostadil at low shear stresses 0.95 and 0.53 Pa (p < 0.05). Sulodexide significantly improved WBV and Hct/WBV ratio (p < 0.05). Incubation with pentosan polysulfate resulted in higher WBV, lower Hct/WBV ratio and deterioration in the aggregation parameters (p < 0.05). Sulodexide may have beneficial effect on a macrorheological parameter; alprostadil may improve a microrheological parameter. Hemorheological alterations could be important in PAD patients with hampered vasodilator capacity.