Kalina Gjorgjievska, Maja Slaninka-Miceska and Gordana Petrusevska
Protective Effects of Aliskiren, Enalapril and Valsartan on Hypertension Target Organs in Spontaneously Hypertensive Rats
Aim: Aliskiren is the first orally active renin inhibitor approved for treatment of essential hypertension. There are as yet no clinical data regarding the ability of aliskiren to prevent clinical end-points or reduce end-organ damage over and above the presumed effects of blood pressure reduction. The aim of this study was to find out if aliskiren has a potential to improve renal function and if it has a protective effect on hypertension target organs (kidney, heart and aorta).
Materials and Methods: The study was conducted on 64 SHR rats (male and female), 20 weeks old, weighing from 250-300 g. Animals were divided into 4 groups and treated with aliskiren (100 mg/kg bw/24 h), enalapril (10 mg/kg bw/24 h) and valsartan (10 mg/kg bw/24 h). Effects of investigated drugs were evaluated by urinalysis and histopathological analysis.
Results: Diuresis was significantly increased in the group of animals treated with enalapril and valsartan. Effect on diuresis with aliskiren was mild and statistically insignificant. No significant difference in urine pH between treated and control group of SHR rats was noted. Albuminuria was decreased in animals treated with enalapril and valsartan. Aliskiren after 28 days of treatment had a statistically insignificant effect on albuminuria in SHR rats. Only certain changes of wall thickness of arteries and arterioles were noted that led to improved perfusion and function of the kidneys more pronounced in rats treated with valsartan and enalapril. Effects of aliskiren on target organs were inferior compared to valsartan and enalapril.
Conclusion: In SHR experimental model aliskiren has minor effects on hypertension target organs when compared to enalapril and valsaratan.
Dragica Zendelovska, Kristina Pavlovska, Emilija Atanasovska, Kalina Gjorgjievska and Marija Petrusevska
Herein, we present a simple and rapid high performance liquid chromatographic (HPLC) method with UV-detection for the direct determination of diazepam in whole blood and serum that can be used for monitoring diazepam levels in clinical samples analysis. The isolation of diazepam and the internal standard bromazepam from serum and whole blood samples was performed using solid phase extraction method with RP select B cartridges. The analytes were separated employing a reversed phase C8 column with a mobile phase composed of 0.1 % (V/V) triethylamine in water (pH 3.5) and acetonitrile (63:37, V/V). UV detection was carried out at 240 nm. Linearity was achieved in the range from 10.0-1000.0 ng/ml for serum and whole blood. The method was applied to spiked and real biological samples after an oral administration of 10 mg diazepam. In conclusion, the proposed method is simple, rapid and provides efficient clean-up of the complex biological matrix and high recovery of diazepam.
Jasmina Trojacanec, Dimce Zafirov, Krume Jakjovski, Kalina Gjorgjievska, Plamen Trojacanec and Nikola Labacevski
Background: Diabetic nephropaty (DN) occurs in approximately 40% of patients with diabetes mellitus, and is the most common cause of end-stage renal disease. The combination of ACE inhibitors with ARB could lead to a more effective inhibition of rennin angiotensin aldosterone system (RAAS).
Aim: The present study was undertaken to evaluate the effects of dual RAAS blockade with ARB (candesartan) and ACE inhibitor (perindopril) in streptozotocin induced diabetic nephropathy versus ACE-inhibitor or ARB alone.
Materials and Methods: Wistar rats (n=125), were used in this investigation. Diabetes was induced by streptozotocin (STZ) 60 mg/kg. The diabetic rats (n=100) were randomly assigned to receive vehicle, ARB-Candesartan (5 mg/kg/per d), ACE inhibitor-Perindopril (6 mg/kg/per d), or a combination of low dose Can+Per (2.5 mg/kg/per d and 3 mg/kg/per d) respectively, from weeks 4-12.
Results: Treatment with candesartan or perindopril as monotherapy, although significantly, only partially prevented the symptoms and signs of DN. Candesartan and perindopril were equally effective in treatment of DN. Combination therapy was more effective than monotherapy with either drug.
Conclusion: The results from this study demonstrate that combination treatment with both ACE and ARB in low doses may offer synergistic blockade of the RAAS, not obtainable with either drug alone.
Kalina Gjorgjievska, Dimce Zafirov, Maja Jurhar-Pavlova, Svetlana Cekovska, Emilija Atanasovska, Kristina Pavlovska and Dragica Zendelovska
Salt sensitive hypertension is known to be a contributing factor for the progression of kidney disease. This study was undertaken to investigate the role of excessive dietary salt on renal function and to evaluate the effect of valsartan and amlodipin given as a combination therapy on blood pressure and parameters specific to the renal function in salt loaded SHR rats. 48 male SHR rats at age of 20 weeks and body weight ranging between 270-350 g were used. SHR rats were divided into 3 groups: control group of rats -SHRC (n = 16) given tab water ad libitum and two salt treated groups in which tab water was replaced with a solution of NaCl (1%) from age of 8 weeks given ad libitum: SHRVAL+AMLO group (n = 16) where investigated drugs were administered at a dose of 10 mg/kg/ b.w. (valsartan) and 5 mg/kg/ b.w. (amlodipin) by gavage and SHR NaCl group (n = 16) that received saline in the same volume and the same time intervals as the SHRVAL+AMLO group. For a period of 12 weeks we have investigated the effect of the VAL+AMLO drug combination on systolic blood pressure (SBP), body weight and renal function tests. Salt loading with 1% solution in the SHR NaCl group has lead to significant increase of blood pressure, proteinuria and decrease in creatinine clearance. Combined treatment with АТ1-receptor blocker and calcium antagonist has managed to control blood pressure and ameliorated renal damage.
Kristina Pavlovska, Marija Petrushevska, Kalina Gjorgjievska, Dragica Zendelovska, Jasmina Tonic Ribarska, Igor Kikerkov, Liljana Labachevska Gjatovska and Emilija Atanasovska
The active metabolite of azathioprine, 6-thioguanine nucleotide (6-TGN) is the main component responsible for the immunosuppressive effect in treatment of inflammatory bowel disease (IBD).
The aim of this study was to assess the correlation between the concentration of 6-thioguanine nucleotide and disease activity, azathioprine-related adverse effects and time duration of treatment in patients with inflammatory bowel disease.
Thirty-four patients were included in this study. Type of disease, gender, time duration of therapy and adverse effects were recorded. Metabolite concentration was determined by high performance liquid chromatography.
Twenty-one percent of patients have experienced an adverse effect, with leucocytopenia most commonly occurring (42.9%). More adverse effects were registered when patients were treated with azathioprine in a period of less than 3 months in comparison to the group of patients that have been under therapy between 3-12 months and more than 12 months (p˂0.05). Most of the patients that presented any adverse effect had high 6-TGN concentration (>450 pmol/8x108 Er). The mean value of 6-TGN metabolite concentration in IBD patients treated with azathioprine was 437.46 pmol/8x108 Er ± 198.82 pmol/8x108. The time duration of azathioprine treatment did not have any significant impact on the achieved 6-TGN concentration (p>0.05).Twenty patients (58.9%) had achieved remission after therapy initiation with azathioprine.
More alertness is recommended to clinicians towards patients in the first 3 months of the therapy. Our study demonstrated that higher 6-TGN concentration is associated with azathioprine toxicity.