Chronotherapeutic effect of fluvastatin on lipid profile in rats

Dyslipidemia is a major risk factor for coronary heart disease [CHD], and its management is important in preventing the occurrence of cardiovascular events. Lipid-altering drug treatment, targeted to patients at high risk for cardiovascular disease, has been shown [in clinical trials] to reduce the incidence of first and recurrent CHD events. Statins are used widely for the treatment of dyslipidemia. They act through reversible competitive inhibition of the hepatic 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. The early use of statin in management of dyslipidemia recommended their morning administration. However, this strategy should be re-evaluated in light of reports showing that the biosynthesis of cholesterol exhibits diurnal periodicity with nocturnal increase in the level of cholesterol precursors. The experiments were performed on forty male albino rats divided after estimation of basic lipid profile into four equal groups, each composed of 10 animals: control normocholesterolemic, hypercholesterolemic non-treated, hypercholesterolemic treated with morning fluvastatin [8mg/kg, for 12[th] weeks] and hypercholesterolemic treated with evening fluvastatin [8mg/kg for 12[th] weeks]. Lipid profile was estimated at the end of the 4[th], 8[th], 12[th] and 16[th] weeks for all animals using spectrophotometeric assay kits and the results were expressed in mg/dl. Both morning and evening treatment with fluvastatin significantly reduced blood cholesterol level and low-density lipoprotein. Significant increase of plasma high density lipoprotein level was observed in evening treated group in comparison with non-treated hypercholesterolemic animals. Interestingly, all these beneficial effects of fluvastatin treatment were more significant when administered in the evening rather than in the morning pattern of treatment. On the other hand, fluvastatin treatment whether given in the morning or in the evening for hypercholesterolemic animals, produced no significant effect on plasma triglyceride level and total lipid level in comparison with non-treated hypercholesterolemic animals. It is concluded that therapeutic efficiency of fluvastatin is best obtained when the drug was administered in the evening rather than in the morning. This most likely occurred due to the circadian rhythm of cholesterol biosynthesis. This chronotherapeutic pattern of fluvastatin recommends its night administration to ensure introduction of the drug at the proper timing thus achieving the best therapeutic effect

Protective effect of quercetin [QRT], a bioflavonoid on stress-induced gastric ulcers in rats

Peptic ulcer is one of the most common diseases which represent a serious medical problem due to its frequency, high economic cost and frequent adverse reactions associated with drugs used in its management. In this work, an attempt was undertaken to investigate the protective effect of quercetin [QRT], the most abundant natural bioflavonoid which is widely distributed in edible plants and has a powerful antioxidant effect on stress-induced gastric ulcers in rats. In this experimental model the pathogenesis of the lesions has been related to the production of reactive oxygen species. The rats were randomly classified into 4 equal groups, [10 animals each] as follows: [1] Control group, [2] Pylorically ligated group in which animals were subjected to pyloric ligation only, [3] Cold restraint stress [CRS] group in which rats were subjected to pyloric ligation, allowed to recover, and then restrained by immobilizaiton and placed in a refrigerator at 4°C for 3 hours, and [4] Quercetin [QRT] treated group that received 50 mg/kg QRT intraperitonealy 1 hour before pyloric ligation and induction of gastric mucosal ulceration by cold restraint stress. Three hours later, all rats were decapitated, their stomachs were removed and the gastric content of groups 2, 3 and 4 were collected. Then, gastric juice parameters [volume, total acidity, total acid output, total pepsin concentration as well as glycoprotein contents] were studied. Also, the effect of QRT on stress induced gastric ulcer parameters [ulcer incidence; ulcer score; ulcer index and preventive index] were investigated in groups 1, 3 and 4. On the other hand, prior to decapitation, blood samples were collected from all animals for measurement of superoxide dismutase [SOD] activity in red blood cell [RBC] lysates as an index of the antioxidant state. The results obtained in the present study clearly demonstrate that intraperitioneal administration of QRT led to a markedly significant reduction in the occurrence of gastric ulceration in all treated rats as evidenced by the reduction of the mean ulcer score and ulcer index with a preventive index of 73.5%. Pretreatment with QRT was also associated with a significant decrease in the total acid and pepsin concentrations as well as a highly significant increase of glycoprotein contents compared with cold restraint group. Furthermore, the administration of QRT significantly increased SOD level as compared to cold restraint group. It is concluded that QRT has a protective effective role against stress-induced gastric ulcer in rats and the relevance of these results was discussed

Simvastatin improves vascular reactivity of rabbit aorta irrespective of its hypocholesterolemic effect

Simvastatin is one of the 3-Hydroxy-3-methylglutaryl coenzyme A reductase [HMG-Co-A] inhibitors known for their hypocholesterolemic effect. Apart from cholesterol lowering, simvastatin exerts other beneficial effects such as reduction of plasma fibrinogen and platelet aggregation, anti-inflammatory, anti-proliferative effects, and decreasing risk of coronary heart disease [CHD] and myocardial infarction. This work aimed at investigating the possible modifying effect of simvastatin on systemic vascular reactivity. Vascular responses to various vasoactive agents were tested on isolated rabbit aortic ring preparations obtained at the end of 16 week duration from control normocholesterolemic [group 1], hypercholesterolemic [group 2] as well as simivastatin-treated normocholesterolemic [group 3] and simvastatin-treated hypercholesterolemic [group 4] animal groups. Hypercholesterolemia was induced in groups 2 and 4 by a high cholesterol diet for the 16 weeks. Treated groups [3 and 4] received simvastatin in a daily dose of 10 mg/kg for 8 weeks starting by the beginning of the 9[th] week. In addition to vascular reactivity studies, plasma cholesterol levels were measured for all animals at the ends of 4[th], 8[th], 12[th] and 16[th] weeks. Simvastatin pretreatment significantly reduced plasma cholesterol levels in group 4 animals in comparison to group 2, decreased contractile responses to nor epinephrine [NE] and augmented relaxation induced by acehylcholine [ACh] in nomocholesterolemic [group 3] and treated hypercholesterolemic [group 4] animals compared with control or hypercholesterolemic groups, respectively. In addition, it augmented sodium nitroprusside [SNP] induced relaxant responses in tissues obtained from group 4 compared with group 2. The vasoprotective effects observed with simivastatin therapy may be mainly attributed to improvement of vascular endothelial function not only under hypercholesterolemic- but also normocholesterolemic conditions. Thus simvastatin therapy may be applied not only to reduce the risk of CHD but also the systemic vascular complications associated with hypercholesterolemia. In addition simvastatin might serve as a prophylactic agent against disturbed vascular reactivity that may develop under certain pathological conditions devoid of hypercholesterolemia

Comparison between morning and evening single dose administration of simvastatin on endothelium-dependent relaxation and superoxide dismutase enzyme level as an antioxident marker in cholesterol-fed rabbits

Statins are widely used hypocholesterolemic drugs that act through reversible competitive inhibition of the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCOA] enzyme. At first, morning use of statins was recommended but now it is known that choesterogenesis follows a circadian rhythm as it occurs at a higher rate during the evening time. Accordingly, accurate timing of statin administration should be re-evaluated in order to obtain the best therapeutic effect. As simvastatin is one of the widely prescribed HMG-CoA reductase inhibitors, it was chosen in this study to test and compare its effectiveness when administered as single dose in the morning and in the evening. The experiments were performed on Newzealand rabbits divided into four equal groups, each composed of 8 animals: control normocholesterolemic, hypercholesterolemic nontreated, hypercholesterolemic treated with morning simvastatin, and hypercholesterolemic treated with evening simvastatin. Animals of control group received a cholesterol-free diet for 16 weeks, while animals of the other three groups were maintained on a high cholesterol diet for an equal duration of time. Treated groups received simvastatin in a single oral daily dose of 10 mg/kg for 8 weeks starting at the beginning of the 9[th] week, administered either in the morning or in the evening. Blood cholesterol level was checked for all animals at the end of the 4[th], 8[th], l2[th] and 16[th] weeks. At the end of the 16[th] week, the level of the anti-oxidant superoxide dismutase [SOD] enzyme was determined in erythrocyte [RBC] lysates obtained from animals of all groups. The animals were then slaughtered and vascular reactivity to acetvlcholine [ACh] was tested on ring preparations obtained from their isolated aortae [ring preparations]. Both morning and evening treatment with simvastatin significantly reduced blood cholesterol level, augmented relaxation induced by [ACh] and increased SOD level in RBCs lysates, in comparison with non-treated hypercholestero!emic group. However, results obtained with the evening dosing regimen were much more significant when compared with the morning dosing schedule. It is concluded that therapeutic efficiency of simvastatin is best obtained when the drug is administered in the evening rather than in the morning. This most likely occurs due to the circadian rhythm of cholesterol biosynthesis that tends to occur at a much greater rate during night as a result of increased availability of cholesterol precursors. This chronotherapeutic pattern of simvastatin recommends its night administration to ensure introduction of the drug at the correct timing thus achieving the best therapeutic effect

Comparison between the effect of bosentan and perindopril on diabetic angiopathy and nephropathy in streptozotocin-induced diabetic rats

Angiopathy and nephropathy are serious problems encountered in the management of diabetes, mellitus. There is accumulating literatrues describing some sort of hystological interaction between angiotensin II [ALI] and endothelins [ETs] in addition to their possible contributing roles in the pathogenesis of diabetic complications. In the present study, the angiotensin converting enzyme inhibitor [ACEI] perindopril to prevent or minimize the development of angiopathy [endothelial dysfunction] and nephropathy in a strepozotocininduced model of diabetes type I in albino rats. Animals were classified into six groups: untreated healthy non diabetic [ND] control rats, healthy [ND] rats treated with perindopril [3 mg/kg/day], healthy [ND] rats treated with bosentan [100 mg/kg/day], untreated diabetic rats, and diabetic rats treated with either perindopril or bosentan in the same doses described before. Rats were rendered diabetic by a single injection, in the tail vein, of 55 mg/kg streptozotocin [STZ] after overnight fast. Treatment with bosentan and perindopril was continued for 16 weeks during which the 24[th] urine volume, urinary albumin content, urine and plasma levels of creatinine as well as systolic blood pressure [SBP] were assessed at the end of each 4 weeks. At the end of the 16[th] week rats were sacrificed and the kidneys were removed for examination of histopathological changes, while the thoracic aortae were removed for assessment of the vasorelaxant effect of acetylcholine [Ach]. Diabetic rats developed typical functional changes manifested by hyperglycemia, polyuria, albuminuria, elevated SBP, reduced response to vasorelaxant effect of ACh in addition to histopathological changes manifested by tubular dilatation, diffuse interstitial edema and decreased density of the brush border of epithelial cells. In the healthy [ND] animals, changes obtained in the different parameters studied were insignificant between the treated and non-treated groups. In diabetic animals, however; both perindopril and bosentan significantly reduced albuminuria and lowered elevated SBP. In addition both drugs improved creatinine clearance and relaxant response to ACh to a large extent. Perindopril was more potent with regard to the hypoalbuminuric effect and the effect on creatinine clearance, while bosentan-induced improvement of vascular reactivity to ACh was more significant. Different potencies of perindopril and bosentan in affecting certain studied parameters suggests that the two drugs work either through different mechanisms or through similar pathways but to different extents. The renoprotective and antiangiopathic effects of both drugs were independent of the blood glucose level because this parameter was not significantly altered by either treatment. In conclusion, it seems that both angiotensin II and endothelins play an important role in the pathogenesis of diabetic angiopathy and nephropathy with probable interaction between the two systems to augment the production of such pathological disorders. Therefore, ACELs and ET receptor antagonists are highly recommended in the management of diabetic and ET receptor antagonists are highly recommended in the management of diabetic complications

Novel vip analogues: relative potency, duration of action and antagonism to relaxant effect of natural vip on guinea pig trachea

This study was performed on two novel VIP analogues; namely, [N1e17, A1a24, A1a25, Va126]-VIP-[1-27]-NH2 [analogue 1] and [Ser [SO3H]3, Nle17-VIP [analogue 2], which were obtained by undergoing certain changes in the amino acid sequence of the VIP molecule in a trial to reach a novel more stable, but still active form of VIP. Relative potency as well as duration of action of the two analogues was tested versus that of native VIP on isolated guinea pig tracheal strips placed in organ baths. Changes in smooth muscle tension were measured by isometric force transducers and recorded continuously. Analogue 1 was significantly more potent and had a significantly longer duration of action than natural VIP as a tracheal relaxant at the lower concentration range of 5 x 10-9 M to 5 x 10-8 M and its maximal relaxing effect was 72% of that of native VIP. Analogue 2 was significantly much less potent than natural VIP at all concentrations tested with maximal potency of only 11% of that of native VIP and showed shorter duration of action. However, it significantly reduced VIP-induced tracheal relaxation. The encouraging results with analogue 1 suggest its clinical trial in therapy of bronchial asthma. As VIP antagonists may potently inhibit the basal growth of cancer cells in vitro and certain tumors in vivo, especially lung carcinoma, analogue 2 may serve as a useful candidate in this respect. The interesting findings with the two analogues suggest further investigation to enhance their potency, whether agonistic [for analogue 1] or antagonistic [for analogue 2], at VIP receptors by additional changes in their molecules to improve the chance of possible clinical applications

Prelminary evaluation of quercetin effect on diclofenac sodium associated gastric ulcer in rats

The effect of quercetin [QRT] in preventing or reducing the diclofenac sodium-induced gastric ulcers was evaluated in rats following over night fasting by using a scanning electron microscopy. The scanning micrographs of stomach specimens showed a marked reduction in the gastric ulceration only when the quercetin is given before the administration of diclofenac sodium. The physicochemical characteristics of diclofenac sodium and quercetin combination were studied using differential scanning calorimetry, IR spectroscopy and X-ray diffractometery. The results revealed that a chemical incompatibility of diclofenac sodium and quercetin undoubtedly has been occurred when they were mixed in one combination. According to aforementioned results, we advise orally taking quercetin only before administration of diclofenac sodium as a prophylactic treatment to protect against its expected gastric disturbances