Colorimetric determination of ramipril, enalapril maleate and fosinopril in their pharmaceutical formulations

Two new spectrophotometric methods were developed for the determination of three angiotensin-converting enzyme inhibitors, namely, ramipril, enalapril maleate and fosinopril. The first method was based on the oxidation of the three drugs by Fe[III] in presence of 1.10-phenanthroline, the formed tris-[Fe-o-phen]complex in acetate buffer and optimum pH was measured at [lambda][max] 510 nm with linear relationship over concentration range from 6-50 micro gml[-1] and molar absorptivity 1.2x10[4] 1 mol[-1]cm[-1] for ramipril and enalapril maleate and 1.8x10[4] 1 mol[-1]cm[-1] for fosinopril. The second method was based on measuring the formed tris -[Fe-bipyridyl]complex in the same condition at [lambda][max] 540 nm with linear relationship in concentration range from 10-54 micro gml[-1] and molar absorptivity of 1.0x10[4] 1 mol[-1]cm[-1] for ramipril, 1.6x10[4] 1 mol[-1]cm[-1] for and enalapril maleate and 1.57x10 [4] mol[-1]cm[-1] for fosinopril. The two methods hold their accuracy and precision well when applied to the determination of the studied drugs in their dosage forms

Targeting apoptosis in the heart of streptozotocin-induced diabetic rats

To address the issue of cardiomyocyte apoptosis as a possible cause of diabetic cardiomyopathy and whether it would be possible to suppress this apoptosis by the use of PPAR gamma agonists [glitazones] and PPAR alpha agonists [fibrates], versus insulin. forty male rats were made diabetic by intraperitoneal [i.p.] streptozotocin [STZ] injection and were divided into four groups: group II [STZ-injected rats], groups III, IV and V [STZ-injected rats treated with insulin, PPAR gamma agonist [rosiglitazone] and PPAR alpha agonist [bezafirate] respectively, for twelve weeks starting one week following STZ injection]. Additionally, ten rats were injected i.p. by a single dose of saline and served as a control for group II. At the end of the experimental period, plasma glucose was measured. Left ventricular [LV] papillary muscles isometric force [developed tension [DT]] was determined. Oxidative stress as assessed by cardiac malondialdehyde [MDA] and reduced glutathione [GSH] concentrations as well as caspase-3 activity as an index of apoptosis were determined. STZ-injection induced diabetes, evidenced by significant higher mean value in plasma glucose concentration in group II compared to that of the control group I. Significant cardiomyopathy could be observed, in the form of significantly decreased DT of LV papillary muscles in group II compared to the control group I. STZ-injection resulted in oxidative stress evidenced by significant higher mean value in cardiac MDA concentration and significant lower mean value in cardiac GSH concentration in group II compared to the control group I. STZ-injection resulted in cardiac apoptosis evidenced by significant higher mean value in cardiac caspase-3 activity in group II compared to the control group I. The use of insulin, rosiglitazone as well as bezafibrate caused a significant decrease in plasma glucose concentration as well as a significant increase in body weight compared to group II. The use of insulin as well as rosiglitazone, but not bezafibrate, decreased cardiac caspase-3 activity and improved oxidative stress parameters evidenced by significant lower mean value in cardiac MDA concentration and significant higher mean value in cardiac GSH concentration compared to group II. Rosigitazone but neither insulin nor bezafibrate resulted in significant improvement of LV papillary muscle DT compared to group II. The results of the present study support the hypothesis that apoptosis plays a key role in the pathophysiology of diabetic cardiomyopathy and demonstrate that the use of PPAR gamma agonists might have a protective role against diabetic cardiomyopathy. We recommend further human studies to evaluate the role of the addition of PPAR gamma agonists to the treatment regimen of diabetes, from the onset of the disease, in protection against diabetic cardiomyopathy. Although the use of PPAR-alpha agonists seems counterintuitive in light of the current findings, the benefit of reduced delivery of fatty acids to the myocardium may outweigh the effects of activating the cardiac PPARalpha pathway in the diabetic patient

Do desipramine and fluoxetine ameliorate the extent of colonic damage induced by acetic acid in rats?

The present study was aimed to compare the anti-inflammatory and antioxidant effects of two antidepressant drugs; desipramine and fluoxetine, administered in two different doses, on experimentally induced colitis in rats. Two doses for each drug [10, 20 mg/kg/d] were injected intraperitoneally in forty eight adult male albino rats for 2 weeks after induction of colitis by intra-colonic administration of 2ml 3% acetic acid. Several parameters including, macroscopic [ulcer score index], microscopic [histological] and biochemical such as myeloperoxidase [MPO], reduced glutathione [GSH], tumor necrosis factor alpha [TNF-alpha] and interleukin-1 Beta [IL-1beta] were measured using standard assay procedures. The study demonstrated that both desipramine and fluoxetine significantly attenuated the extent and the severity of the macroscopic and microscopic histological signs of cell damage. Both drugs significantly reduced tissue MPO activity in a dose dependent manner. Both desipramine and fluoxetine at either dose increased significantly the GSH in colonic tissue. On the contrary, both desipramine and fluoxetine significantly reduced TNF-alpha and IL-beta in a dose dependent manner. However, desipramine at the dose of 20 mg/kg produced more decrease in the level of TNF-alpha compared to the effect of the smaller dose, and on the contrary, fluoxetine at the dose of 10 mg/kg showed more decrease in the level of IL-beta compared to the effect of the larger dose. The available data indicate that both desipramine and fluoxetine have anti-inflammatory and antioxidants effects in experimentally induced colitis in rats opening the avenue to their possible protective role in patients with inflammatory bowel disease

Role of modulation of vascular endothelial growth factor and tumor necrosis factor-alpha in gastric ulcer healing in diabetic rats

To assess the role of modulation of vascular endothelial growth factor and tumor necrosis factor-alpha in gastric ulcer healing in streptozotocin [STZ]- induced diabetic rats. forty male rats were made diabetic by intraperitoneal [i.p] STZ infection and ten rats were injected i.p. by a single dose of saline and served as a control for group II Six weeks following STZ or saline injection, gastric ulcers were induced by serosal application of acetic acid. Three days after acetic acid application, rats were divided into: group I[normal control], group II [STZ-injected rats], groups III. IV and V [STZ-injected rats treated with insulin, insulin and phosphodiesterase [PDE] inhibitor [pentoxifylline] [PTX] and insulin and Hydroxymethylglutaryl Coenzyme A [HMG-CoA] reductase inhibitor [simvastatin] respectively, for seven days following acetic acid application. At the end of the experimental period, plasma glucose was measured. Gastric ulcer area as well as gastric tumor necrosis factor- alpha [TNF-alpha], vascular endothelial growth factor [VEGF] and haemoglobin [Hb] concentrations were determined. STZ-injection induced diabetes, evidenced by significant higher mean value in plasma glucose concentration in group II compared to that of the control group [I] Significant delay in ulcer healing could be observed, in the form of significant increase in gastric ulcer area in group II compared to the control group I. STZ-injection resulted in significant increase in gastric TNF-alpha as well as a significant decrease in gastric VEGF concentrations together with a significant decrease in gastric angiogenic response evidenced by a significant decrease in gastric Hb concentration in group II compared to the control group I. The use of insulin, as well as combinations of insulin and PTX or simvastatin caused a significant decrease in plasma glucose concentration as well as a significant increase in gastric ulcer healing [evidenced by a significant decrease in ulcer area], gastric VEGF and gastric Hb concentration as well as significant decrease in gastric TNF-alpha compared to group II. A significant difference in gastric ulcer area and gastric TNF-alpha could be observed between rat that received combinations of insulin and PTX or simvastatin compared to rats that received insulin only. A significant difference in gastric VEGF and Hb was also found between the group that received combination of insulin and simvastatin compared to the group that received insulin only. Experimental DM impairs ulcer healing, depending upon the increased release of proinflammatory cytokines [e.g. TNF-alpha] and the attenuation of angiogenesis Insulin reversed this impairment of ulcer healing in diabetic rats, mainly due to the enhancement of angiogenesis and reduction in expression of TNF-alpha in the ulcer area. Phosphodiesterase [PDE] inhibitor [pentoxifylline], via suppressing TNF-alpha and hydroxymethylglutaryl coenzyme A [HMG-CoA] reductase inhibitor [simvastatin]. via suppressing TNF-alpha and increasing VEGF, are beneficial in enhancing gastric ulcer healing. These findings support the notion that impairment of healing of gastric ulcers in DM results from impairment of angiogenic response of the gastric mucosa to injury together with upregulotion of gastric TNF-alpha and suggest the feasibility of a novel treatment strategy for patients in whom impairment of ulcer healing complication of DM

Role of the trace metals, selenium and zinc, in pilocarpine-induced epilepsy in rats

Excitotoxic brain lesions, such as epilepsy, lead to increasing destruction of neurons, in the course of few hours after the insult. The deadly cascade of events possibly involves detrimental actions by free radicals, proinflammatory cytokines and the activation of pro-apoptotic transcription factors, which finally result in neuronal destruction. Several reports suggest that the level of some trace elements play a vital role in seizure conditions to prevail. The aim of the present study was to assess the possible modulatory role of the trace elements, selenium and zinc on pilocarpine-induced epilepsy in rats.The study was carried out on 40 male albino rats, weighing 150-200 grams that were divided into the following groups each of 10 rats: Group I: control rats that received intraperitoneal [i.p.] saline, Group II: pilocarpine induced epilepsy, Group 111: selenium pretreated for 3 weeks before pilocarpine injection and Group IV: zinc pretreated for 3 weeks before pilocarpine injection. The seizure latency and severity for each rat was recorded. Twenty four hours following pilocarpine injection, rats were exsanguinated and the following parameters were determined: cerebral caspase-3 activity [as a marker of apoptosis], interleukin-lbeta [IL-ljB], reduced glutathione [GSH] and malondialdehyde [MDA] concentrations, serum neuron specific enolase[NSE] concentration [as a marker of brain injury].Intraperitoneal injection of pilocarpine in rats resulted in progression to limbic seizures with progressing behavioural scores at various time intervals [recorded every 30 minutes up to 2 hours]. Latency to forelimb clonus was 51.86 +/- 1.89 min. The results of the present study demonstrated significantly increased cerebral MDA concentration together with significant decrease in cerebral GSH concentration in non-treated pilocarpine injected rats compared to normal control rats. A significant increase in cerebral caspase-3 activity, and in cerebral 1L-1/beta as well as in serum NSE concentrations could be observed in non-treated pilocarpine-injected rats compared to normal control rats. Pretreatment with selenium or zinc reduced the severity of pilocarpine- induced seizures. In addition, both trace elements decreased the latency to attain the forelimb clonus [score 4]. A significant decrease in cerebral MDA and IL-1/beta, serum NSE concentrations could be observed in selenium and zinc-treated rats compared to non-treated pilocarpine-injected rats. A significant' increase in cerebral GSH concentration was observed in zinc-treated, but not in selenium-treated ones.The results of the present study confirm the role of the trace elements, selenium and zinc, in mitigating epilepsy. Further human studies to evaluate the role of trace elements in epilepsy are recommended. Furthermore, since antiepileptic drugs [AEDs] are reported to induce zinc and selenium deficiency,thus combining these trace elements with AEDs are worthy to be evaluated

protective effect of nigella sativa oil and the derived thymoquinone and nigellone against thioacetamide induced liver fibrosis in rats

The present study examined the effect of oral administration of Nigella saliva oil [NSO], thymoquinone [TQ], the main active principle of the volatile oil of NSO and nigellone [NG], the less toxic carbonyl polymer of TQ, on progress of thioacetamide [TAA] -induced liver fibrosis in rats. Sixty male albino rats weighing 150-200 g/rat were classified into 6 groups as follows: group I, [saline-control], group II [TAA-induced liver injury], group III [NSO-treated], group IV [TQ-treated], group V [NG-treated] and group VI [propylene glycol - treated]. NSO, TQ, NG and propylene glycol were given daily orally for 6 weeks starting with TAA administration. Propylene glycol was the vehicle of TQ and NG. TAA-injury [group II] caused a significant rise in the portal pressure and serum concentrations of tumor necrosis factor -alpha, transforming growth factor - beta[1] and malondialdehyde. Moreover, liver function tests [serum aspartate and alanine aminotransferases, alkaline phosphatase and gamma-glutamyl transferase activities and serum albumin concentration] were significantly impaired in group II as compared to group I. Liver tissues obtained from rats treated by TAA had higher hydroxyproline and lower reduced glutathione contents as compared to saline-control [group I]. Administration NSO, TQ or NG caused significant and similar protective effects against all TAA-induced haemodynamic and biochemical impairments. This study suggests that NSO, TQ and NG are significantly and probably equally effective against TAA-induced liver injury and fibrosis. Inhibition of synthesis and/or release of TNF-alpha and TGF-beta[1] as well as inhibition of tissue oxidative stress may be of particular importance

Role of rosiglitazone and pravastalin in freund's adjuvant arthritis and mixed-type hypersensitivity in rats

Recent studies have shown that peroxisome proliferator- activated receptor- gamma [PPAR gamma] may participate in control of inflammation, especially in modulating the production of inflammatory mediators. Similarly, the cholesterol lowering drugs, statins, have been found to exhibit anti-inflammatory properties that are beyond their lipid lowering effects. The present study was conducted to investigate the effect of a PPAR gamma agonist [rosiglitazone] and a statin [pravastatin] on immunologically mediated chronic inflammation. Two models were chosen, namely, Freund's adjuvant arthritis [FA] and mixed- type hypersensitivity [MH] in rats. The effect of these drugs was assessed on the basis of biochemical markers in blood and / or inflammatory exudate. The investigated drugs were given orally daily during the course of inflammation development. The results of the present study demonstrated that, in either model, rosiglitazone and pravastatin reduced the elevated serum and exudate [local] leukotriene B[4] [LTB[4]] and interleukine-6 [IL-6] levels. The anti-inflammatory effect of these drugs was also accompanied by reduction or normalization of elevated systemic and or local levels of lipid peroxide [LP], superoxide dismutase [SOD], and reduced glutathione [GSH]. It could be concluded that long-term treatment with rosiglitazone or pravastatin confers a good anti-inflammatory activity against arthritis in rat, leading to improvement of the oxidative stress induced by the arthritic insult. The reparative effect of these drugs could be mediated via reduction of LTB[4] and IL-6

Possible neuroprotective effect of some drugs modulating Nitric Oxide apoptotic pathway in L-2 chloropropionic acid-induced neuronal injury in rats

There is a recent evidence supporting that neuronal injury may be dependent upon the generation of the free radical nitric oxide [NO] with the subsequent induction of programmed cell death [apoptosis]. The aim of the present study was to assess the contribution of NO and the possible neuroprotective effect of two drugs modulating NO-apoptotic pathway, namely minocycline and ebselen, in L-2 chloropropionic acid [L-CPA] -induced neuronal injury in the rat. The present study was conducted on 40 male albino rats that were divided into: Group I; normal rats that served as control Group II; rats in which cerebellar neuronal injury was induced by L-CPA, Groups III and IV; rats with L-CPA -induced neuronal injury that received minocycline and ebselen respectively for 2 days starting half an hour before dosing with L-CPA. Forty-eight hours following L-CPA administration, signs characteristic of cerebellar ataxia, including hind limb weakness and abnormal gait were recorded, The ability of the rat to lift [retract] its hindlimbs was measured. Rats were then exsanguinated, cerebellum isolated for the determination of cerebellar: Nitric oxide synthase [NOS] activity, caspase-3 activity as an index of apoptosis, sodium concentration as a measure of cerebellar edema and glutamate concentration as a marker for cerebellar granule cell necrosis. The results of the present study demonstrated a significant increase in: the time taken by rats to retract hindlimbs, cerebellar NOS and caspase-3 activities as well as in sodium concentration, in group II compared to group I. A significant decrease in cerebellar glutamate concentration could be observed in group II compared to group I. Treatment with minocycline and ebselen resulted in significant decrease in cerebellar NOS activity and active caspase-3 and sodium concentrations together with a significant increase in cerebellar glutamate concentration compared to non-treated rats receiving L-CPA. In conclusion, the present work demonstrated that neuronal injury, induced by L-CPA, is associated with increased NOS activity resulting in increased NO production, which has been suggested to play a role in the mediation of that injury. We demonstrated that drugs that reduce the activity of NOS and caspases, like minocycline and ebselen are capable of blocking neurotoxicity. These results provide an experimental rationale for the evaluation of the role of NO-apoptotic pathway and the possible therapeutic potential of minocycline and ebselen in human neurological disorders

New insights into the modulatory role of serotonin reuptake inhibitors in myocardial ischemia reperfusion injury in rabbits

In view of the importance of serotonin in the pathogenesis of myocardial infarction [MI] and the reported decrease in platelet serotonin concentration associated with the treatment with selective serotonin reuptake inhibitors [SSRIs], the present study was planned to test the hypothesis of decreased risk of MI associated with the use of SSRIs in rabbits exposed to myocardial ischemia reperfusion injury [MIRI], with or without cigarette smoking. The present study was conducted on 50 New Zealand White male rabbits grouped into: group I [sham-operated], group II [coronary artery ligated and reperfused for induction of MIRI], group III [smoking for eight weeks and then coronary artery ligated and reperfused], group IV [treated with fluoxetine for three weeks before coronary artery ligation and reperfusion] and group V [smoking for eight weeks and treated with fluoxetin for three weeks, starting from the 6[th] week of smoking, before coronary artery ligation and reperfusion]. Six hours following coronary artery ligation and reperfusion, relaxation response of left anterior coronary artery [LACA] segments to acetylcholine [Ach] was assessed and plasma cardiac troponin T[cTnT], homocysteine [Hcy] and urinary cotinine concentrations as well as percentage of platelet aggregation in response to adenosine diphosphate [ADP] were measured. MIRI resulted in a significant attenuation of ACh-induced relaxation in LACA segments compared to normal sham-operated rabbits. A significant decrease in Ach-induced relaxation in smoking MIRI compared to non-smoking MIRI rabbits could be also detected. A significant increase in percentage of platelet aggregation in response to ADP and in plasma Hcy and cTnT concentrations could be detected in MIRI rabbits compared to sham-operated rabbits with a significant difference between smoking and non-smoking MIRI rabbits. Fluoxetine treatment significantly improved endothelium-dependent relaxation to ACh in LACA segments obtained from nonsmoking and smoking MIRI rabbits. Fluoxetine treatment also resulted in significant decrease in plasma Hyc and cTnT concentrations and in percent of platelet aggregation compared to non-treated smoking and non-smoking MIRI rabbits. The data of the present study support the notion that platelets play a role in MI. It could be concluded that SSRIs could be protective against MI by inhibiting serotonin-mediated platelet activation and exerting favorable effect on endothelial function. Future clinical trials, well designed and carefully conducted should elucidate the potential benefits of SSRIs in multiple thrombotic events like MI and unstable angina

possible renoprotective effect of angiotensin converting enzyme inhibitors and statins on renal ischemia reperfusion injury in rats

Ischemia-reperfusion-induced renal injury is the most common cause of acute renal failure [ARF]. Angiogenesis is an important phenomenon associated with recovery from ischemia. The aim of the present study was to assess the possible renoprotective effect of manipulating angiogenesis by trandolapril [an angiotensin converting enzyme [ACE] inhibitor] and simvastatin [a 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor] in ischemic ARF in rat. The present study was conducted on 40 male albino rats that were divided into four groups. Group I included normal Sham-operated rats that served as control for group II, Group II were rats in which renal ischemia reperfusion injury [RIRI] was induced and Group III and Group IV consisted of rats that received trandolapril and simvastatin respectively, orally daily starting two days before and continuing for two days after the induction of RIRI. At the end of the experimental period, serum urea and creatinine concentrations and creatinine clearance were assessed. Moreover, serum and renal vascular endothelial growth factor [VEGF] levels, renal caspase-3 activity [as an index of apoptosis], renal hemoglobin content [as an index of angiogenesis] and renal oxidative stress parameters [malondialdhyde [MDA] and reduced glutathione [GSH] concentrations] were assessed. A significant increase in serum urea, creatinine concentrations and in renal VEGF, MDA concentrations and caspase-3 activity together with a significant decrease in creatinine clearance and renal GSH concentration has been observed in non-treated rats killed two days after RIRI compared to Sham-operated rats. Administration of trandolapril or simvastatin resulted in a significant decrease in serum urea and creatinine concentrations and in renal caspase-3 activity and renal MDA concentration as well as a significant increase in creatinine clearance and renal hemoglobin and GSH concentrations in rats killed two days following RIRI compared to non-treated rats with RIRI. A significant increase in renal VEGF concentration could be observed in simvastatin-, but not in trandolapril-treated rats killed two days following RIRI compared to non-treated rats with RIRI. The present study demonstrated the proangiogenic effect and the possible renoprotective role of trandolapril and simvastatin in rats with RIRI. It has been found that the proangiogenic effect of trandolapril is independent of VEGF, while that of simvastatin might involve several factors including VEGF

possible reno- and vascufoprotective of drugs that inhibit the renin angiotensin system in diabetic rats

Aim: The renin angiotensin system [RAS] plays an important role in the development of diabetic renovascular pathology characteristic of diabetic nephropathy [DN]. Through inhibition of RAS by different mechanisms, angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II type 1 receptor blockers [ARBs] could slow the progression of diabetic renovascular disease. Thus, the present study was undertaken to test the hypothesis that a combination of an ACEI [fosinopril] and an ARB [candesartan] could exert additive reno- and vasculoprotective effects in uninephrectomized [UNE], streptozotocin [STZ] -induced diabetic rats. Material and Fifty male albino rats weighing 150-200 g were used in the present study. Rats were divided into five groups [each of ten rats]; ten rats of them were taken as normal sham-operated group. The remaining forty rats were subjected to left unilateral nephrectomy and then three weeks later, diabetes was induced by a single intravenous injection of STZ. The UNE STZ - diabetic rats were further subdivided into: control rats that were given no additional treatment but insulin s.c., UNE STZ -diabetic rats treated with fosinopril in addition to insulin for 16 weeks, UNE STZ - diabetic rats treated with candesartan in addition to insulin for 16 weeks and the fifth group was UNE STZ -diabetic rats treated with a combination of fosinopril and candesartan in addition to insulin for 16 weeks. UNE STZ - diabetic rats exhibited the characteristic features of diabetic renal disease including increased BP, plasma creatinine [PCr], urinary albumin excretion [UAE], kidney weight [KW], BG and glycosylated hemoglobin [HbAIc] together with decreased urinary creatinine [UCr] and creatinine clearance [CrCI]. Furthermore, control rats showed significant elevations in plasma transforming growth factor-beta 1 [TGF-D 1] and in renal malondialdehyde [MDA] associated with significant reduction in renal reduced glutathione [GSH]. Edothalial dysfunction [ED] of renal arteries isolated from STZ-diabetic rats, evidenced by a significant decrease in percentage of maximal relaxation in response to acetylcholine [ACH], has been also demonstrated. Oral administration of fosinopril or candesartan for 16 weeks in UNE STZ diabetic rats produced significant decreases in KW,BP, PCr,UAE, plasma TGED1 and renal MDA concentration together with significant increase in UCr, CrC 1 and renal GSH concentration. Vasculoprotective effect of fosinopril and candesartan has been also found, evidenced by a significant increase in the percentage of maximal relaxation in response to Ach in renal arteries isolated from UNR STZ-diabetic rats treated with fosinopril or candesartan Treatment of UNE diabetic rats with a combination of an ACEI [Fosinopril] and an ARB [candesartan] improved most of the estimated biochemical parameters as well as BP more significantly than either drug alone, but the combination of both drugs did not result in a significant difference in the percentage of maximal relaxation in response to Ach in renal arteries compared to either drug given alone. Conclusions: the results of the present study demonstrated that ACEIs and ARBs have a comparable degree of reno- and vasculoprotection in UNE STZ- induced diabetic rats Moreover, the present study demonstrated an additive renoprotective effect of combination therapy with ACEIs and ARBs over monotherapy with either class alone

Role of peroxisome proliferator activated receptor [PPAR] agonists in experimental liver fibrosis in rats

The ligand-dependent transcription factors, peroxisome proliferator-activated receptors [PPARs] are expressed in hepatic stellate cells [HSCs], which are the cells reported to play a central role in liver fibrosis. It has been reported that the transcriptional activity of PPAR gamma and alpha is reduced during activation of HSCs. The aim of the present study was to evaluate whether oral administration of pioglitazone [alpha PPAR gamma ligand], and bezafibrate [alpha PPAR alpha ligand], might retard liver fibrosis in rats. Fifty male albino rats weighing 150-200 g were used in the present study. Rats were divided into five groups, each often rats. Group I, injected intraperitonealy [i.p.] by thioacetamide [TAA]. Group II, injected i.p. by saline. Groups III and IV, treated with bezafibrate and pioglitazone respectively, orally starting from the first day of TAA administration. Group V, served as a control group for groups III and IV. The duration of the study was six weeks. Administration of TAA to rats for six weeks resulted in significant increases in portal pressure, serum cytokines [tumor necrosis factor-alpha TNF-alpha and transforming growth factor-beta 1 TGF-beta 1], hepatic hydroxyproline [HPO], and serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] associated with a significant decrease in hepatic glycogen concentration. On the other hand, the two PPAR ligands, pioglitazone and bezafibrate, produced a significant decrease in portal pressure, a significant decrease in serum TNF-alpha and TGF-beta 1, a significant improvement in all the estimated parameters of liver function, as well as a significant decrease in hepatic HPO concentration in rats that received the drugs for six weeks compared to the control untreated rats. The results of the present study demonstrated that the PPAR agonists, pioglitazone and bezafibrate were effective in preventing the fibrogenic process via modulating the action of the cytokines TNF-alpha and TGF- beta1. Further studies on humans are needed in order to assess the clinical use of PPAR agonists in patients with liver fibrosis

Role of oxidative stress in streptozotocin-induced diabetic neuropathy in rats

To assess the contribution of oxidative stress in the pathophysiology of diabetic neuropathy and the possible protective effect of L-carnitine, coenzyme Q 10 [CoQ10] and acetylsalicylic acid [ASA] in streptozotocin-included diabetic neuropathy in rats. We also examined whether the studied drugs can promote satisfactory regeneration of sciatic nerve fibers following sciatic nerve crushing. Twenty rats were used as control and were divided into two groups. 10 rats each: Group I a was injected intraperitoneal [i.p.] by a single dose of saline and served as a control for group II a, group I b similar to group I a but with induced sciatic nerve crushing and served as control for group II b. Eighty rats were made diabetic by i.p streptozotocin [STZ] injection and were divided into: group II a [STZ-injected rats], group II b [STZ-injected rats with sciatic nerve crushing], groups III a, IV a and V a [STZ-injected rats treated with L-carnitine, CoQ1O and ASA respectively, for six weeks starting one week following STZ injection], groups III b, IV b and V b [STZ-injected rats,with sciatic nerve crushing, that received the same drugs as groups III a, IV a and V a]. At the end of the experimental period, distal motor latency [DL], maximum peak and peak to peak amplitude of compound muscle action potential [CMAP] were measured by percutaneous sciatic nerve stimulation. Blood samples were collected for measurement of plasma glucose and malondialdehyde [MDA] concentrations. The sciatic nerve was isolated for measuring reduced glutathione [GSH] concentration. STZ-injection induced diabetes, evidenced by significant higher mean value in plasma glucose concentration in groups IIa and IIb compared to that of the control groups Ia and Ib respectively. Significant sciatic nerve dysfunction could be observed, in the form of significantly prolonged DL and significantly decreased maximum peak and peak to peak amplitude of CMAP, in groups IIa and IIb compared to the control groups Ia and Ib respectively. STZ-injection resulted in oxidative stress evidenced by significant higher mean value in plasma MDA concentration and significant lower mean value in sciatic nerve GSH concentration in groups IIa and IIb compared to the control groups Ia and Ib respectively. Sciatic nerve crushing in group I b resulted in significant prolongation of DL and significant decrease in maximum peak and peak to peak amplitude of CMAP compared to group I a. Sciatic nerve crushing in group I b also resulted in significant lower mean value of sciatic nerve GSH concentration compared to group I a. The use of L-carnitine, CoQ10 as well as ASA, did not cause a significant change in plasma glucose concentration nor in body weight compared to groups IIa and IIb. The use of the above mentioned drugs improved oxidative stress parameters evidenced by significant lower mean value in plasma MDA concentration and significant higher mean value in sciatic nerve GSH concentration compared to groups IIa and IIb. The increase in sciatic nerve GSH concentration in groups III b and IV b that received L-carnitine and CoQ10 respectively, was significant compared to group Vb that received ASA as an antioxidant, whereas no significant difference in plasma MDA was found between different drug-treated groups. The use of the studied drugs resulted in significant improvement of DL as well as significant increase in maximum peak and peak to peak amplitude of CMAP compared to groups IIa and IIb. Group V a showed significant higher mean value in the maximum peak and peak to peak amplitude of CMAP compared to groups III a and IV a. Also group V b showed significant higher mean value in the maximum peak and peak to peak amplitude of CMAP compared to group III b. The results of the present study support the hypothesis that oxidative stress plays a key role in the pathophysiology of diabetic neuropathy and demonstrate that the use of antioxidants might have a protective role against diabetic neuropathy as well as a role in enhancing regeneration of functional nerve fibers. We recommend further human studies to evaluate the role of the addition of natural antioxidants, like L-carnitine or CoQ10, as well as ASA to the treatment regimen of diabetes, from the onset of the disease, in protection against diabetic neuropathy

study on some pharmacologic manipulations of diet-induced obesity in rats

Aim: Obesity is a major health problem that represents an energy imbalance associated with complications, including cardiovascular disease, diabetes, and an increased mortality rate. The aim of the present work was to study some pharmacological manipulations of diet-induced obesity [DIO] in rats. Subjects and The study was conducted on 60 adult male albino rats that were divided into two groups; the DIO group fed high-calorie diet [HCD] [n=48] and the normal control group [n=12] fed normal laboratory diet. After 8 weeks, DIO rats were subdivided into four subgroups [each of 12 rats] that received the lipase inhibitor [orlistat], or the PPAR-gamma agonist [rosiglitazone], or the beta3-agonist [trecadrine] or a vehicle orally for 3 weeks. After the specified period, the following obesity variables were recorded: body weight, obesity index, food intake and rectal temperature. Blood samples were withdrawn for determination of serum metabolic parameters: glucose, triglycerides [TG], free fatty acids [FFA], leptin and insulin levels. Rats were sacrificed; and the remaining obesity variables were measured: retroperitoneal and interscapular fat as well as liver weight. The use of a HCD for 8 weeks resulted in a significant increase in all the measured obesity variables [except for rectal temperature] together with a significant increase in all the measured serum parameters as compared to rats that received normal laboratory diet. Orlistat administration for 3 weeks caused a significant decrease in all obesity variables with no significant change in food intake. A significant decrease in serum TG, FFA, insulin and leptin levels was also evident. Rosiglitazone-treated rats exhibited a significant decrease in liver weight together with a significant increase in fat pads weight and rectal temperature. Trecadrine produced significant reduction in obesity variables except for interscapular fat weight and rectal temperature that were significantly increased. Significant improvements in all serum metabolic parameters were noted with rosiglitazone and trecadrine treatment. Conclusions: From the current study, it can be concluded that lipase inhibitors and beta 3 agonists are effective in reducing body weight, while PPAR-gamma agonists are effective in improving insulin sensitivity and lipid abnormalities and so are rather effective as an adjuvant therapy to control the subsequent metabolic derangements relevant to obesity. Extrapolating these findings, especially the role of beta3-agonists, awaits further human trials before recommending it as a standard antiobesity drug

Synthesis and evaluation of some new 2.4- [1H.3H] -quinazolinedione derivatives as potential analgesic and anti-inflammatory agents

A series of 1-[3-trifluoromethylphenyl]-2, 4-[1H,3H]- quinazolinedione derivatives was synthesized as potential analgesic and anti- inflammatory agents. Structures were confirmed by elemental analysis and spectral data. Five compounds were tested for analgesic and anti- inflammatory activities. Two compounds II and VI exhibited significant analgesic and anti-inflammatory activities compared with flufenamic acid

Rett Syndrome: a difficult differential diagnosis in prelingual non-verbal children

Rett's disease, is a condition rarely met with in clinical phoniatric practice. The present work deals with 2 girls [3 and 3.8 years] met with during a period of 17 years. The routine scheme applied on brain damaged motorly handicapped children was applied on both girls. Both cases showed severe and nearly equal affection of all abilities motoric, manual reflexive, mental, social and language abilities. Although, no special therapeutic program was reported in the literature yet language and physical therapy were presented as a trial. The results of applying both lines of therapy are unsatisfactory regarding the period of follow up. Rett's disease should be suspected by the treating team when the response to language and physical therapy is rather slow, a point of prognostic significance more work is still needed to collect and study these cases in order to understand the pathophysiology of this rare condition

Determination of diclofenac sodium through the formation of charge transfer complex with chloranil

A colorimetric method for the determination of diclofenac sodium was developed. The method depends upon formation of colored change transfer complex between diclofenac sodium and chloranil. The complex formed in ethyl alcohol showing maximum absorbance at 545 nm. The different parameters were carefully studied and optimized. The concentration ranges adhering to Beer's law are 0.08-0.8 mg/ml. The method were applied of redetermination of diclofenac sodium in pure form or in pharmaceutical preparation