الفهرس 
I Dedicate This Work ToOnly 14 pages are availabe for public view
 |  | from | 164 |  |  |
| | | from | 164 | | |
Abstract
This present study was conducted to investigate of the possible effects of tadalafil and furosemide in both conventional and NP forms on the renal failure induced with glycerol and adenine in rats. To assess the renoprotective effect, established models of glycerol-induced ARF and adenine- induced CRF tests were used. Two sets of experiments were attempted. Acute study in which the animals were injected i.m. with a single dose of glycerol and tadalafil or furosemide in their conventional and NP forms. While in chronic study, the animals were orally adminestered adenine and daily doses of tadalafil or furosemide in their conventional and NP forms for four weeks.
Glycerol- induced ARF (8 ml/kg, im) was equally distributed to both hind legs. Rats are deprived of food and water for 24 h before glycerol administration after which they were sacrificed for kidney function evaluation. The present results, showed that significant decline was seen in the urine volume in glycerol –induced ARF rats, while treatment with tadalafil (10 mg/kg, oral), furosemide (20 mg/kg, i.m.) and their combination either in conventional or NP forms elevate this parameter. In addittion, the present study showed a significant elevation of urinary albumin, glucose and ketone bodies levels in glycerol- induced ARF. However, treatment with tadalafil (10mg/kg, oral), furosemide (20 mg/kg, i.m.) and their combination either in conventional or NP forms decrease these parameters.
Moreover, the present results showed a significant decrease of urinary osmolarity and specific gravity levels was found in glycerol- induced ARF, while treatment with tadalafil (10 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms elevate these parameters. Also, in the present study, a significant elevation was seen in the urea and creatinine levels in glycerol –induced ARF rats while treatment with tadalafil (10mg/kg, oral), furosemide (20mg/kg,i.m.) and their combination either in conventional or NP forms attenuated their levels. The previous results suggested the renoprotective effects of both tadalafil and furosemide or their combination particularly NP forms.
The present study showed a significant elevation in the tissue malondialdehyde levels and significant decrease in tissue reduced glutathione levels in glycerol –induced ARF rats, while treatment with tadalafil (10 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms improve these parameters. Also, a significant decline was seen in the kidney tissue nitrite levels in glycerol –induced ARF rats, while treatment with tadalafil (10 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms elevate the nitrite level. These data showed that the investigated drugs have a powerful anti -oxidant effect particularly NP forms.
Each of tadalafil (10 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination, both in conventional and NP forms, significantly decreased NGAL and KIM-1 in renal cortex particularly with NP forms at 24 h after glycerol treatment. In addition, the present study showed a significant elevation of interleukin 1β expression and caspase-3 in renal cortex in glycerol- induced ARF while treatment with tadalafil (10 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms showed great improvement. These data showed that the investigated drugs have anti-inflammatory and anti-apoptotic effects particularly NP forms.
Addition of 0.75% w/w adenine to the diet of rats for 4 weeks gained general acceptance as a model to study CRF. The present study, showed that water intake, urinary albumin, urinary glucose and total ketones were significantly elevated while urinary output, urine osmolarity and urine specific gravity were significantly decreased in adenine- induced CRF rats. Treatment with tadalafil (5 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms showed marked improvement.
In the present study, we found that serum creatinine and blood urea nitrogen were significantly elevated while blood total proteins was significantly decreased. Treatment with tadalafil (5 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms improve these levels. Moreover, a significant elevation was seen in the tissue malondialdehyde levels and a significant decrease in the tissue reduced glutathione levels in adenine –induced CRF rats, while treatment with tadalafil (5 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms improve these parameters. The previous data showed that the investigated drugs have marked renoprotective and anti- oxidant effects particularly NP forms.
The present results showed a significant decline in the tissue nitrite levels in adenine–induced CRF rats, while treatment with tadalafil (5 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms elevate these levels. In addition, tadalafil (5 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms intervention significantly decreased NGAL and KIM-1 in renal cortex after adenine treatment. These data showed that the investigated drugs have anti- oxidant and anti- inflammatory effects particularly NP forms.
A significant elevation of caspase-3 and IL-1β expression in damaged proximal convoluted tubules in adenine- induced CRF while treatment with tadalafil (5 mg/kg, oral), furosemide (20 mg/kg,i.m.) and their combination either in conventional or NP forms showed great improvement. These data showed that the investigated drugs have anti- inflammatory and anti-apoptotic effects particularly NP forms.
Interestingly for the first time, tadalafil NPs and tadalafil- furosemide NPs combination showed higher improvement in the kidney function parameters compared to their conventional forms suggesting the higher enhancement with nanoparticulation compared to their conventional forms in both ARF and CRF.
In conclusion, The present study indicated the possible renoprotective effect of both tadalafil and furosemide in their conventional and NP forms in both glycerol- induced ARF and adenine –induced CRF. These renoprotective effects might be mediated by anti-inflammatory, anti- oxidant and anti- apoptotic effects. However, NP forms of investigated drugs showed higher improvement, there are no clinically-approved NPs that specifically target the kidney tissue for therapeutic or imaging applications. Thus, further studies should be done for the application of NPs- loaded dugs towards kidney diseases.