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In vivo toxicity and immunomodulatory effects of Leishmanicidal thiadiazole derivatives
Abstracts
Poster – [A-10-106-1] In Vivo Efficacy of 1, 3, 4-Thiadiazole Derivatives in BALB/c mice Fatemeh Poorrajaba, Sussan Kabudanian Ardestanib, Alireza Foroumadic, Abbas Shafieec a Department of Biochemistry, Medicinal Science of Yazd Shahid Sadouqhi University, P.O. Box 8915173149, Yazd, Iran b Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145–1384, Tehran, Iran c Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran E-mail address: [email protected] (F. Poorrajab) Introduction: Following infection with Leishmania major, genetically susceptible BALB/c mice develop large cataneous lesions that lead to visceral infection. The infection progression is associated with type 2 cell-mediated immunity. Recently, we tried to complete the in vitro analysis by investigating in vivo efficiency of the analogs. Materials and Methods: Following parasite inoculation, and i.p. drug administration of 5 and 20 mg/kg/5 days doses, the course and size of cutaneous lesions, histopathology of liver, parasite loads in spleen through Limiting Dilution Assay as well as spleen cell activation assays through profile of cytokine secretions, were studied. Results: The analogs significantly decreased lesion size and progression of with granuloma formation which correlate with disease regression in hosts, moreover, represented immunomodulatory effects; stimulating IFN-γ expression and suppressing IL-10 and IL-5 production, favoring type 1 immune responses and parasite resolving. Conclusion: Our results highlight marked differences between the thiadiazol derivatives in compare to current anti-leishmanial drug. Even more, the in vivo Leishmania treatments indicate the immunomodulatory function play an essential role for enhancing cell-mediated immunity for complete clearance of the pathogen. Keywords: 1, 3, 4-thiadiazole derivatives, Leishmania, Immune-modulator, Type I and type 2 response doi:10.1016/j.clinbiochem.2011.08.304
Poster – [A-10-106-2] In vivo toxicity and immunomodulatory effects of Leishmanicidal thiadiazole derivatives Fatemeh Poorrajaba, Sussan Kaboudanian Ardestanib, Alireza Foroumadic, Abbas Shafieec a Department of Biochemistry, Medicinal Science of Yazd Shahid Sadouqhi University, P.O. Box 8915173149, Yazd, Iran b Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran c Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran E-mail address: [email protected] (F. Poorrajab) Introduction: Leishmania spp. causes a broad spectrum of diseases collectively known as leishmaniasis. Herein, we evaluate the in vivo toxicity of a series of nitroheteroaryl-1, 3, 4-thiadiazoles with in vivo potent activity to heal lethal leishmaniasis in BALB/c mice. Materials and methods: Following i.p. administration of 100– 200 mg/kg doses of the analogs, the in vivo acute toxicity was determined by assessment of the activity profiles of the sera enzymes (GOT/AST) and (GPT/ALT), histopathology of visceral organs. The in vitro formation of antimicrobial agents, ROS and RNS in drug-stimulated splenocytes and peritoneal macrophage, respectively were determined. Results: The compounds induce no observable change in the activity profiles GOT and GPT and no considerably lesion in the liver. In contrast, the compounds significantly induced T helper I-stimulating secretion of inflammatory cytokines IFN-γ and IL-12, whereas suppressed T helper
S129
2-inducing cytokine IL-10 to 20 fold. Interestingly the in vitro experiments exhibited the compounds can also stimulate ROS and Nox. Conclusion: In note with the fact that, there is a correlation between Th1-inducing cytokine production of IFN-γ and IL-12, the oxidative burst within professional phagocytic cells. Our in vivo studies emphasize that the compounds may have a drastic effect on pathogen elimination in highly-susceptible BALB/c mice. Keywords: In vivo toxocity, Immunomodulatory, Spleen lymphocytes doi:10.1016/j.clinbiochem.2011.08.305
Poster – [A-10-107-1] Study of correlation of endogenous creatinine clearance with estimated (calculated) glomerular filtration rate in assessment of renal function Jarin Akhter Dept. of Boichemistry, Jalalabad Ragib-Rabeya Medical College, Sylhet, Bangladesh E-mail address: [email protected] Introduction: To find the correlation of endogenous creatinine clearance with estimated (calculated) glomerular filtration rate in assessment of renal function this cross sectional study was carried out in the department of MAG Osmani Medical College, Sylhet from July 2007 to June 2008. A total of 97 (ninety seven) subjects with an age ranging from 18 to 70 years were studied. Fifty eight patients with CCR < 90 ml/min were considered as chronic kidney disease (CKD) patients designated as group-I and 39 (thirty nine) study subjects with CCR ≥ 90 ml/min were considered as healthy subjects designated as group-II. CCR was measured by collection of 24 h urine volume. Subjects with urinary tract infection, renal stone and dialysis or transplant patients were excluded from this study. Mean creatinine clearance values of group-I by CCR, (with 24 h urine collection), CG and MDRD formulas were 54.06 ± 22.61 ml/min, 61.54 ± 34.39 ml/min and 73.51 ± 37.42 ml/min, respectively. Mean creatinine clearance values of group-II by CCR, CG and MDRD formulas were 108.28 ± 17.46 ml/min, 100.45 ± 29.50 ml/min and 125.39 ± 42.01 ml/min respectively. In our study significant difference of creatinine clearance between CCR and MDRD methods was observed and there was no significant difference of creatinine clearance between CCR and CG methods in both chronic kidney disease patients and normal subjects. Conclusion: This result indicates that the Cockcroft–Gault equation correlated better than MDRD when compared with CCR for assessment of renal function both in CKD and normal subjects. But both CG and MDRD formulas are useful in assessment of renal function in CKD. Therefore, it may be suggested that eGFR is a useful effort to improve the identification of patients with renal impairment and Cockcroft–Gault (CG) formula is correlated with CCR (using 24 h urine volume) in both normal and CKD patients. Both CG and MDRD can be used in clinical practice for assessment of CKD. Further studies are recommended to confirm the generalizability of our findings with large sample size and categorizing the patients with renal impairment. Keywords: CCR (Creative Clearance Rate), CG (Cockcroft and Gault), CKD (Chronic Kidney Disease), eGFR(Estimated glomerular filtration rate), GFR (Glomerular filtration rate), iGFR (Isotope GFR), MDRD (Modification of diet renal disease study)
doi:10.1016/j.clinbiochem.2011.08.306
Poster – [A-10-106-1] In Vivo Efficacy of 1, 3, 4-Thiadiazole Derivatives in BALB/c mice Fatemeh Poorrajaba, Sussan Kabudanian Ardestanib, Alireza Foroumadic, Abbas Shafieec a Department of Biochemistry, Medicinal Science of Yazd Shahid Sadouqhi University, P.O. Box 8915173149, Yazd, Iran b Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145–1384, Tehran, Iran c Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran E-mail address: [email protected] (F. Poorrajab) Introduction: Following infection with Leishmania major, genetically susceptible BALB/c mice develop large cataneous lesions that lead to visceral infection. The infection progression is associated with type 2 cell-mediated immunity. Recently, we tried to complete the in vitro analysis by investigating in vivo efficiency of the analogs. Materials and Methods: Following parasite inoculation, and i.p. drug administration of 5 and 20 mg/kg/5 days doses, the course and size of cutaneous lesions, histopathology of liver, parasite loads in spleen through Limiting Dilution Assay as well as spleen cell activation assays through profile of cytokine secretions, were studied. Results: The analogs significantly decreased lesion size and progression of with granuloma formation which correlate with disease regression in hosts, moreover, represented immunomodulatory effects; stimulating IFN-γ expression and suppressing IL-10 and IL-5 production, favoring type 1 immune responses and parasite resolving. Conclusion: Our results highlight marked differences between the thiadiazol derivatives in compare to current anti-leishmanial drug. Even more, the in vivo Leishmania treatments indicate the immunomodulatory function play an essential role for enhancing cell-mediated immunity for complete clearance of the pathogen. Keywords: 1, 3, 4-thiadiazole derivatives, Leishmania, Immune-modulator, Type I and type 2 response doi:10.1016/j.clinbiochem.2011.08.304
Poster – [A-10-106-2] In vivo toxicity and immunomodulatory effects of Leishmanicidal thiadiazole derivatives Fatemeh Poorrajaba, Sussan Kaboudanian Ardestanib, Alireza Foroumadic, Abbas Shafieec a Department of Biochemistry, Medicinal Science of Yazd Shahid Sadouqhi University, P.O. Box 8915173149, Yazd, Iran b Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran c Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran E-mail address: [email protected] (F. Poorrajab) Introduction: Leishmania spp. causes a broad spectrum of diseases collectively known as leishmaniasis. Herein, we evaluate the in vivo toxicity of a series of nitroheteroaryl-1, 3, 4-thiadiazoles with in vivo potent activity to heal lethal leishmaniasis in BALB/c mice. Materials and methods: Following i.p. administration of 100– 200 mg/kg doses of the analogs, the in vivo acute toxicity was determined by assessment of the activity profiles of the sera enzymes (GOT/AST) and (GPT/ALT), histopathology of visceral organs. The in vitro formation of antimicrobial agents, ROS and RNS in drug-stimulated splenocytes and peritoneal macrophage, respectively were determined. Results: The compounds induce no observable change in the activity profiles GOT and GPT and no considerably lesion in the liver. In contrast, the compounds significantly induced T helper I-stimulating secretion of inflammatory cytokines IFN-γ and IL-12, whereas suppressed T helper
S129
2-inducing cytokine IL-10 to 20 fold. Interestingly the in vitro experiments exhibited the compounds can also stimulate ROS and Nox. Conclusion: In note with the fact that, there is a correlation between Th1-inducing cytokine production of IFN-γ and IL-12, the oxidative burst within professional phagocytic cells. Our in vivo studies emphasize that the compounds may have a drastic effect on pathogen elimination in highly-susceptible BALB/c mice. Keywords: In vivo toxocity, Immunomodulatory, Spleen lymphocytes doi:10.1016/j.clinbiochem.2011.08.305
Poster – [A-10-107-1] Study of correlation of endogenous creatinine clearance with estimated (calculated) glomerular filtration rate in assessment of renal function Jarin Akhter Dept. of Boichemistry, Jalalabad Ragib-Rabeya Medical College, Sylhet, Bangladesh E-mail address: [email protected] Introduction: To find the correlation of endogenous creatinine clearance with estimated (calculated) glomerular filtration rate in assessment of renal function this cross sectional study was carried out in the department of MAG Osmani Medical College, Sylhet from July 2007 to June 2008. A total of 97 (ninety seven) subjects with an age ranging from 18 to 70 years were studied. Fifty eight patients with CCR < 90 ml/min were considered as chronic kidney disease (CKD) patients designated as group-I and 39 (thirty nine) study subjects with CCR ≥ 90 ml/min were considered as healthy subjects designated as group-II. CCR was measured by collection of 24 h urine volume. Subjects with urinary tract infection, renal stone and dialysis or transplant patients were excluded from this study. Mean creatinine clearance values of group-I by CCR, (with 24 h urine collection), CG and MDRD formulas were 54.06 ± 22.61 ml/min, 61.54 ± 34.39 ml/min and 73.51 ± 37.42 ml/min, respectively. Mean creatinine clearance values of group-II by CCR, CG and MDRD formulas were 108.28 ± 17.46 ml/min, 100.45 ± 29.50 ml/min and 125.39 ± 42.01 ml/min respectively. In our study significant difference of creatinine clearance between CCR and MDRD methods was observed and there was no significant difference of creatinine clearance between CCR and CG methods in both chronic kidney disease patients and normal subjects. Conclusion: This result indicates that the Cockcroft–Gault equation correlated better than MDRD when compared with CCR for assessment of renal function both in CKD and normal subjects. But both CG and MDRD formulas are useful in assessment of renal function in CKD. Therefore, it may be suggested that eGFR is a useful effort to improve the identification of patients with renal impairment and Cockcroft–Gault (CG) formula is correlated with CCR (using 24 h urine volume) in both normal and CKD patients. Both CG and MDRD can be used in clinical practice for assessment of CKD. Further studies are recommended to confirm the generalizability of our findings with large sample size and categorizing the patients with renal impairment. Keywords: CCR (Creative Clearance Rate), CG (Cockcroft and Gault), CKD (Chronic Kidney Disease), eGFR(Estimated glomerular filtration rate), GFR (Glomerular filtration rate), iGFR (Isotope GFR), MDRD (Modification of diet renal disease study)
doi:10.1016/j.clinbiochem.2011.08.306