Pub Date : 2008-06-03DOI: 10.2174/1874143600802010054
H. J. Derijks, E. Heerdink, R. Janknegt, F. H. P. Koning, B. Olivier, A. Loonen, A. Egberts
Antidepressants have different receptor binding profiles, which are related to therapeutic action and adverse drug reactions. We constructed a model to classify antidepressants on the basis of their binding properties of most common transporter- and receptor sites. Receptor binding was quantified by calculating receptor occupancy for the 5-HT (serotonin) reuptake transporter, norepinephrinic reuptake transporter, 5-HT2C-receptor, M3-receptor, H1-receptor and 1- receptor. To identify groups of antidepressants that show similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principle component analysis (PCA) were used. In addition, to visualize (a)symmetry between binding profiles of antidepressants, radar plots were constructed. On the basis of both analyses, four clusters of antidepressants which exert similar pharmacological properties were identified. Potentially, this model could be a helpful tool in medical practice and may be used as a prediction model for adverse effects of drugs entering the market.
{"title":"Visualizing pharmacological activities of antidepressants: A novel approach","authors":"H. J. Derijks, E. Heerdink, R. Janknegt, F. H. P. Koning, B. Olivier, A. Loonen, A. Egberts","doi":"10.2174/1874143600802010054","DOIUrl":"https://doi.org/10.2174/1874143600802010054","url":null,"abstract":"Antidepressants have different receptor binding profiles, which are related to therapeutic action and adverse drug reactions. We constructed a model to classify antidepressants on the basis of their binding properties of most common transporter- and receptor sites. Receptor binding was quantified by calculating receptor occupancy for the 5-HT (serotonin) reuptake transporter, norepinephrinic reuptake transporter, 5-HT2C-receptor, M3-receptor, H1-receptor and 1- receptor. To identify groups of antidepressants that show similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principle component analysis (PCA) were used. In addition, to visualize (a)symmetry between binding profiles of antidepressants, radar plots were constructed. On the basis of both analyses, four clusters of antidepressants which exert similar pharmacological properties were identified. Potentially, this model could be a helpful tool in medical practice and may be used as a prediction model for adverse effects of drugs entering the market.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"14 1","pages":"54-62"},"PeriodicalIF":0.0,"publicationDate":"2008-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82405619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-04-11DOI: 10.2174/1874143600802010024
Hairong Song, Å. Sidén, Z. Hassan
Roscovitine is a potent inhibitor of cyclin-dependent kinases (CDKs) that competes with the ATP binding pocket of kinases. Roscovitine has been shown to have cytotoxic effect on cancer cell lines in vitro and also in tumor xenografts in vivo. A strong synergistic effect in combination with conventional cytostatics has been reported in cancer cell lines in vitro. In this study, the mechanisms of roscovitineinduced cell death were investigated in human leukemic cell lines HL-60, Jurkat and K562. Cells were incubated with roscovitine (0.5-200 mol/L) up to 24 hours and cell viability and proliferation were studied using resazurin and H-thymidine incorporation assays, respectively. Cell cycle and mitochondrial membrane potential were analyzed using flow cytometry, apoptosis was assessed using morphological criteria in Giemsa staining and apoptotic pathways using Western blot analysis. Both viability and proliferation were inhibited in a concentration-dependent manner in all cell lines. Estimated IC50 was 17, 24 and 47 mol/L for HL-60, Jurkat and K562, respectively. Loss of mitochondrial membrane potential, release of cytochrome c, active fragment of caspase-3 and cleaved PARP were observed in all three cell lines. The cleaved fragments of caspase-2 and -8 were observed in HL-60 and Jurkat cells and the order of appearance differed between these two cell lines, while none of these fragments was observed in K562 cells. Thus, roscovitine is a potent inducer of apoptosis in leukemic cells and apoptosis has been mediated through different pathways depending on the cell line.
{"title":"Multiple Pathways of Apoptosis Induced by Roscovitine in Leukemic Cell Lines In Vitro","authors":"Hairong Song, Å. Sidén, Z. Hassan","doi":"10.2174/1874143600802010024","DOIUrl":"https://doi.org/10.2174/1874143600802010024","url":null,"abstract":"Roscovitine is a potent inhibitor of cyclin-dependent kinases (CDKs) that competes with the ATP binding pocket of kinases. Roscovitine has been shown to have cytotoxic effect on cancer cell lines in vitro and also in tumor xenografts in vivo. A strong synergistic effect in combination with conventional cytostatics has been reported in cancer cell lines in vitro. In this study, the mechanisms of roscovitineinduced cell death were investigated in human leukemic cell lines HL-60, Jurkat and K562. Cells were incubated with roscovitine (0.5-200 mol/L) up to 24 hours and cell viability and proliferation were studied using resazurin and H-thymidine incorporation assays, respectively. Cell cycle and mitochondrial membrane potential were analyzed using flow cytometry, apoptosis was assessed using morphological criteria in Giemsa staining and apoptotic pathways using Western blot analysis. Both viability and proliferation were inhibited in a concentration-dependent manner in all cell lines. Estimated IC50 was 17, 24 and 47 mol/L for HL-60, Jurkat and K562, respectively. Loss of mitochondrial membrane potential, release of cytochrome c, active fragment of caspase-3 and cleaved PARP were observed in all three cell lines. The cleaved fragments of caspase-2 and -8 were observed in HL-60 and Jurkat cells and the order of appearance differed between these two cell lines, while none of these fragments was observed in K562 cells. Thus, roscovitine is a potent inducer of apoptosis in leukemic cells and apoptosis has been mediated through different pathways depending on the cell line.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"14 1","pages":"24-30"},"PeriodicalIF":0.0,"publicationDate":"2008-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86518345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-03-27DOI: 10.2174/1874143600802010020
M. Mansour, S. Bakheet, A. Aleisa, S. Al-Rejaie, A. Al-Yahya, Mubarak El-Ameen, O. Al‐shabanah
Abstract: Doxorubicin (DOX) has a wide spectrum of antitumor activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from enhanced oxidative stress caused by oxygen centered free radicals. The present study was performed to investigate the influence of the antioxidant 6-gingerol on cardiotoxicity in-duced by doxorubicin (DOX). A single dose of DOX (20 mg/kg i.p.) induced myocardial toxicity after 48 hrs, manifested biochemically by a significant elevation in the following serum enzymes activities: creatine phosphokinase (E.C.2.7.3.2), lactate dehydrogenase (E.C.1.1.1.27), aspartate transaminase (E.C.2.6.1.1) and serum cardiac isoenzyme creatine phos-phokinase (MB). Administration of 6-gingerol (10 mg/kg/day p.o.) in drinking water starting 5 days before and continuing during the experimental period significantly ameliorated myocardial toxicity induced by DOX. The amelioration of car-diotoxicity was evidenced by significant reductions in serum enzymes activities and cardiac isoenzyme. The current data support 6-gingerol as a potentially selective cardioprotective agent, against cardiotoxicity induced by DOX and it may therefore improve the therapeutic index of DOX.
{"title":"Protective Effect of 6-Gingerol Against Cardiotoxicity Induced by Doxorubicin","authors":"M. Mansour, S. Bakheet, A. Aleisa, S. Al-Rejaie, A. Al-Yahya, Mubarak El-Ameen, O. Al‐shabanah","doi":"10.2174/1874143600802010020","DOIUrl":"https://doi.org/10.2174/1874143600802010020","url":null,"abstract":"Abstract: Doxorubicin (DOX) has a wide spectrum of antitumor activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from enhanced oxidative stress caused by oxygen centered free radicals. The present study was performed to investigate the influence of the antioxidant 6-gingerol on cardiotoxicity in-duced by doxorubicin (DOX). A single dose of DOX (20 mg/kg i.p.) induced myocardial toxicity after 48 hrs, manifested biochemically by a significant elevation in the following serum enzymes activities: creatine phosphokinase (E.C.2.7.3.2), lactate dehydrogenase (E.C.1.1.1.27), aspartate transaminase (E.C.2.6.1.1) and serum cardiac isoenzyme creatine phos-phokinase (MB). Administration of 6-gingerol (10 mg/kg/day p.o.) in drinking water starting 5 days before and continuing during the experimental period significantly ameliorated myocardial toxicity induced by DOX. The amelioration of car-diotoxicity was evidenced by significant reductions in serum enzymes activities and cardiac isoenzyme. The current data support 6-gingerol as a potentially selective cardioprotective agent, against cardiotoxicity induced by DOX and it may therefore improve the therapeutic index of DOX.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"55 1","pages":"20-23"},"PeriodicalIF":0.0,"publicationDate":"2008-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79465539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-02-28DOI: 10.2174/1874143600802010017
S. Matsumoto, S. Yoshida, M. Ikeda, C. Saiki, M. Takeda
The protein kinase C (PKC) inhibitor bisindolymaleimide Ro-31-8425 (Ro-31-8425) decreases the peak tetro- dotoxin-resistant (TTX-R) Na + (Nav1.8) current in nodose ganglion (NG) neurons, and this decrease is not altered by si- multaneous application of 8-bromo-cAMP (8-Br-cAMP), phorbol 12-myristate 13-acetate (PMA, a PKC activator) or forskolin (a cAMP analogue). Intracellular application of the endogenous protein kinase A (PKA) inhibitor, protein kinase inhibitor (PKI) abolishes the increase in the peak Nav1.8 current that occurs in response to the applications of 8-Br- cAMP, PMA, forskolin, or prostaglandin E2 (PGE2, an adenyl cyclase activator). At a higher concentration (0.5 mM) compared with a sufficient concentration (0.01 mM) to block the cAMP-stimulant Nav1.8 current, PKI still attenuated the Ro-31-8425-induced decrease in peak Nav1.8 current. When we considered these results together, cAMP-stimulant- induced modification of Nav1.8 currents is mediated by the activation of both PKA and PKC, and PKC may be located upstream of PKA.
{"title":"Effects of PKC and PKA Inhibitors on the cAMP-Stimulant-Induced Enhancement of Tetrodotoxin-Resistant Na + (Nav1.8) Currents","authors":"S. Matsumoto, S. Yoshida, M. Ikeda, C. Saiki, M. Takeda","doi":"10.2174/1874143600802010017","DOIUrl":"https://doi.org/10.2174/1874143600802010017","url":null,"abstract":"The protein kinase C (PKC) inhibitor bisindolymaleimide Ro-31-8425 (Ro-31-8425) decreases the peak tetro- dotoxin-resistant (TTX-R) Na + (Nav1.8) current in nodose ganglion (NG) neurons, and this decrease is not altered by si- multaneous application of 8-bromo-cAMP (8-Br-cAMP), phorbol 12-myristate 13-acetate (PMA, a PKC activator) or forskolin (a cAMP analogue). Intracellular application of the endogenous protein kinase A (PKA) inhibitor, protein kinase inhibitor (PKI) abolishes the increase in the peak Nav1.8 current that occurs in response to the applications of 8-Br- cAMP, PMA, forskolin, or prostaglandin E2 (PGE2, an adenyl cyclase activator). At a higher concentration (0.5 mM) compared with a sufficient concentration (0.01 mM) to block the cAMP-stimulant Nav1.8 current, PKI still attenuated the Ro-31-8425-induced decrease in peak Nav1.8 current. When we considered these results together, cAMP-stimulant- induced modification of Nav1.8 currents is mediated by the activation of both PKA and PKC, and PKC may be located upstream of PKA.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"120 1","pages":"17-19"},"PeriodicalIF":0.0,"publicationDate":"2008-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77723598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-02-14DOI: 10.2174/1874143600802010001
T. Maurice, J. Espallergues, C. Zussy, J. Meunier, Clémence Borys, Elodie George, P. Romieu
Cocaine-seeking behavior can be investigated in rodents using the conditioned place preference (CPP) paradigm. CPP can be extinguished and then reactivated using cocaine priming. To study the role of dopaminergic receptors in CPP reinstatement, CPP was induced in Swiss mice using cocaine (30 mg/kg ip) and extinguished with saline. CPP reactivation was examined by treatment with the D1 receptor antagonist SCH23,390 (0.03-1 mg/kg), the D2 antagonist raclopride (0.1-3 mg/kg) or the D3 antagonist U-99,194A (20-40 mg/kg), alone or before cocaine (15 mg/kg). Cocaine priming reactivated CPP up to 220% of the post-conditioning response. SCH23,390 and raclopride induced, alone at 0.3 mg/kg, reactivation of cocaine-induced CPP, but only SCH23,390 blocked the cocaine-induced reactivation. U99,194A failed to promote CPP reactivation alone or to affect the cocaine response. CPP reactivation involving contextual learning could be induced using a single-reconditioning session after extinction. Treatment with cocaine or raclopride, but not SCH23,390, induced CPP reactivation. Finally, the emotional state of mice was tested during reactivation under drug treatments in the elevated maze procedure and an anxiety state was measured after 0.3 mg/kg SCH23,390. These observations showed that in cocaine-conditioned animals and then extinguished, blockade of D1 receptors induces an anxiogeniclike state, able to promote a cocaine-sensitive CPP reactivation. Blockade of D2 receptor promoted a cocaine-mimetic CPP reactivation. Therefore, two different psychological states underlie CPP reactivation by drug priming: a 'drug craving CPP' induced by dopamine systems-mediated anxiety and a 'drug retrieval CPP' promoted by incentive learning processes.
{"title":"Different Psychological States Sustain Drug-Induced Reactivation of Cocaine Conditioned Place Preference in the Mouse","authors":"T. Maurice, J. Espallergues, C. Zussy, J. Meunier, Clémence Borys, Elodie George, P. Romieu","doi":"10.2174/1874143600802010001","DOIUrl":"https://doi.org/10.2174/1874143600802010001","url":null,"abstract":"Cocaine-seeking behavior can be investigated in rodents using the conditioned place preference (CPP) paradigm. CPP can be extinguished and then reactivated using cocaine priming. To study the role of dopaminergic receptors in CPP reinstatement, CPP was induced in Swiss mice using cocaine (30 mg/kg ip) and extinguished with saline. CPP reactivation was examined by treatment with the D1 receptor antagonist SCH23,390 (0.03-1 mg/kg), the D2 antagonist raclopride (0.1-3 mg/kg) or the D3 antagonist U-99,194A (20-40 mg/kg), alone or before cocaine (15 mg/kg). Cocaine priming reactivated CPP up to 220% of the post-conditioning response. SCH23,390 and raclopride induced, alone at 0.3 mg/kg, reactivation of cocaine-induced CPP, but only SCH23,390 blocked the cocaine-induced reactivation. U99,194A failed to promote CPP reactivation alone or to affect the cocaine response. CPP reactivation involving contextual learning could be induced using a single-reconditioning session after extinction. Treatment with cocaine or raclopride, but not SCH23,390, induced CPP reactivation. Finally, the emotional state of mice was tested during reactivation under drug treatments in the elevated maze procedure and an anxiety state was measured after 0.3 mg/kg SCH23,390. These observations showed that in cocaine-conditioned animals and then extinguished, blockade of D1 receptors induces an anxiogeniclike state, able to promote a cocaine-sensitive CPP reactivation. Blockade of D2 receptor promoted a cocaine-mimetic CPP reactivation. Therefore, two different psychological states underlie CPP reactivation by drug priming: a 'drug craving CPP' induced by dopamine systems-mediated anxiety and a 'drug retrieval CPP' promoted by incentive learning processes.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"52 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2008-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85230968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-02-12DOI: 10.2174/1874143600802010010
K. Venkova, D. Earnest, B. Meerveld
Gastric contractions induced by non-steroidal anti-inflammatory drugs (NSAIDs) contribute to mucosal ulceration. The goal of the present study was to investigate whether maintaining normal gastric motility provides protection against NSAIDs. A rat model of indomethacin-induced gastric mucosal injury and muscle hypercontratility was used to evaluate the protective effect of pretreatment with the 5-HT4 receptor agonist tegaserod (1 mg/kg b.i.d.) in comparison to the effect of the proton pump inhibitor omeprazole (20 mg/kg b.i.d). Indomethacin induced mucosal ulceration associated with hypercontractility of isolated antral muscle strips in response to KCl, carbachol, 5-HT or electrical field stimulation. Pretreatment with tegaserod alone or in combination with omeprazole prevented both mucosal ulceration and muscle hypercontractility. In contrast, omeprazole protected the mucosa without preventing the development of muscle hypercontractility. The results show that activation of peripheral 5-HT4 receptors promotes normal contractility of the antrum suggesting a different mechanism of gasrtoprotection against NSAIDs.
{"title":"Protective Effect of Tegaserod Against Indomethacin-Induced Gastric Injury in the Rat","authors":"K. Venkova, D. Earnest, B. Meerveld","doi":"10.2174/1874143600802010010","DOIUrl":"https://doi.org/10.2174/1874143600802010010","url":null,"abstract":"Gastric contractions induced by non-steroidal anti-inflammatory drugs (NSAIDs) contribute to mucosal ulceration. The goal of the present study was to investigate whether maintaining normal gastric motility provides protection against NSAIDs. A rat model of indomethacin-induced gastric mucosal injury and muscle hypercontratility was used to evaluate the protective effect of pretreatment with the 5-HT4 receptor agonist tegaserod (1 mg/kg b.i.d.) in comparison to the effect of the proton pump inhibitor omeprazole (20 mg/kg b.i.d). Indomethacin induced mucosal ulceration associated with hypercontractility of isolated antral muscle strips in response to KCl, carbachol, 5-HT or electrical field stimulation. Pretreatment with tegaserod alone or in combination with omeprazole prevented both mucosal ulceration and muscle hypercontractility. In contrast, omeprazole protected the mucosa without preventing the development of muscle hypercontractility. The results show that activation of peripheral 5-HT4 receptors promotes normal contractility of the antrum suggesting a different mechanism of gasrtoprotection against NSAIDs.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"24 1","pages":"10-16"},"PeriodicalIF":0.0,"publicationDate":"2008-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73540004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-07DOI: 10.2174/1874143600701010030
R. Said, M. Abdel-Rehim, B. Sadeghi, S. Al-Hashemi, Z. Hassan, Moustapha Hassan
Preclinical studies on pharmacokinetics in animals usually require at least 3-5 animals per time point. The use of several animals in each time point may increase the result variation due to individual dosing errors and interand intraindividual variation among animals. Moreover, a large number of animals has to be euthanized in these experiments. In the present paper, the pharmacokinetics of the anticancer drug, cyclophosphamide was investigated using serial bleeding from the tail vein and compared with the kinetics obtained from traditional retro-orbital sinus bleeding in mice. Cyclophosphamide (100 mg/kg) was administered intraperitoneally to two groups of mice. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 5 and 6 hr. In the first group (n=6), 20 L blood samples were collected from the tail-vein by serial bleeding. In the second group, 3 animals were killed at each time point and blood was collected from both tail vein and retro-orbital sinus. Cyclophosphamide analysis in whole blood was carried out using LC-MS/MS with on-line sample preparation utilizing microextraction by packed sorbent (MEPS). Pharmacokinetics including AUC, tmax, Cmax and half – life were estimated using WinNonLin. Cyclophosphamide concentrations in blood obtained after sampling through tail vein were close to those obtained after retro-orbital bleeding within the same animal. No significant differences in estimated pharmacokinetic parameters were found when serial tail vein bleeding was compared to retro-orbital bleeding. Our results indicate that serial sampling using tail vein in mice can be a good alternative to retro-orbital sampling method. The method is reliable, easy and can be used for early preclinical kinetic studies. However, more studies are needed to evaluate different drug categories.
{"title":"Cyclophosphamide Pharmacokinetics in Mice: A Comparison Between Retro Orbital Sampling Versus Serial Tail Vein Bleeding","authors":"R. Said, M. Abdel-Rehim, B. Sadeghi, S. Al-Hashemi, Z. Hassan, Moustapha Hassan","doi":"10.2174/1874143600701010030","DOIUrl":"https://doi.org/10.2174/1874143600701010030","url":null,"abstract":"Preclinical studies on pharmacokinetics in animals usually require at least 3-5 animals per time point. The use of several animals in each time point may increase the result variation due to individual dosing errors and interand intraindividual variation among animals. Moreover, a large number of animals has to be euthanized in these experiments. In the present paper, the pharmacokinetics of the anticancer drug, cyclophosphamide was investigated using serial bleeding from the tail vein and compared with the kinetics obtained from traditional retro-orbital sinus bleeding in mice. Cyclophosphamide (100 mg/kg) was administered intraperitoneally to two groups of mice. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 5 and 6 hr. In the first group (n=6), 20 L blood samples were collected from the tail-vein by serial bleeding. In the second group, 3 animals were killed at each time point and blood was collected from both tail vein and retro-orbital sinus. Cyclophosphamide analysis in whole blood was carried out using LC-MS/MS with on-line sample preparation utilizing microextraction by packed sorbent (MEPS). Pharmacokinetics including AUC, tmax, Cmax and half – life were estimated using WinNonLin. Cyclophosphamide concentrations in blood obtained after sampling through tail vein were close to those obtained after retro-orbital bleeding within the same animal. No significant differences in estimated pharmacokinetic parameters were found when serial tail vein bleeding was compared to retro-orbital bleeding. Our results indicate that serial sampling using tail vein in mice can be a good alternative to retro-orbital sampling method. The method is reliable, easy and can be used for early preclinical kinetic studies. However, more studies are needed to evaluate different drug categories.","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"39 1","pages":"30-35"},"PeriodicalIF":0.0,"publicationDate":"2008-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88683865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.2174/1874143600802010070
Kennon Heard, Robert Palmer, Nancy R Zahniser
Patients with acute cocaine poisoning present with life-threatening symptoms involving several organ systems. While the effects of cocaine are myriad, they are the result of a limited number of cocaine-protein interactions, including monoamine transporters, neurotransmitter receptors and voltage-gated ion channels. These primary interactions trigger a cascade of events that ultimately produce the clinical effects. The purpose of this article is to review the primary interactions of cocaine and the effects that these interactions trigger. We also describe the progression of symptoms observed in cocaine poisoning as they relate to serum cocaine concentrations.
{"title":"Mechanisms of acute cocaine toxicity.","authors":"Kennon Heard, Robert Palmer, Nancy R Zahniser","doi":"10.2174/1874143600802010070","DOIUrl":"10.2174/1874143600802010070","url":null,"abstract":"<p><p>Patients with acute cocaine poisoning present with life-threatening symptoms involving several organ systems. While the effects of cocaine are myriad, they are the result of a limited number of cocaine-protein interactions, including monoamine transporters, neurotransmitter receptors and voltage-gated ion channels. These primary interactions trigger a cascade of events that ultimately produce the clinical effects. The purpose of this article is to review the primary interactions of cocaine and the effects that these interactions trigger. We also describe the progression of symptoms observed in cocaine poisoning as they relate to serum cocaine concentrations.</p>","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"2 9","pages":"70-78"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703432/pdf/nihms90033.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28279208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.2174/1874143600802010031
Bobby D Nossaman, Philip J Kadowitz
Peroxynitrite (PN) is generated by the reaction of nitric oxide (NO) and superoxide in one of the most rapid reactions in biology. Studies have reported that PN is a cytotoxic molecule that contributes to vascular injury in a number of disease states. However, it has become apparent that PN has beneficial effects including vasodilation, inhibition of platelet aggregation, inhibition of inflammatory cell adhesion, and protection against ischemia/reperfusion injury in the heart. It is our hypothesis that PN may serve to inactivate superoxide and prolong the actions of NO in the circulation. This manuscript reviews the beneficial effects of PN in the cardiovascular system.
亚硝酸过氧化物（PN）由一氧化氮（NO）和超氧化物反应生成，是生物学中最快速的反应之一。研究报告称，过氧化亚硝酸盐是一种细胞毒性分子，在多种疾病状态下会导致血管损伤。不过，PN 显然具有有益的作用，包括扩张血管、抑制血小板聚集、抑制炎症细胞粘附以及防止心脏缺血/再灌注损伤。我们的假设是，PN 可使超氧化物失活，延长 NO 在循环中的作用时间。本手稿回顾了 PN 对心血管系统的有益作用。
{"title":"Potential Benefits of Peroxynitrite.","authors":"Bobby D Nossaman, Philip J Kadowitz","doi":"10.2174/1874143600802010031","DOIUrl":"10.2174/1874143600802010031","url":null,"abstract":"<p><p>Peroxynitrite (PN) is generated by the reaction of nitric oxide (NO) and superoxide in one of the most rapid reactions in biology. Studies have reported that PN is a cytotoxic molecule that contributes to vascular injury in a number of disease states. However, it has become apparent that PN has beneficial effects including vasodilation, inhibition of platelet aggregation, inhibition of inflammatory cell adhesion, and protection against ischemia/reperfusion injury in the heart. It is our hypothesis that PN may serve to inactivate superoxide and prolong the actions of NO in the circulation. This manuscript reviews the beneficial effects of PN in the cardiovascular system.</p>","PeriodicalId":22907,"journal":{"name":"The Open Pharmacology Journal","volume":"2 ","pages":"31-53"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659344/pdf/nihms63629.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28060635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-12-13DOI: 10.2174/1874143600701010027
L. Reynaud, M. A. Carleo, M. Talamo, G. Borgia
Nowadays HCV-related chronic hepatitis represents one of the main challenge for infectious diseases for many reasons: the dimension of the phenomenon, as millions of patients are afflicted with this pathology in the world, the dra- matic consequences on the quality of their life, the economic and sanitary efforts sustained by the society, but also the stimulating results in therapeutic approach due to the introduction of interferons in monotherapy first and association ther- apy (IFN plus ribavirin) later in modern protocols. The results obtained with these therapies are very encouraging even if medical doctors and patients know very well that this therapy is related to some side effects that grow dramatically in number with the progression of scientific knowledge. The Authors review the literature on the relationship among HCV, IFN therapy and diabetes to understand better damages and benefits of this long debated matter and possibly add their contribution to clinical and therapeutic strategies.
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