Devendra Pratap Singh, M.Pharm, MBA (Ph.D) | B V PATEL PERD CENTRE (original) (raw)
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Papers by Devendra Pratap Singh, M.Pharm, MBA (Ph.D)
There is a need to find/discover novel leads to treat complex and/or multi-factorial-pathogenic d... more There is a need to find/discover novel leads to treat complex and/or multi-factorial-pathogenic disease(s) like Nonsteroidal anti-inflammatory drugs (NSAID)-induced gastroenteropathy or gastrointestinal (GI) toxicity as it has emerged as an important medical and socioeconomic problem. There is no approved therapeutic strategy to prevent NSAID-induced enteropathic damage and highly effective gastro-protective drugs such as ranitidine hydrochloride (RAN) exacerbate it. In this purview, the multi target drug discovery approach (MTDD), combination approach and hit to lead strategies based on the foundation of ethnopharmacology and/or reverse pharmacology holds strong potential. Hence, the primary objectives of the current study were to explore the mechanism behind the preventative/curative effects of quercetin (QCT) on RAN exacerbated diclofenac sodium (DIC)-induced enteropathic damage and to assess the effects of co-administration of QCT and RAN on DIC-induced gastropathic damage in rats. Rats were treated twice daily with QCT (35, 50 and 100 mg kg-1 PO) and/or RAN (15 mg kg-1 PO) or vehicle for a total of 10 days. In some experiments, DIC (9 mg kg-1) was administered orally twice daily for the final 5 days of RAN/QCT+RAN/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day (free access to water). 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, alteration in xanthine oxidase (XO) activity, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The macroscopic, haematological, biochemical and histological evidences suggested that, though, RAN prevented the DIC-induced gastric injury, it exacerbated enteropathic damage. However, QCT not only significantly attenuated the RAN-induced exacerbation of enteropathic damage caused by DIC at the doses of 50 and 100 mg kg-1, but, this combination provided complete GI safety against the toxic effects of DIC too. The mechanisms behind the gastro-enteroprotective ability of QCT may be related to its ability to inhibit XO activity thus, preventing enhanced oxidative stress on GI tissues, prevent lipid peroxidation, IP alteration and alteration in GI luminal pH. The preventative effects of QCT on NSAID-induced gastroenteropathy were ably supported by the QCT induced prevention of GI blood loss and serum protein loss. These pharmaco-mechanistic results of QCT are aligning to combination based MTDD approach and hence we propose it as a promising lead to treat NSAID-gastroenteropahty and related complications.
Management of NSAID-induced gastrointestinal toxicity is a challenge and requires the availabilit... more Management of NSAID-induced gastrointestinal toxicity is a challenge and requires the availability of appropriate experimental animal models that are as close to humans as possible and a proper understanding of its etiopathogenesis. Our first objective was to develop a rat model for NSAID-induced gastroenteropathy and also to explore if co-administration of NSAID and proton pump inhibitor (PPI) contributes to exacerbation of NSAID-enteropathy. Rats were treated twice daily with pantoprazole sodium (PTZ; 10 mg/kg peroral) or vehicle for a total of 10 days. In some experiments, Diclofenac sodium (DCF; 9 mg/kg) or vehicle was administered orally twice daily for the final 5 days of PTZ/vehicle administration. After the last dose on 9 th day, rats in all the groups were fasted but water was provided ad libitum. 12 hours after the last dose on 10 th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. The macroscopic, histological and biochemical evidences suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy. Based on literature search we have also developed the probable cascade and interplay between various confounding factors of gastroenteropathy with special focus on TNF-α as a promising futuristic therapeutic target. Translation of this knowledge may aid in development of clinically relevant therapeutic interventions/strategies for the management of NSAID induced gastroenteropathy.
A B S T R A C T Management of Nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropat... more A B S T R A C T Management of Nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy has emerged as a major medical and socioeconomic problem mainly because the highly efficacious gastroprotective drugs i.e. proton pump inhibitors (PPIs) like pantoprazole sodium (PTZ), worsen the NSAID-induced enteropathic damage and lack of approved therapeutic strategies/interventions to prevent this damage. Hence, the primary objective of the current study was to assess whether we can protect the GI mucosa against gastroenteropathic damage caused by diclofenac sodium (DIC) in rats by co-administration of PTZ and quercetin (QCT). Rats were treated twice daily with QCT (35, 50 and 100 mg kg À1 peroral) and/or PTZ (4 mg kg À1) or vehicle for a total of 10 days. In some experiments, DIC (9 mg kg À1) was administered orally twice daily for the final 5 days of PTZ/QCT + PTZ/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day, but, water was provided ad libitum. 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The experimental evidences suggested that co-administration of QCT with PTZ significantly attenuated the exacerbation of NSAID-induced enteropathic damage in a dose dependent manner. The combination of PTZ 4 mg kg À1 and QCT at the doses of 50 or 100 mg kg À1 was found to effective in preventing the DIC-induced gastroenteropathy. The present report focuses on the gastroenteroprotective ability of QCT and the mechanisms may be related to its ability to prevent GI blood loss, the lipid peroxidation, intestinal permeability alteration and alteration in GI luminal pH.
The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and... more The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enterop-athy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo. (Translational Research 2016;175:76–91)
Introduction: Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastr... more Introduction:
Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy.
Methods:
Rats were treated twice daily with pantoprazole sodium (PTZ; 10 mg/kg peroral) or vehicle for a total of 10 days. In some experiments, Diclofenac sodium (DCF; 9 mg/kg) or vehicle was administered orally twice daily for the final 5 days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12 hours after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated.
Results:
The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ.
Conclusions:
This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit, serum albumin, serum total protein levels and IP alteration, known to occur in patients receiving NSAIDs. Additionally, this paper provides yet another evidence for PPI induced exacerbation of NSAID enteropathy.
Keywords: NSAIDs; Gastroenteropathy; Methods; PPIs; Rats; Enteropathy; Haemorrhagic lesions
There is a need to find/discover novel leads to treat complex and/or multi-factorial-pathogenic d... more There is a need to find/discover novel leads to treat complex and/or multi-factorial-pathogenic disease(s) like Nonsteroidal anti-inflammatory drugs (NSAID)-induced gastroenteropathy or gastrointestinal (GI) toxicity as it has emerged as an important medical and socioeconomic problem. There is no approved therapeutic strategy to prevent NSAID-induced enteropathic damage and highly effective gastro-protective drugs such as ranitidine hydrochloride (RAN) exacerbate it. In this purview, the multi target drug discovery approach (MTDD), combination approach and hit to lead strategies based on the foundation of ethnopharmacology and/or reverse pharmacology holds strong potential. Hence, the primary objectives of the current study were to explore the mechanism behind the preventative/curative effects of quercetin (QCT) on RAN exacerbated diclofenac sodium (DIC)-induced enteropathic damage and to assess the effects of co-administration of QCT and RAN on DIC-induced gastropathic damage in rats. Rats were treated twice daily with QCT (35, 50 and 100 mg kg-1 PO) and/or RAN (15 mg kg-1 PO) or vehicle for a total of 10 days. In some experiments, DIC (9 mg kg-1) was administered orally twice daily for the final 5 days of RAN/QCT+RAN/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day (free access to water). 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, alteration in xanthine oxidase (XO) activity, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The macroscopic, haematological, biochemical and histological evidences suggested that, though, RAN prevented the DIC-induced gastric injury, it exacerbated enteropathic damage. However, QCT not only significantly attenuated the RAN-induced exacerbation of enteropathic damage caused by DIC at the doses of 50 and 100 mg kg-1, but, this combination provided complete GI safety against the toxic effects of DIC too. The mechanisms behind the gastro-enteroprotective ability of QCT may be related to its ability to inhibit XO activity thus, preventing enhanced oxidative stress on GI tissues, prevent lipid peroxidation, IP alteration and alteration in GI luminal pH. The preventative effects of QCT on NSAID-induced gastroenteropathy were ably supported by the QCT induced prevention of GI blood loss and serum protein loss. These pharmaco-mechanistic results of QCT are aligning to combination based MTDD approach and hence we propose it as a promising lead to treat NSAID-gastroenteropahty and related complications.
Management of NSAID-induced gastrointestinal toxicity is a challenge and requires the availabilit... more Management of NSAID-induced gastrointestinal toxicity is a challenge and requires the availability of appropriate experimental animal models that are as close to humans as possible and a proper understanding of its etiopathogenesis. Our first objective was to develop a rat model for NSAID-induced gastroenteropathy and also to explore if co-administration of NSAID and proton pump inhibitor (PPI) contributes to exacerbation of NSAID-enteropathy. Rats were treated twice daily with pantoprazole sodium (PTZ; 10 mg/kg peroral) or vehicle for a total of 10 days. In some experiments, Diclofenac sodium (DCF; 9 mg/kg) or vehicle was administered orally twice daily for the final 5 days of PTZ/vehicle administration. After the last dose on 9 th day, rats in all the groups were fasted but water was provided ad libitum. 12 hours after the last dose on 10 th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. The macroscopic, histological and biochemical evidences suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy. Based on literature search we have also developed the probable cascade and interplay between various confounding factors of gastroenteropathy with special focus on TNF-α as a promising futuristic therapeutic target. Translation of this knowledge may aid in development of clinically relevant therapeutic interventions/strategies for the management of NSAID induced gastroenteropathy.
A B S T R A C T Management of Nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropat... more A B S T R A C T Management of Nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy has emerged as a major medical and socioeconomic problem mainly because the highly efficacious gastroprotective drugs i.e. proton pump inhibitors (PPIs) like pantoprazole sodium (PTZ), worsen the NSAID-induced enteropathic damage and lack of approved therapeutic strategies/interventions to prevent this damage. Hence, the primary objective of the current study was to assess whether we can protect the GI mucosa against gastroenteropathic damage caused by diclofenac sodium (DIC) in rats by co-administration of PTZ and quercetin (QCT). Rats were treated twice daily with QCT (35, 50 and 100 mg kg À1 peroral) and/or PTZ (4 mg kg À1) or vehicle for a total of 10 days. In some experiments, DIC (9 mg kg À1) was administered orally twice daily for the final 5 days of PTZ/QCT + PTZ/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day, but, water was provided ad libitum. 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The experimental evidences suggested that co-administration of QCT with PTZ significantly attenuated the exacerbation of NSAID-induced enteropathic damage in a dose dependent manner. The combination of PTZ 4 mg kg À1 and QCT at the doses of 50 or 100 mg kg À1 was found to effective in preventing the DIC-induced gastroenteropathy. The present report focuses on the gastroenteroprotective ability of QCT and the mechanisms may be related to its ability to prevent GI blood loss, the lipid peroxidation, intestinal permeability alteration and alteration in GI luminal pH.
The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and... more The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enterop-athy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo. (Translational Research 2016;175:76–91)
Introduction: Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastr... more Introduction:
Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy.
Methods:
Rats were treated twice daily with pantoprazole sodium (PTZ; 10 mg/kg peroral) or vehicle for a total of 10 days. In some experiments, Diclofenac sodium (DCF; 9 mg/kg) or vehicle was administered orally twice daily for the final 5 days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12 hours after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated.
Results:
The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ.
Conclusions:
This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit, serum albumin, serum total protein levels and IP alteration, known to occur in patients receiving NSAIDs. Additionally, this paper provides yet another evidence for PPI induced exacerbation of NSAID enteropathy.
Keywords: NSAIDs; Gastroenteropathy; Methods; PPIs; Rats; Enteropathy; Haemorrhagic lesions