aaruni saxena | University of Rostock (original) (raw)
Papers by aaruni saxena
European Journal of Pharmacology, Dec 1, 2013
Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of as... more Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX-1) enzyme. In order to examine the interference of common NSAIDs with the anti-platelet activity of aspirin the human platelet rich plasma from voluntary donors was used for arachidonic acid-induced aggregation and determination of thromboxane synthesis. Further, docking studies were used to explain the molecular basis of the NSAID/aspirin interaction. The experimental results showed that celecoxib, dipyrone (active metabolite), ibuprofen, flufenamic acid, naproxen, nimesulide, oxaprozin, and piroxicam significantly interfere with the anti-platelet activity of aspirin, while diclofenac, ketorolac and acetaminophen do not. Docking studies suggested that NSAIDs forming hydrogen bonds with Ser530, Arg120, Tyr385 and other amino acids of the COX-1 hydrophobic channel interfere with antiplatelet activity of aspirin while non interfering NSAIDs do not form relevant hydrogen bond interactions within the aspirin binding site. In conclusion, docking analysis of NSAID interactions at the COX-1 active site appears useful to predict their interference with the anti-platelet activity of aspirin. The results, demonstrate that some NSAIDs do not interfere with the antiplatelet action of aspirin while many others do and provide a basis for understanding the observed differences among individual non-aspirin NSAIDs.
![Research paper thumbnail of [Final accepted version, unedited] Exploring the inhibitory mechanisms of indazole compounds against SAH/MTAN-mediated quorum sensing utilizing QSAR and docking](https://attachments.academia-assets.com/113465472/thumbnails/1.jpg)
](Drug Target Insights, Nov 29, 2022
Cardiovascular Diabetology, Apr 7, 2016
Background: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing... more Background: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. Study design and methods: The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissuespecific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.
Circulation, Nov 17, 2020
Introduction: With advancement in interventional cardiology an increase in the number of percutan... more Introduction: With advancement in interventional cardiology an increase in the number of percutaneous coronary intervention (PCI) procedures has been noted in the elderly. However, the post procedure complication and mortality remain a challenge for the physicians. This study aimed to estimate the survival among men and women above 80 years of age who undergo primary PCI for treatment of ST elevation myocardial infarction. Methods: We analyzed the data collected prospectively from our cardiac center. The patients were followed up over 10 years. Most patient received stents followed by anti-platelet drugs and preventive measures to avoid further cardiac event. Kaplan Meier curves were generated to study survival post PCI (SPSS v2.2). Survival curves were developed to determine the influence of age, sex, type of stent and degree of coronary flow (TIMI 0-3) on post procedure survival. Results: From 2010 to 2019, total 502 patients >80 years received PCI (282 males, 218 females). The median survival in the male and female population were 2.16 yrs. (95% CI 1.66 - 2.66) and 2.36 yrs. (95% CI 1.72-2.99)(P= 0.18). Significant difference of around 1 year (2.7 yrs. octogenarian vs 1.6 yrs. nonagenarian, p<0.001, see figure 1) was found in post PCI survival between octogenarian and nonagenarian. However, the survival was longer in case of Bare metal stents (BMS)(n= 113) as compared to Drug eluting stents(DES)(n= 274) (2.7 yrs. vs. 2.0yr, p<0.001). Similarly, post procedure TIMI flow analysis shows maximum survival in TIMI 3 followed by TIMI 2 and TIMI 1 ensuring the significance of TIMI grade flow. Conclusions: Our results demonstrate that PPCI in elderly patients have a better outcome and longer survival in octogenarians than nonagenarians. Similarly, use of BMS could be considered over DES in population above 80 years of age irrespective of gender. No difference in post PCI survival in male and female population.
Thrombosis and Haemostasis, 2013
Inhibition of platelet function by aspirin results from irreversible inhibition of platelet cyclo... more Inhibition of platelet function by aspirin results from irreversible inhibition of platelet cyclooxygenase (COX)-1. While sufficient inhibition is obtained at antiplatelet doses (75-325 mg/day) in most (≥95%) treated patients, the antiplatelet effect of aspirin and subsequent cardiovascular risk reduction is much less in clinical settings and diseasedependent. Several reasons for this "high on treatment platelet reactivity" are known. This paper reviews the evidence for an interaction between aspirin and other COX inhibitors, namely non-steroidal antiinflammatory drugs (NSAIDs). Numerous experimental studies demonstrated a pharmacodynamic interaction between aspirin and NSAIDs. This likely occurs within the hydrophobic substrate channel of platelet COX-1 and might be explained by molecular competition between inhibitor drugs and substrate (arachidonic acid) at overlapping binding sites. This interaction is found with some compounds, notably ibuprofen and dipyrone (metamizole), but not with others, such as di-clofenac and acetaminophen (paracetamol). Hence, this interaction is not a class effect of NSAIDs and/or non-steroidal analgesics but rather due to specific structural requirements which still remain to be defined. In vivo studies on healthy subjects and patients tend to confirm this type of interaction as well as large differences between NSAIDs and non-steroidal analgesics, respectively. These interactions may be clinically relevant and may increase the cardiovascular risk in longterm treatment for primary and secondary cardiovascular prevention in patients with chronic inflammation, such as rheumatoid arthritis. These patients have an elevated risk for myocardial infarctions and may require chronic antiplatelet treatment by aspirin in addition to treatment of inflammatory pain.
Circulation, Nov 20, 2012
Topics in medicinal chemistry, 2015
Ebola virus disease (EVD) is a notoriously dreadful disease. The acute viral syndrome, which has ... more Ebola virus disease (EVD) is a notoriously dreadful disease. The acute viral syndrome, which has an incubation period ranging from 2 to 21 days, is characterized by fever and diarrhea, along with bleeding diathesis. Mortality rates are high. The natural reservoir is thought to be the fruit bat of the Pteropodidae family. Nonhuman primates, including monkeys, chimpanzees, and gorillas, are primary hosts to the virus. Transmission occurs through direct contact with bodily fluids containing the virus. Currently available laboratory tests include the rapid diagnostic tests ELISA and PCR. A patient’s chance of survival depends on multiple factors, such as the initial viral load at the time of exposure, their immune response to the virus, and access to proper care. Currently, there is no specific treatment or cure; however, clinical management mainly consists of supportive measures. Novel drugs and vaccines are undergoing clinical trials to determine their safety and efficacy for use in humans.
This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antii... more This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) in human blood platelets. ASA is widely used all around the globe to prevent atherothrombotic events. Multi-morbid patients suffering from cardiovascular and rheumatological disorders including rheumatoid arthritis or osteoarthritis need a comedication of ASA with NSAID drugs. Hence, potential NSAID/ASA drug interactions, possibly affecting the cardioprotective effect of ASA, are of great interest. The present research aimed to determine which NSAIDs would decrease the anti-platelet activity of ASA. Using arachidonic acid-induced platelet aggregation and thromboxane formation108 in platelet rich plasma from healthy donors, the effect of NSAIDs on the antiplatelet activity of ASA was studied experimentally. It turned out that celecoxib, dipyrone, fenoprofen, flufenamic acid, ibuprofen, methylaminoantipyrin, mefenamic acid, nabumetone, naproxen, nimesulide, NS-398, oxaprozin, phenazone, piroxicam, propylphenazone, sulindac sulfide and tolmetin clearly decreased the antiplatelet activity of ASA. In contrast, acetaminophen, diclofenac, flurbiprofen, indomethacin and ketoprofen did not decrease the antiplatelet activity of ASA. The data was further used to design a QSAR model which showed that the IC50 and selectivity of NSAID towards COX-1 might predict the effect of NSAID on the antiplatelet activity of ASA. Further investigation aimed to identify the reasons for the interference of NSAIDs with the antiplatelet activity of ASA by molecular docking studies, which were performed for all NSAIDs on COX-I protein (PDB ID: 1CQE). Docking studies suggested that NSAIDs, forming hydrogen bonds with Ser 530, Arg 120, Tyr 385 and some other amino acids in the COX-I hydrophobic channel, play role in determining whether a particular NSAID might decrease the antiplatelet activity of ASA or not. NSAIDs which decreased the antiplatelet activity of ASA in the in vitro experiments mostly showed one or more hydrogen bond interactions with Ser 530, Tyr 385 or Arg 120. Less or no hydrogen bond interactions were seen in docking studies of NSAIDs which did not decrease the antiplatelet activity of ASA in the in vitro experiments. Therefore, hydrogen bond interactions with Ser 530 and Tyr 385 were found to be most relevant for NSAIDs effects on the antiplatelet activity of ASA.
Medicinal Chemistry Research, Feb 6, 2008
The pharmacokinetics of piperacillin-tazobactam were investigated in another set of six patients ... more The pharmacokinetics of piperacillin-tazobactam were investigated in another set of six patients suffering from renal failure undergoing either continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) at 1 L/h and 2 L/h for 12 hours. Piperacillin 4g/tazobactam 0.5 g was given on three successive treatment periods and their concentration in plasma and ultrafiltrate/dialysate was measured. Piperacillin and tazobactam form a b-lactam-b-lactamase inhibitor combination with a broad spectrum of antibacterial activity against Gram-positive and Gramnegative pathogens. This combination is quite often used for the empirical treatment of infection in intensive care patients. The main aim of this study was to determine the pharmacokinetics of both of these drugs in critically ill patients with acute renal failure treated by continuous venovenous hemodialysis (CVVHD) and to correlate these pharmacokinetic parameters with the dose given to the patient. In view of the fixed doses given to human beings unlike in the case of experimental animals where one considers dose per unit of body weight (mg/kg) and the fixed dose 4.0 g piperacillin and 0.5 g tazobactam for six and eight patients, respectively, the correlations were neither expected nor observed. Hence the effect of the parameters defining the patients viz. body weight, age, sex etc. on their response to fixed drug doses are considered to be useful for the better management of treatment. Understanding the relationship of these independent parameters , with the pharmacokinetic parameter Clcvvhd as a dependent parameter, may be useful in anuric intensive care patients during continuous venovenous hemodialysis treated with piperacillin and tazobactam. Hence, the quantitative pharmacokinetic patients
Current Medicinal Chemistry, 2022
![Research paper thumbnail of [Final accepted version, unedited] Exploring the inhibitory mechanisms of indazole compounds against SAH/MTAN-mediated quorum sensing utilizing QSAR and docking](https://attachments.academia-assets.com/113465470/thumbnails/1.jpg)
](Drug Target Insights
The world is under the great threat of antimicrobial resistance (AMR) leading to premature deaths... more The world is under the great threat of antimicrobial resistance (AMR) leading to premature deaths. Micro-organisms can produce AMR via quorum sensing mechanisms utilizing S-adenocylhomocystiene/methiothioadenosine nucleosidase (SAH/MTAN) biosynthesis. But there is no specific drug developed till date to stop theSAH/MTAN which is a crucial target for the discovery of anti quorum sensing compound. It has been shown that the indazole compounds causes inhibition of SAH/MTA nucleosidase mediated quorum sensing, but the biochemical mechanisms have not yet been explored.Therefore, in this original research, an attempt has been made to explore essential structural features of these compounds by QSAR and molecular docking of indazole compounds having inhibition of SAH/MTA nucleosidase mediated quorum sensing. The validated QSAR predicted five essential descriptors and the molecular docking helps to identify the active binding amino acid residues involved in ligand receptor interaction are re...
Current Neuropharmacology
: Neurodegeneration is the progressive loss of structure or function of neurons, which may ultima... more : Neurodegeneration is the progressive loss of structure or function of neurons, which may ultimately involve cell death. The most common neurodegenerative disorder in the brain happens with Alzheimer's disease (AD), the most common cause of dementia. It ultimately leads to neuronal death, thereby impairing the normal functionality of the central or peripheral nervous system. The onset and prevalence of AD involve heterogeneous etiology, either in terms of genetic predisposition, neurometabolomic malfunctioning, or lifestyle. The worldwide relevancies are estimated to be over 45 million people. The rapid increase in AD has led to a concomitant increase in the research work directed towards discovering a lucrative cure for AD. The neuropathology of AD comprises the deficiency in the availability of neurotransmitters and important neurotrophic factors in the brain, extracellular betaamyloid plaque depositions, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Current pharmaceutical interventions utilizing synthetic drugs have manifested resistance and toxicity problems. This has led to the quest for new pharmacotherapeutic candidates naturally prevalent in phytochemicals. This review aims to provide an elaborative description of promising Phyto component entities having activities against various potential AD targets. Therefore, naturopathy may combine with synthetic chemotherapeutics to longer the survival of the patients.
Circulation, Nov 16, 2021
Additional file 1. Methods.
Additional file 2. Risk analysis and risk mitigation measures.
Circulation, 2020
Introduction: With advancement in interventional cardiology an increase in the number of percutan... more Introduction: With advancement in interventional cardiology an increase in the number of percutaneous coronary intervention (PCI) procedures has been noted in the elderly. However, the post procedure complication and mortality remain a challenge for the physicians. This study aimed to estimate the survival among men and women above 80 years of age who undergo primary PCI for treatment of ST elevation myocardial infarction. Methods: We analyzed the data collected prospectively from our cardiac center. The patients were followed up over 10 years. Most patient received stents followed by anti-platelet drugs and preventive measures to avoid further cardiac event. Kaplan Meier curves were generated to study survival post PCI (SPSS v2.2). Survival curves were developed to determine the influence of age, sex, type of stent and degree of coronary flow (TIMI 0-3) on post procedure survival. Results: From 2010 to 2019, total 502 patients >80 years received PCI (282 males, 218 females). The...
This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antii... more This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) in human blood platelets. ASA is widely used all around the globe to prevent atherothrombotic events. Multi-morbid patients suffering from cardiovascular and rheumatological disorders including rheumatoid arthritis or osteoarthritis need a comedication of ASA with NSAID drugs. Hence, potential NSAID/ASA drug interactions, possibly affecting the cardioprotective effect of ASA, are of great interest. The present research aimed to determine which NSAIDs would decrease the anti-platelet activity of ASA. Using arachidonic acid-induced platelet aggregation and thromboxane formation108 in platelet rich plasma from healthy donors, the effect of NSAIDs on the antiplatelet activity of ASA was studied experimentally. It turned out that celecoxib, dipyrone, fenoprofen, flufenamic acid, ibuprofen, methylaminoantipyrin, mefenamic acid, nabumetone, naproxen, nimesulide, NS-39...
Current Medicinal Chemistry, 2021
European Journal of Pharmacology, Dec 1, 2013
Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of as... more Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX-1) enzyme. In order to examine the interference of common NSAIDs with the anti-platelet activity of aspirin the human platelet rich plasma from voluntary donors was used for arachidonic acid-induced aggregation and determination of thromboxane synthesis. Further, docking studies were used to explain the molecular basis of the NSAID/aspirin interaction. The experimental results showed that celecoxib, dipyrone (active metabolite), ibuprofen, flufenamic acid, naproxen, nimesulide, oxaprozin, and piroxicam significantly interfere with the anti-platelet activity of aspirin, while diclofenac, ketorolac and acetaminophen do not. Docking studies suggested that NSAIDs forming hydrogen bonds with Ser530, Arg120, Tyr385 and other amino acids of the COX-1 hydrophobic channel interfere with antiplatelet activity of aspirin while non interfering NSAIDs do not form relevant hydrogen bond interactions within the aspirin binding site. In conclusion, docking analysis of NSAID interactions at the COX-1 active site appears useful to predict their interference with the anti-platelet activity of aspirin. The results, demonstrate that some NSAIDs do not interfere with the antiplatelet action of aspirin while many others do and provide a basis for understanding the observed differences among individual non-aspirin NSAIDs.
Drug Target Insights, Nov 29, 2022
Cardiovascular Diabetology, Apr 7, 2016
Background: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing... more Background: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. Study design and methods: The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissuespecific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.
Circulation, Nov 17, 2020
Introduction: With advancement in interventional cardiology an increase in the number of percutan... more Introduction: With advancement in interventional cardiology an increase in the number of percutaneous coronary intervention (PCI) procedures has been noted in the elderly. However, the post procedure complication and mortality remain a challenge for the physicians. This study aimed to estimate the survival among men and women above 80 years of age who undergo primary PCI for treatment of ST elevation myocardial infarction. Methods: We analyzed the data collected prospectively from our cardiac center. The patients were followed up over 10 years. Most patient received stents followed by anti-platelet drugs and preventive measures to avoid further cardiac event. Kaplan Meier curves were generated to study survival post PCI (SPSS v2.2). Survival curves were developed to determine the influence of age, sex, type of stent and degree of coronary flow (TIMI 0-3) on post procedure survival. Results: From 2010 to 2019, total 502 patients >80 years received PCI (282 males, 218 females). The median survival in the male and female population were 2.16 yrs. (95% CI 1.66 - 2.66) and 2.36 yrs. (95% CI 1.72-2.99)(P= 0.18). Significant difference of around 1 year (2.7 yrs. octogenarian vs 1.6 yrs. nonagenarian, p<0.001, see figure 1) was found in post PCI survival between octogenarian and nonagenarian. However, the survival was longer in case of Bare metal stents (BMS)(n= 113) as compared to Drug eluting stents(DES)(n= 274) (2.7 yrs. vs. 2.0yr, p<0.001). Similarly, post procedure TIMI flow analysis shows maximum survival in TIMI 3 followed by TIMI 2 and TIMI 1 ensuring the significance of TIMI grade flow. Conclusions: Our results demonstrate that PPCI in elderly patients have a better outcome and longer survival in octogenarians than nonagenarians. Similarly, use of BMS could be considered over DES in population above 80 years of age irrespective of gender. No difference in post PCI survival in male and female population.
Thrombosis and Haemostasis, 2013
Inhibition of platelet function by aspirin results from irreversible inhibition of platelet cyclo... more Inhibition of platelet function by aspirin results from irreversible inhibition of platelet cyclooxygenase (COX)-1. While sufficient inhibition is obtained at antiplatelet doses (75-325 mg/day) in most (≥95%) treated patients, the antiplatelet effect of aspirin and subsequent cardiovascular risk reduction is much less in clinical settings and diseasedependent. Several reasons for this "high on treatment platelet reactivity" are known. This paper reviews the evidence for an interaction between aspirin and other COX inhibitors, namely non-steroidal antiinflammatory drugs (NSAIDs). Numerous experimental studies demonstrated a pharmacodynamic interaction between aspirin and NSAIDs. This likely occurs within the hydrophobic substrate channel of platelet COX-1 and might be explained by molecular competition between inhibitor drugs and substrate (arachidonic acid) at overlapping binding sites. This interaction is found with some compounds, notably ibuprofen and dipyrone (metamizole), but not with others, such as di-clofenac and acetaminophen (paracetamol). Hence, this interaction is not a class effect of NSAIDs and/or non-steroidal analgesics but rather due to specific structural requirements which still remain to be defined. In vivo studies on healthy subjects and patients tend to confirm this type of interaction as well as large differences between NSAIDs and non-steroidal analgesics, respectively. These interactions may be clinically relevant and may increase the cardiovascular risk in longterm treatment for primary and secondary cardiovascular prevention in patients with chronic inflammation, such as rheumatoid arthritis. These patients have an elevated risk for myocardial infarctions and may require chronic antiplatelet treatment by aspirin in addition to treatment of inflammatory pain.
Circulation, Nov 20, 2012
Topics in medicinal chemistry, 2015
Ebola virus disease (EVD) is a notoriously dreadful disease. The acute viral syndrome, which has ... more Ebola virus disease (EVD) is a notoriously dreadful disease. The acute viral syndrome, which has an incubation period ranging from 2 to 21 days, is characterized by fever and diarrhea, along with bleeding diathesis. Mortality rates are high. The natural reservoir is thought to be the fruit bat of the Pteropodidae family. Nonhuman primates, including monkeys, chimpanzees, and gorillas, are primary hosts to the virus. Transmission occurs through direct contact with bodily fluids containing the virus. Currently available laboratory tests include the rapid diagnostic tests ELISA and PCR. A patient’s chance of survival depends on multiple factors, such as the initial viral load at the time of exposure, their immune response to the virus, and access to proper care. Currently, there is no specific treatment or cure; however, clinical management mainly consists of supportive measures. Novel drugs and vaccines are undergoing clinical trials to determine their safety and efficacy for use in humans.
This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antii... more This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) in human blood platelets. ASA is widely used all around the globe to prevent atherothrombotic events. Multi-morbid patients suffering from cardiovascular and rheumatological disorders including rheumatoid arthritis or osteoarthritis need a comedication of ASA with NSAID drugs. Hence, potential NSAID/ASA drug interactions, possibly affecting the cardioprotective effect of ASA, are of great interest. The present research aimed to determine which NSAIDs would decrease the anti-platelet activity of ASA. Using arachidonic acid-induced platelet aggregation and thromboxane formation108 in platelet rich plasma from healthy donors, the effect of NSAIDs on the antiplatelet activity of ASA was studied experimentally. It turned out that celecoxib, dipyrone, fenoprofen, flufenamic acid, ibuprofen, methylaminoantipyrin, mefenamic acid, nabumetone, naproxen, nimesulide, NS-398, oxaprozin, phenazone, piroxicam, propylphenazone, sulindac sulfide and tolmetin clearly decreased the antiplatelet activity of ASA. In contrast, acetaminophen, diclofenac, flurbiprofen, indomethacin and ketoprofen did not decrease the antiplatelet activity of ASA. The data was further used to design a QSAR model which showed that the IC50 and selectivity of NSAID towards COX-1 might predict the effect of NSAID on the antiplatelet activity of ASA. Further investigation aimed to identify the reasons for the interference of NSAIDs with the antiplatelet activity of ASA by molecular docking studies, which were performed for all NSAIDs on COX-I protein (PDB ID: 1CQE). Docking studies suggested that NSAIDs, forming hydrogen bonds with Ser 530, Arg 120, Tyr 385 and some other amino acids in the COX-I hydrophobic channel, play role in determining whether a particular NSAID might decrease the antiplatelet activity of ASA or not. NSAIDs which decreased the antiplatelet activity of ASA in the in vitro experiments mostly showed one or more hydrogen bond interactions with Ser 530, Tyr 385 or Arg 120. Less or no hydrogen bond interactions were seen in docking studies of NSAIDs which did not decrease the antiplatelet activity of ASA in the in vitro experiments. Therefore, hydrogen bond interactions with Ser 530 and Tyr 385 were found to be most relevant for NSAIDs effects on the antiplatelet activity of ASA.
Medicinal Chemistry Research, Feb 6, 2008
The pharmacokinetics of piperacillin-tazobactam were investigated in another set of six patients ... more The pharmacokinetics of piperacillin-tazobactam were investigated in another set of six patients suffering from renal failure undergoing either continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) at 1 L/h and 2 L/h for 12 hours. Piperacillin 4g/tazobactam 0.5 g was given on three successive treatment periods and their concentration in plasma and ultrafiltrate/dialysate was measured. Piperacillin and tazobactam form a b-lactam-b-lactamase inhibitor combination with a broad spectrum of antibacterial activity against Gram-positive and Gramnegative pathogens. This combination is quite often used for the empirical treatment of infection in intensive care patients. The main aim of this study was to determine the pharmacokinetics of both of these drugs in critically ill patients with acute renal failure treated by continuous venovenous hemodialysis (CVVHD) and to correlate these pharmacokinetic parameters with the dose given to the patient. In view of the fixed doses given to human beings unlike in the case of experimental animals where one considers dose per unit of body weight (mg/kg) and the fixed dose 4.0 g piperacillin and 0.5 g tazobactam for six and eight patients, respectively, the correlations were neither expected nor observed. Hence the effect of the parameters defining the patients viz. body weight, age, sex etc. on their response to fixed drug doses are considered to be useful for the better management of treatment. Understanding the relationship of these independent parameters , with the pharmacokinetic parameter Clcvvhd as a dependent parameter, may be useful in anuric intensive care patients during continuous venovenous hemodialysis treated with piperacillin and tazobactam. Hence, the quantitative pharmacokinetic patients
Current Medicinal Chemistry, 2022
Drug Target Insights
The world is under the great threat of antimicrobial resistance (AMR) leading to premature deaths... more The world is under the great threat of antimicrobial resistance (AMR) leading to premature deaths. Micro-organisms can produce AMR via quorum sensing mechanisms utilizing S-adenocylhomocystiene/methiothioadenosine nucleosidase (SAH/MTAN) biosynthesis. But there is no specific drug developed till date to stop theSAH/MTAN which is a crucial target for the discovery of anti quorum sensing compound. It has been shown that the indazole compounds causes inhibition of SAH/MTA nucleosidase mediated quorum sensing, but the biochemical mechanisms have not yet been explored.Therefore, in this original research, an attempt has been made to explore essential structural features of these compounds by QSAR and molecular docking of indazole compounds having inhibition of SAH/MTA nucleosidase mediated quorum sensing. The validated QSAR predicted five essential descriptors and the molecular docking helps to identify the active binding amino acid residues involved in ligand receptor interaction are re...
Current Neuropharmacology
: Neurodegeneration is the progressive loss of structure or function of neurons, which may ultima... more : Neurodegeneration is the progressive loss of structure or function of neurons, which may ultimately involve cell death. The most common neurodegenerative disorder in the brain happens with Alzheimer's disease (AD), the most common cause of dementia. It ultimately leads to neuronal death, thereby impairing the normal functionality of the central or peripheral nervous system. The onset and prevalence of AD involve heterogeneous etiology, either in terms of genetic predisposition, neurometabolomic malfunctioning, or lifestyle. The worldwide relevancies are estimated to be over 45 million people. The rapid increase in AD has led to a concomitant increase in the research work directed towards discovering a lucrative cure for AD. The neuropathology of AD comprises the deficiency in the availability of neurotransmitters and important neurotrophic factors in the brain, extracellular betaamyloid plaque depositions, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Current pharmaceutical interventions utilizing synthetic drugs have manifested resistance and toxicity problems. This has led to the quest for new pharmacotherapeutic candidates naturally prevalent in phytochemicals. This review aims to provide an elaborative description of promising Phyto component entities having activities against various potential AD targets. Therefore, naturopathy may combine with synthetic chemotherapeutics to longer the survival of the patients.
Circulation, Nov 16, 2021
Additional file 1. Methods.
Additional file 2. Risk analysis and risk mitigation measures.
Circulation, 2020
Introduction: With advancement in interventional cardiology an increase in the number of percutan... more Introduction: With advancement in interventional cardiology an increase in the number of percutaneous coronary intervention (PCI) procedures has been noted in the elderly. However, the post procedure complication and mortality remain a challenge for the physicians. This study aimed to estimate the survival among men and women above 80 years of age who undergo primary PCI for treatment of ST elevation myocardial infarction. Methods: We analyzed the data collected prospectively from our cardiac center. The patients were followed up over 10 years. Most patient received stents followed by anti-platelet drugs and preventive measures to avoid further cardiac event. Kaplan Meier curves were generated to study survival post PCI (SPSS v2.2). Survival curves were developed to determine the influence of age, sex, type of stent and degree of coronary flow (TIMI 0-3) on post procedure survival. Results: From 2010 to 2019, total 502 patients >80 years received PCI (282 males, 218 females). The...
This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antii... more This thesis studies the interaction of aspirin (acetylsalicylic acid, ASA) and nonsteroidal antiinflammatory drugs (NSAIDs) in human blood platelets. ASA is widely used all around the globe to prevent atherothrombotic events. Multi-morbid patients suffering from cardiovascular and rheumatological disorders including rheumatoid arthritis or osteoarthritis need a comedication of ASA with NSAID drugs. Hence, potential NSAID/ASA drug interactions, possibly affecting the cardioprotective effect of ASA, are of great interest. The present research aimed to determine which NSAIDs would decrease the anti-platelet activity of ASA. Using arachidonic acid-induced platelet aggregation and thromboxane formation108 in platelet rich plasma from healthy donors, the effect of NSAIDs on the antiplatelet activity of ASA was studied experimentally. It turned out that celecoxib, dipyrone, fenoprofen, flufenamic acid, ibuprofen, methylaminoantipyrin, mefenamic acid, nabumetone, naproxen, nimesulide, NS-39...
Current Medicinal Chemistry, 2021