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Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen ^†.

ABSTRACT: Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including a malignant pleural mesothelioma (MPM) one, a very chemoresistant tumor. The main reason of the increased activity relies on the enhanced lipophilicity of these Pt(IV) conjugates that in turn promotes increased cellular accumulation. A quick Pt(IV)?Pt(II) reduction generates the active cisplatin metabolite. The NSAID adjuvant action seems to be almost independent from cyclooxygenase-2 (COX-2) expression in the tumor cells under investigation (lung A-549, colon HT-29, HCT 116, SW480, ovarian A2780, and biphasic MPM MSTO-211H), but it seems to rely (at least in part) on the activation of the NSAID activated gene, NAG-1 (a member of the transforming growth factor beta, TGF-?, superfamily), which has been suggested to be involved in NSAID antiproliferative activity.

SUBMITTER: Ravera M

PROVIDER: S-EPMC6627341 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen <sup>†</sup>.

Ravera Mauro M Zanellato Ilaria I Gabano Elisabetta E Perin Elena E Rangone Beatrice B Coppola Marco M Osella Domenico D

International journal of molecular sciences 20190624 12

Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including a malignant pleural mesothelioma (MPM) one, a very chemoresistant tumor. The main reason of the increased activity relies on the enhanced lipophilicity of these Pt(IV) conju ...[more]

PMID: 31238499

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Project description:BackgroundIn 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states' powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics).Methods and findingsThis was an ecologic study with a time-trend analysis of FDC sales volumes (2007-2012) and a cross-sectional examination of 2011-2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval ("approved" and "unapproved"), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011-2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved; anti-psychotics: ten formulations, three (30%) approved, seven (70%) unapproved. After 1 May 2002, the proportions of approved FDC formulations increased for NSAIDs (26%/28%) and anti-psychotics (0%/38%) and decreased for metformin (100%/75%) and anti-depressants/benzodiazepines (20%/18%), and the overall proportion approved remained similar before and after that date. FDC formulations gave rise to multiple branded products, ranging from 211 anti-psychotic FDC products from ten formulations to 2,739 NSAID FDC products from 124 formulations. The proportions of FDC sales volumes arising from unapproved formulations were as follows: anti-depressants/benzodiazepines, 69%; anti-psychotics, 43%; NSAIDs, 28%; and metformin, 0.4%. Formulations including drugs banned/restricted internationally comprised over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. Across the four therapeutic areas, 14 FDC formulations were approved in the UK and 22 in the US.ConclusionsThere was evidence supporting concerns about FDCs. Metformin excepted, substantial numbers of centrally unapproved formulations for NSAID, anti-depressant/benzodiazepine, and anti-psychotic FDCs were marketed; sales volumes were high. The legal need for central approval of new drugs before manufacture has been in place continuously since 1961, including for FDCs meeting the applicable legal test. Proportions of centrally unapproved formulations after 1 May 2002 did not decrease overall, and no ambiguity was found about states' licensing powers. Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally and undertaking a review of benefits and risks for patients in ceasing or switching to other medicines. Drug laws need to be amended to ensure the safety and effectiveness of medicines marketed in India.

Project description:Globally, usage of non-steroidal anti-inflammatory drugs (NSAIDs) in elderly with chronic pain has been reported as frequent. Though NSAIDs are fundamental in maintaining their quality of life, the risk of polypharmacy, drug interactions and adverse effects is of paramount importance as the elderly usually require multiple medications for their co-morbidities. If prescriptions are not appropriately monitored and managed, they are likely to expose patients to serious drug interactions and potentially fatal adverse effects. This study was conducted to assess the appropriateness of NSAIDs use and determine the risk of NSAIDs related potential interactions in elderly. An analytical cross-sectional study was conducted among elderly out-patients (aged 60 and above) who visited three hospitals in Asmara, Eritrea, between August 22 and September 29, 2018. A stratified random sampling design was employed and data was collected using an interview-based questionnaire and by abstracting information from patients' prescriptions and medical cards. Descriptive and analytical statistics including chi-square test and logistic regression were employed using IBM SPSS (version 22). A total of 285 respondents were enrolled in the study with similar male to female ratio. One in four of all respondents were chronic NSAIDs users and NSAIDs risk practice was reported in 24%. Using chronic NSAIDs without prophylactic gastro-protective agents, self-medication, polypharmacy and drug-drug interactions were the main problems identified. A total of 322 potential interactions in 205 patients were identified and of which, 97.2% were classified as moderate, 0.6% severe and the rest were mild. Those who involved in self-medication were more likely to be exposed to drug interactions. Diabetes (AOR = 2.39, 95% CI: 1.14, 5.02) and hypertension (AOR = 9.06, 95% CI: 4.00, 20.51) were associated with chronic NSAIDs use and incidence of potential drug interactions (AOR = 3.5, 95%CI: 1.68, 4.3; AOR = 2.81, 95%CI: 1.61, 4.9 respectively), while diabetes AOR = 4.5, 95% CI: 2.43, 8.35) and cardiac problems (AOR = 4.29, 95% CI: 1.17, 15.73) were more likely to be associated with incidence of polypharmacy. In conclusion, chronic use of NSAIDs without gastro-protective agents and therapeutic duplication of NSAIDs were commonly which requires attention from programmers, health facility managers and healthcare professionals to safeguard elderlies from preventable harm.

Project description:Introduction: The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products, and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents. Methods: To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology. Results: We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC50 values of 138.2 and 76.7 µM, respectively). A weaker inhibition of hP2X1R, hP2X4R, and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) inhibited hP2X3R, rP2X3R, and hP2X7R (IC50 values of 221 µM, 264.1 µM, and ∼900 µM, respectively), calling into question its use as a non-selective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP application or increasing concentrations of the agonist α,β-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results suggest a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains, inhibits the gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R, and hP2X7R. Discussion: Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac, which are rarely reached in the therapeutic range, may play a minor role in analgesia compared to the high-potency cyclooxygenase inhibition but may explain the known side effect of taste disturbances caused by diclofenac.

Project description:Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) without a medical prescription and their frequent prevalence in aquatic habitats, there are major health and environmental issues. NSAIDs have been found in surface water and wastewater in concentrations ranging from ng/L to μg/L all over the world. The purpose of this study was to determine the relationship between NSAIDs (diclofenac, ketoprofen, paracetamol and ibuprofen) exposure and associated adverse effects in the assessment of indirect human health risks posed by Danio rerio (zebrafish) and Environmental Risk Assessment (ERA) of these NSAIDs in aquatic environments. Therefore, the objectives of this study were to (i) reveal abnormality endpoints of early developmental stages, after exposure of zebrafish and (ii) perform an ecological risk assessment of aquatic organisms upon exposure to NSAIDs detected in surface waters based on the risk quotients (RQs) method. According to the toxicity data collected, all of the malformations appeared after diclofenac exposure at all concentrations. The most notable malformations were the lack of pigmentation and an increase in yolk sac volume, with EC50 values of 0.6 and 1.03 mg/L, respectively. The results obtained for the ERA revealed RQs higher than 1 for all the four NSAIDs chosen, posing ecotoxicological pressure in aquatic environments. Overall, our findings provide a critical contribution to the formulation of high-priority actions, sustainable strategies and strict regulations that minimize the negative effects of NSAIDs on the aquatic ecosystem.•To determine the LC50, lethal conditions such as coagulation, absence of heartbeat and blood flow, absence of tail separation and development of somites were taken into account.•The EC50 was calculated using sublethal parameters such as blood coagulation, pericardial edema, yolk sac edema or hypertrophy.•The 4 compounds present a high risk individually and in mixture with a RQ >> 1.

Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used group of pharmaceuticals. The high consumption and the uncontrolled disposal of unused drugs into municipal waste or their deposit in landfills can result in an increased concentration of these compounds in soils. Moreover, these drugs can affect the microbial activity. However, there is a lack of knowledge about these effects or it is very limited. Therefore, the objective of this study was to compare the impact of selected commercially available NSAIDs, i.e., diclofenac (DCF), naproxen (NPX), ibuprofen (IBF) and ketoprofen (KTP), applied at concentrations of 1 and 10 mg/kg soil, on the activity of soil microorganisms during the 90-day experiment. To ascertain this impact, substrate-induced respiration (SIR), soil enzyme activities, i.e., dehydrogenase (DHA), acid and alkaline phosphatases (PHOS-H and PHOS-OH) and urease (URE) as well as changes in the rates of nitrification and ammonification processes were determined. In addition, the number of culturable bacteria and fungi were enumerated. In general, the obtained data showed a significant stimulatory effect of NSAIDs on the microbial activity. Higher concentrations of NSAIDs caused a greater effect, which was observed for SIR, PHOS-H, PHOS-OH, URE, N-NO3- and N-NH4+, even during the whole incubation period. Moreover, the number of heterotrophic bacteria and fungi increased significantly during the experiment, which was probably a consequence of the evolution of specific microorganisms that were capable of degrading NSAIDs and used them as an additional source of carbon and energy. However, an inhibitory effect of NPX, IBF or KTP for SIR, DHA, on both phosphatases and culturable bacteria and fungi was observed at the beginning of the experiment. At lower concentrations of NSAIDs, in turn, the effects were negligible or transient. In conclusion, the application of NSAIDs altered the biochemical and microbial activity of soil what may cause the disturbance in soil functioning. It is reasonable to assume that some components of the NSAID formulations could stimulate soil microorganisms, thus resulting in an increase in biochemical activities of the soil.

Dataset Information

Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen ^†.

Publications

Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen <sup>†</sup>.

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Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen †.

Publications

Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen <sup>†</sup>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Antiproliferative Activity of Pt(IV) Conjugates Containing the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ketoprofen and Naproxen ^†.