Anti-rheumatoid Agent Research Articles

Bioactive Molecules against Rheumatoid Arthritis by Suppressing Pyroptosis.

Rheumatoid arthritis is an inflammatory disease, and pyroptosis is a form of death associated with an inflammatory response. Pyroptosis, which occurs in synovial and osteoblastic cells, can exacerbate the development of rheumatoid arthritis. The inhibition of pyroptosis of these cells can, therefore, clearly be used as a therapeutic strategy against rheumatoid arthritis. Here, we have summarized the current status of progress in the treatment of rheumatoid arthritis by targeting cellular pyroptosis. We have identified seven compounds, including a cyclic RNA, a microRNA, a peptide, and a cytokine (protein), that may influence the progression of rheumatoid arthritis by regulating the initiation of pyroptosis. All of these compounds have been shown to have anti-rheumatoid effects in vitro and/or in vivo and have the potential to be developed as anti-rheumatoid agents. These findings may help to accelerate the development of anti-rheumatoid arthritis drugs.

The Anti-inflammatory and Anti-arthritis Activity of Garcinia travancorica in a Rat Model: A Proof of Concept with Computational Studies.

Background Rheumatoid arthritis is a progressive disease of human joints characterized by severe pain, stiffness, and tissue damage at the local site. Bone and cartilaginous tissue damage at the synovial joints is initiated by the production of autoantibody induced by inflammatory signaling through cytokines. Objective This study aimed to evaluate the efficacy of Garcinia travancorica against acute and chronic inflammation in a rat model after designing the ligand library and target identification using computational analysis. Methods Acute inflammation was induced by carrageen, and chronic inflammation was induced by Freund's complete adjuvant in the plantar surface of the rats. The petroleum ether, ethanolic, and aqueous extracts in three divided doses (75 mg/kg, 150 mg/kg, and 300 mg/kg) were administered orally. Diclofenac sodium (10 mg/kg), prednisolone (5 mg/kg), and methotrexate (0.5 mg/kg) were used as standard. Various parameters were evaluated, and statistical significance between means was analyzed using one-way ANOVA, followed by Dunnett's multiple range test. Results: Docking-based in-silico screening of the ligand library has revealed the potential of Polyanxanthone-C as an anti-rheumatoid agent, which is supposed to deliver its therapeutic effect by synergistic targeting of interleukin-1, interleukin-6, and tumor necrosis factor receptor type-1. Conclusion: This plant has the potential to be used in the treatment of arthritis-related disorders.

Activated, Pro-Inflammatory Th1, Th17, and Memory CD4+ T Cells and B Cells Are Involved in Delayed-Type Hypersensitivity Arthritis (DTHA) Inflammation and Paw Swelling in Mice.

Delayed-type hypersensitivity arthritis (DTHA) is a recently established experimental model of rheumatoid arthritis (RA) in mice with pharmacological values. Despite an indispensable role of CD4+ T cells in inducing DTHA, a potential role for CD4+ T cell subsets is lacking. Here we have quantified CD4+ subsets during DTHA development and found that levels of activated, pro-inflammatory Th1, Th17, and memory CD4+ T cells in draining lymph nodes were increased with differential dynamic patterns after DTHA induction. Moreover, according to B-cell depletion experiments, it has been suggested that this cell type is not involved in DTHA. We show that DTHA is associated with increased levels of B cells in draining lymph nodes accompanied by increased levels of circulating IgG. Finally, using the anti-rheumatoid agents, methotrexate (MTX) and the anti-inflammatory drug dexamethasone (DEX), we show that MTX and DEX differentially suppressed DTHA-induced paw swelling and inflammation. The effects of MTX and DEX coincided with differential regulation of levels of Th1, Th17, and memory T cells as well as B cells. Our results implicate Th1, Th17, and memory T cells, together with activated B cells, to be involved and required for DTHA-induced paw swelling and inflammation.

Abstract 1014: Repurposing the anti-rheumatic gold compound auranofin for high-grade serous ovarian cancer therapy

Abstract Auranofin (AF) is a gold compound approved in 1985 as a main treatment against rheumatoid arthritis. However, as new anti-rheumatoid agents displaced the use of AF, there have been studies aiming to repurpose the drug to treat other diseases, including cancer. In this study, we investigated the potentiality of AF to impair the growth of high-grade serous ovarian cancer (HGSOC) cells regardless of platinum (CDDP) sensitivity. Preliminary studies utilizing a colorimetric proliferation assay revealed that HGSOC cells that are clinically sensitive (PEO1) or resistant (PEO4) to CDDP-based chemotherapy are both equally sensitive to the growth inhibition induced by AF. The resistant factor estimated for AF-defined as the ratio between IC50 values calculated for the resistant cells and for the sensitive ones—was close to one, suggesting that CDDP-resistant PEO4 cells are equally sensitive to AF than CDDP-sensitive PEO1 cells. As expected, the resistant factor for CDDP was 12-fold higher in PEO4 compared to PEO1. The toxicity of AF against HGSOC cells was further studied exposing PEO1 to various concentrations of AF and assessing cell number, cell viability, and cell cycle traverse after 72 h. Results showed that AF, in a dose-dependent manner, blocked cell proliferation and caused accumulation of cells with hypo-diploid DNA content, suggesting that AF-induced cytotoxicity was associated not only with inhibition of cell proliferation but also with cell death likely driven via apoptosis. We further studied the long-term or residual toxicity of AF by exposing PEO1 cells that were alive, after 72 h treatment with AF, to a clonogenic survival assay. The results clearly demonstrated that even if not dying within 72 h, the cells were affected in a manner not compatible with long-term cell cycle progression as demonstrated by the formation of ‘abortive' colonies (i.e. colonies with few cells that show abnormal phenotypes). Finally, as AF is a pro-oxidant agent, we evaluated whether AF-induced cell death was mediated by oxidative stress by incubating PEO1 cells with AF in the presence or absence of the anti-oxidant N-acetyl-cysteine (NAC). PEO1 cells treated with AF and NAC showed no decrease in cell viability and cell number in comparison to PEO1 cells treated with AF alone. This data reveals that AF most likely induces cell death in a reactive oxygen species (ROS)-dependent manner. In conclusion, our results suggest that AF can equally impair the growth of CDDP-sensitive or -resistant HGSOC cells, and that its toxicity is likely mediated by oxidative stress. Citation Format: Farah H. Abdalbari, Alicia A. Goyeneche, Elvis Martinez-Jaramillo, Siham Sabri, Carlos M. Telleria. Repurposing the anti-rheumatic gold compound auranofin for high-grade serous ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1014.

Quality indicators of hymatomelanic acids preparation as a potential anti-rheumatoid agent

The article studies the influence of hymatomelanic acids, one of the fractions of humic substances of peloids, on the course of rheumatoid arthritis. This substance was standardized by using physicochemical analysis. The elemental composition of the substance as well as a number of spectral (IR, NMR) characteristics were revealed. The list of components formed as a result of hydrolysis of the initial preparation and their relative content was determined. Fatty acids and their derivatives are the predominant constituents of peloid hymatomelanic acid hydrolyzate. The tissues of immunocompetent organs including regional lymph nodes, spleen, and also rat liver were studied. For the experiment, a model of adjuvant arthritis was selected and four groups of animals were formed. They were withdrawn from the experiment on the 17, 21 and 26 day. The histological picture indicated that when modeling rheumatoid arthritis, such pathological changes in the immunocompetent organs of rats as edema of the parenchyma and stroma, sclerosis, thickening of the walls of blood vessels, develop during the whole period of observation. A list of descriptors of the studied drug was obtained and it was found that the use of peloid himatomelanic acids in the model of adjuvant arthritis had a pronounced anti-inflammatory effect, as evidenced by the normalization of the morphofunctional state of the spleen, regional lymph nodes and liver.

Pharmacological mechanism of immunomodulatory agents for the treatment of severe cases of COVID-19 infection.

ObjectiveCoronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1β. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19.MethodsA systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF.ResultsHere, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application.ConclusionIt is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.

Targeting PKCι-PAK1 in EGFR-mutation positive non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1 were abrogated. The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.

Liposomal glutathione as a promising candidate for immunological rheumatoid arthritis therapy

Nano-medicine can passively accumulate in chronic inflammatory tissues via the enhanced permeability and retention phenomenon, or by being conjugated with a ligand that can bind to receptors over expressed by cells inside chronic inflammatory tissues, contributing to reduced systemic side-effects and increased efficacy. This article highlights the utilization of nanomedicine for potential treatment of rheumatoid arthritis. Rheumatoid arthritis was induced in rat model via 2 weeks intradermal injection of pristane at the base of the tail in a daily dose of 150 μl. Susceptible rat strains developed severe arthritis with a sudden onset 3 weeks post pristane injection. Three weeks post pristane administration; rats were treated intravenously with glutathione or liposomal-glutathione in a dose of 5 mg/kg daily for 30 days. Concomitant supplementation with the aforementioned antioxidants effect on proinflammatory marker C-reactive protein (CRP) was assessed. On the other hand, oxidative stress biomarker malondialdehyde (MDA) and rheumatoid factor (RF) compared with pristane treated group was also investigated. The results elucidated that glutathione and liposomal -glutathione significantly reduced rheumatoid factor, malondialdehyde and C-reactive protein levels with the superiority of liposomal -glutathione in this side reflecting its pronounced effect as anti-rheumatoid agent.

Folate Conjugated Double Liposomes Bearing Prednisolone and Methotrexate for Targeting Rheumatoid Arthritis.

This investigation was aimed to explore the targeting potential of folate conjugated double liposomes (fDLs) bearing combination of synergistic drugs (Prednisolone and Methotrexate) for effective management of the rheumatoid arthritis (RA). To overcome the drawbacks of monotherapy, a combination of prednisolone (PRD) (an anti-inflammatory agent) and methotrexate (MTX) (a disease modifying anti-rheumatoid agent, DMARDs) was chosen for dual targeting approach. fDLs were prepared in two steps i.e. development of inner liposomes (ILs) using thin film casting method followed by encapsulation of ILs within folate conjugated outer liposomes (double liposomes; fDLs). Developed liposomes were characterized for various physicochemical parameters and in vivo performance. fDLs were prepared using FA-PEG-4000-NH-DSPE conjugate. These double liposomes were having 429.3 ± 3.6nm in size with 0.109 PDI, 8.01 ± 0.3mV zeta potential (ζ) and 66.7 ± 3.9% and 45.3 ± 1.7% entrapments of PRD and MTX, respectively. After 24h, the concentrations of PRD in blood were observed to be 8.66 ± 3.11 (ILs) and 15.13 ± 0.81% (DLs) while concentration of MTX were found to be 10.89 ± 0.69 and 2.34 ± 3.15% when given as ILs and fDLs, respectively. The concentration of both drugs in inflamed joint was observed to be higher than that in the non-inflamed joints. The folate conjugated double liposomes possess superior targeting efficiency than conjugated and unconjugated single liposomes.

Mechanism of Action of Methotrexate Against Zika Virus.

Zika virus (ZIKV), which is associated with microcephaly in infants and Guillain-Barré syndrome, reemerged as a serious public health threat in Latin America in recent years. Previous high-throughput screening (HTS) campaigns have revealed several potential hit molecules against ZIKV, including methotrexate (MTX), which is clinically used as an anti-cancer chemotherapy and anti-rheumatoid agent. We studied the mechanism of action of MTX against ZIKV in relation to its inhibition of dihydrofolate reductase (DHFR) in vitro using Vero and human neural stem cells (hNSCs). As expected, an antiviral effect for MTX against ZIKV was observed, showing up to 10-fold decrease in virus titer during MTX treatment. We also observed that addition of leucovorin (a downstream metabolite of DHFR pathway) rescued the ZIKV replication impaired by MTX treatment in ZIKV-infected cells, explaining the antiviral effect of MTX through inhibition of DHFR. We also found that addition of adenosine to ZIKV-infected cells was able to rescue ZIKV replication inhibited by MTX, suggesting that restriction of de novo synthesis adenosine triphosphate (ATP) pools suppresses viral replication. These results confirm that the DHFR pathway can be targeted to inhibit replication of ZIKV, similar to other published results showing this effect in related flaviviruses.

Evaluation of drug use pattern and quality of life in patients suffering from rheumatoid arthritis - A cross-sectional study at a tertiary care teaching hospital

Background: Rheumatoid arthritis (RA) is the most common autoimmune arthritis and it affects 1% of the adult population in India. It is an inflammatory disease which leads to bilateral joint pain and swelling. The swelling destroys joints and results in permanent deformities like ankylosis. Aims and Objectives: The objectives of this study were to study and evaluate the prescribing pattern in patients suffering from RA and to evaluate the quality of life (QoL) in RA patients. Materials and Methods: After getting permission from the Indian Council of Medical Research and Institutional Review Board, the study was started. Informed consent form of individual patient was obtained. All the patients of either sex attending rheumatology department and diagnosed with RA and receiving antirheumatoid drugs for 1 month were matriculate in the study and patients suffering along with osteoarthritis, and the newly diagnosed patient was excluded from the study. Results: A total of 50 patients were enrolled for the study which shows middle-aged people suffered more with female dominance and mostly used drug being methotrexate and hydroxychloroquine. RAQoL average being 17 which showed impaired QoL. Prescribing pattern in RA relied more on disease-modifying antirheumatoid agents. Conclusion: Commonly used drugs were disease-modifying antirheumatoid agents. It was found that the majority of the cost is borne by the patient as there are few drugs available at the hospital pharmacy which can be given free. Polypharmacy was common, being the cost burden to the patients.

Beneficial role of virgin coconut oil supplementation against acute methotrexate chemotherapy-induced oxidative toxicity and inflammation in rats

BackgroundMethotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid agent whose efficacy is limited by marked organ toxicities associated with oxidative stress. The study investigated beneficial effect of virgin coconut oil (VCO) supplementation on MTX-induced oxidative stress and inflammation in rats. MethodsRats were divided into 4 groups (n=6): Control, MTX (20mg/kg bw), VCO (5%)+MTX and VCO (15%)+MTX. The pre-treatment with VCO for 14 days was followed by single intraperitoneal injection of MTX and the rats were sacrificed after 3 days. Serum activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were determined. Interleukin-6 (IL-6), C-reactive protein (CRP) and nitric oxide (NO) levels were also evaluated. ResultsMTX induced a distinct diminution in serum activities of oxidative stress markers (SOD, CAT, GPx and GSH), while lipid peroxidation considerably increased demonstrated by MDA level. Similarly, levels of IL-6, CRP and NO increased prominently in MTX control rats. The VCO supplementation markedly enhanced resistance to the MTX-induced biochemical alterations in rats. ConclusionVCO can be a useful adjuvant natural product in MTX chemotherapy by reducing oxidative stress and pro-inflammatory responses.

Novel electrospun nanofibrous matrices prepared from poly(lactic acid)/poly(butylene adipate) blends for controlled release formulations of an anti-rheumatoid agent

In the present work, a series of novel formulations consisting of poly(lactic acid)/poly(butylene adipate) (PLA/PBAd) electrospun blends was examined as controlled release matrices for Leflunomide's active metabolite, Teriflunomide (TFL). The mixtures were prepared using different ratios of PLA and PBAd in order to produce nanofibrous matrices with different characteristics. Miscibility studies of the blended polymeric fibers were performed through differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Hydrolytic degradation in the prepared fibers was evaluated at 37°C using a phosphate buffered saline solution. Different concentrations of (TFL) (5, 10, 15wt.%) were incorporated into nanofibers for examining the drug release behavior in simulated body fluids (SBF), at 37°C. The drug-loaded nanofibrous formulations were further characterized by Fourier Transform Infrared Spectroscopy (FTIR) spectroscopy, DSC and XRD. Gel permeation chromatography (GPC) analysis was used to evaluate the mechanism of TFL release. Artificial neural networks (ANN) and multi-linear-regression (MLR) models were used to evaluate the effect of % content of PBAd (X1) and TFL (X2) on an initial burst effect and a dissolution behavior. It was found that PLA/PBAd nanofibers have different diameters depending on the ratio of used polyesters and added drug. TFL was incorporated in an amorphous form inside the polymeric nanofibers. In vitro release studies reveal that a drug release behavior is correlated with the size of the nanofibers, drug loading and matrix degradation after a specific time. ANN dissolution modeling showed increased correlation efficacy compared to MLR.

Abstract 3710: Targeted inhibition of arginase-1 may underline the suppression of the development of colonic neoplasia in a transgenic APC Min mouse model.

Abstract Colorectal cancer (CRC) is the third-leading malignancy in the United States. This year alone, about 141,210 new cases of colorectal cancer will be diagnosed and more than 49,380 people will die from the disease. Strategies have focused on early screening practices and the prevention of the development of colonic adenomas that serve as precursors of invasive colon cancers. We have recently showed that chloroquine (CQ) an anti-malarial and anti-rheumatoid agent has the capacity to competitively inhibit intracellular arginase-1 (ARG-1) and that this inhibition increases the nuclear localization of the cell cycle regulator p53 protein in colon cancer cell lines. However, the mechanism of CQ-induced inhibition of ARG-1 that results in the up-regulation of p53 is unclear. The goal of the current study was to examine the chemopreventive efficacy of CQ in the development of colonic neoplasia and to further evaluate the possible mechanism(s) of action. In this regard, six weeks old Apc(Min/+) mice were treated daily (except Saturdays and Sundays) with 0-50 mg CQ/kg body wt. via oral gavage for forty days. Post-treatment, mice were sacrificed and jejunum and colon were retrieved and preserved in 10% formalin for observation of any gross pathological changes. The results of this study showed an increased in prevalence of colonic adenomas in untreated mice compared with treated mice (< 0.05). Interestingly, histochemical analysis showed significant numbers of adenomas with high-grade dysplasia (as evidenced by the presence of increased fibrous tissue core) in untreated control mice in comparison with drug-treated mice (<0.05).Since emerging studies have identified the overexpression of ARG-1 in a variety of human malignancies, including cancer of the colon, we then investigated the impact of CQ on ARG-1 levels. To this end, HT-29 cells were co-incubated with CQ (0-50 μM) for 24 h and the levels of ARG-1 were determined by western blot assay. Surprisingly, our result showed that CQ-induced inhibition of ARG-1 level corresponded to the diminution of β-catenin protein via to its phosphorylation. Further immuno- fluorescence analysis showed an increased level of nuclear localization of GFP tagged p53 (GFP-p53) and p21 in transiently transfected HT-29 cells upon CQ treatment. The observation that targeting ARG-1 results in a corresponding decrease in β-catenin level is intriguing, since the Wnt/β-catenin signaling is fundamental to colon carcinogenesis and spontaneous tumorigenesis in Apc(Min/+) mice and patients with familial adenomatous polyposis.In conclusion, our cumulative findings indicate that CQ ameliorates the development of colonic neoplasia and that the inhibition of ARG-1 and β-catenin may contribute to its chemopreventive effects in intestinal tumorigenesis. Citation Format: Efe W. Iyamu, Mohammad S. Niaz, Aramandla Ramesh, Amos Sakwe, Kieosha Williams, Billy R. Ballard, Samuel E. Adunyah. Targeted inhibition of arginase-1 may underline the suppression of the development of colonic neoplasia in a transgenic APC Min mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3710. doi:10.1158/1538-7445.AM2013-3710

Chloroquine inhibits glutamate‐induced death of a neuronal cell line by reducing reactive oxygen species through sigma‐1 receptor

Chloroquine, a widely used anti-malarial and anti-rheumatoid agent, has been reported to induce apoptotic and non-apoptotic cell death. Accumulating evidence now suggests that chloroquine can sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis by inhibiting autophagy. However, chloroquine is reported to induce GM1 ganglioside accumulation in cultured cells at low μM concentrations and prevent damage to the blood brain barrier in mice. It remains unknown whether chloroquine has neuroprotective properties at concentrations below its reported ability to inhibit lysosomal enzymes and autophagy. In the present study, we demonstrated that chloroquine protected mouse hippocampal HT22 cells from glutamate-induced oxidative stress by attenuating production of excess reactive oxygen species. The concentration of chloroquine required to rescue HT22 cells from oxidative stress was much lower than that sufficient enough to induce cell death and inhibit autophagy. Chloroquine increased GM1 level in HT22 cells at low μM concentrations but glutamate-induced cell death occurred before GM1 accumulation, suggesting that GM1 induction is not related to the protective effect of chloroquine against glutamate-induced cell death. Interestingly, BD1047 and NE-100, sigma-1 receptor antagonists, abrogated the protective effect of chloroquine against glutamate-induced cell death and reactive oxygen species production. In addition, cutamesine (SA4503), a sigma-1 receptor agonist, prevented both glutamate-induced cell death and reactive oxygen species production. These findings indicate that chloroquine at concentrations below its ability to inhibit autophagy and induce cell death is able to rescue HT22 cells from glutamate-induced cell death by reducing excessive production of reactive oxygen species through sigma-1 receptors. These results suggest potential use of chloroquine, an established anti-malarial agent, as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases.

Atypical Protein Kinase Cι Expression and Aurothiomalate Sensitivity in Human Lung Cancer Cells

The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKC iota. ATM inhibits non-small lung cancer (NSCLC) growth by binding PKC iota and blocking activation of a PKC iota-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway. Here, we assessed the growth inhibitory activity of ATM in a panel of human cell lines representing major lung cancer subtypes. ATM inhibited anchorage-independent growth in all lines tested with IC(50)s ranging from approximately 300 nmol/L to >100 micromol/L. ATM sensitivity correlates positively with expression of PKC iota and Par6, but not with the PKC iota binding protein p62, or the proposed targets of ATM in rheumatoid arthritis (RA), thioredoxin reductase 1 or 2. PKC iota expression profiling revealed that a significant subset of primary NSCLC tumors express PKC iota at or above the level associated with ATM sensitivity. ATM sensitivity is not associated with general sensitivity to the cytotoxic agents cis-platin, placitaxel, and gemcitabine. ATM inhibits tumorigenicity of both sensitive and insensitive lung cell tumors in vivo at plasma drug concentrations achieved in RA patients undergoing ATM therapy. ATM inhibits Mek/Erk signaling and decreases proliferative index without effecting tumor apoptosis or vascularization in vivo. We conclude that ATM exhibits potent antitumor activity against major lung cancer subtypes, particularly tumor cells that express high levels of the ATM target PKC iota and Par6. Our results indicate that PKC iota expression profiling will be useful in identifying lung cancer patients most likely to respond to ATM therapy in an ongoing clinical trial.

Cytotoxicity of chloroquine in isolated rat hepatocytes

Chloroquine is a synthetic quinoline being used as an antimalaria and antirheumatoid agent. Several cases of hepatotoxicity have been reported with the use of chloroquine. However, the mechanism(s) of its hepatotoxic effect is unknown. The purpose of this study was to investigate the cytotoxic mechanism of chloroquine. Cytotoxicity was studied using freshly isolated rat hepatocytes incubated in Krebs-Henseleit buffer under a flow of 95% O(2) and 5% CO(2). Chloroquine was toxic towards hepatocytes and caused cell death with an ED(50) of about 100 mm in 2 h. The events before cell death were rapid GSH depletion and lipid peroxidation. Cytochrome P-450 inhibitors, troleandromycine, cimetidine and quinidine increased the cytotoxicity of chloroquine. Antioxidants significantly prevented the cytotoxicity of chloroquine. Depleting the hepatocyte GSH beforehand increased the chloroquine cytotoxicity. Preventing chloroquine metabolism by specific P-450 inhibitors increased its toxicity, suggesting that a major part of its toxicity is mediated by chloroquine and not by its metabolites. A depletion of the antioxidant defense system is involved in the mechanism of cytotoxicity.

Population pharmacodynamics of romazarit.

1. The response to romazarit, a disease modifying anti-rheumatoid agent, was observed in patients with rheumatoid arthritis (RA) in a double-blind placebo controlled study. 2. Two hundred and twenty-four patients were recruited from 11 centres and treated with placebo or romazarit at a dose of 200 mg or 450 mg every 12 h for up to 24 weeks. Disease activity was measured using the Ritchie Index (RI). Plasma concentrations of romazarit were measured at each of up to eight assessments of RI. 3. The effect of romazarit was examined using analysis of variance (ANOVA) in 164 patients who contributed 61% of observations of disease activity. Observations after 12 weeks of treatment were excluded from ANOVA. 4. A population pharmacokinetic-dynamic model for the time course of disease progress and the response to placebo and romazarit was used to describe observations from all patients. 5. The population model suggested that the effect of romazarit was on the rate of progress of the disease and was describable by an Emax model. Concentration was a better predictor of response than dose. 6. Romazarit was significantly better than placebo in improving the RI in patients with RA. The placebo efficacy of romazarit treatment was similar to that associated with placebo treatment. 7. The population model provided a more complete description and explanation of the clinical pharmacology and therapeutic potential of romazarit than ANOVA.

Rheumatoid Arthritis: Newer Treatment Modalities

DOI: http://dx.doi.org/10.5915/15-4-12431 With the introduction of the newer nonsteroidal anti-inflammatory drugs (NSAIDs) and penicillamine, our therapeutic armamentarium for the rheumatoid disease group had been significantly broadened. ln addition, there has been a renewed interest in anti-malarials, the use of some immunosuppressive agents, and plasmapheresis. The purpose of this article is to offer a helpful therapeutic scheme in the selection of these newer anti-rheumatoid agents. Furthermore, we have attempted to incorporate the clinical and laboratory profiles of rheumatoid patients into the treatment scheme. Rheumatoid arthritis can be divided into three subgroups: seronegative rheumatoid arthritis, sero-positive rheumatoid arthritis, and hybrid rheumatoid arthritis. Such classification offers a guideline in selecting the most suitable anti-arthritic agents. This paper was presented at the 16 annual oonvention of the Islamic Medical Association of North America, September 2-5, 1983.

Drug Interactions and Reactions Update

Elderly patients take a large number of drugs, especially psychoactive agents, and polypharmacy seems to be the rule in acute hospital settings and in institutions alike. Knowledge about alteration in drug response, with aging, is still at a preliminary and investigational stage, and the problem is compounded by the fact that there are relatively few drugs for which a special geriatric dosage is recommended. It appears to be common practice to keep the elderly in “chemical strait jackets” in some institutions, with emphasis on the use of antipsychotic and sedative/hypnotic combinations. Use of these agents has reached such proportions in Britain and America that it has become necessary to warn that antipsychotic drugs should be used only to treat acute behavior disorders in such patients. The potential for drug-drug interactions in the elderly patient is, therefore, large, and, in the community, the most common categories of prescribed drugs taken by the elderly are psychotropics, diuretics, and antipyretic/analgesics. In addition, analgesics and laxatives are often taken as nonprescribed medicines. Poor compliance with medication instructions, hoarding of drugs, and inadequate knowledge of the purpose of medication are very common. The eventual sequel to these factors is hospitalization; diuretics, hypotensives, antiparkinsonian agents, and psychotropics carry the greatest risk of evoking serious adverse drug reactions. Some specific drugs or groups of drugs present peculiar problems to the aged patient; these agents are relatively few in number and include digoxin, hypotensives, diuretics, nonsteroidal antiinflammatory agents, benzodiazepines, phenothiazines, lithium, and other psychoactive drugs. Currently, lithium and the antirheumatoid agent benoxaprofen are causing much concern in regard to the elderly. With lithium, there are adverse effects suggestive of neurotoxicity, and interactions with concurrent neuroleptic and/or antidepressant therapy, diuretics, and low salt diet are involved. As for benoxaprofen, reports in the past few months have causally linked this drug with fatal cholestatic jaundice and other serious reactions; this drug has now been withdrawn from clinical use. Health professionals must use extreme care when treating an elderly patient with drugs.