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Wagay, Javeed Iqbal, and Kirti Jain. "Phytochemical Analysis and Antimicrobial Activity of Iris kashmiriana and Iris ensata Extracts against Selected Microorganisms." Journal of Drug Delivery and Therapeutics 8, no. 6 (November 15, 2018): 28–34. http://dx.doi.org/10.22270/jddt.v8i6.1975.
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Infectious diseases are the second leading cause for worldwide death. Treatment of infections continues to be difficult in modern time because of the severe side effects of some drugs and the growing resistance to antibacterial agents. Over the past few decades the use of antibiotics is under threat as many commonly used antibiotics have become less effective against certain illnesses due to emergence of multi drug-resistant bacteria. In the present study the effects of 3 types of solvents, chloroform, ethyl acetate and methanol were investigated to determine the presence of various phytochemical constituent, total phenolic content, total flavonoids content and in vitro antimicrobial activity from rhizomes of Iris kashmiriana (Kashmir Iris) and Iris ensata (Japanese Iris), belong to family Iridaceae. The reason for selecting in vitro method was to minimize the usage of experimental animals. The antimicrobial activity of chloroform, ethyl acetate and methanol extract of rhizomes of Iris kashmiriana and Iris ensata were evaluated on bacterial strains of Bacillus cereus, Pseudomonas auregenosa, Proteus vulgaris and Eschirichia coli and fungal strains of Candida albicans and Aspergillus niger by agar well diffusion method. The preliminary phytochemical studies and quantitative analysis of alkaloids, phenol and flavonoids were performed by well reported method. These extracts were further subjected to TLC (Thin layer chromatography analysis). The chemical contents of the Iris kashmiriana and Iris ensata were presented as total phenolic content and total flavonoids content. Phytochemical screening of the extract showed the presence of some common compounds like phenols, terpenoids, flavonoids, carbohydrate etc. The antimicrobial potential of the plant extract was evaluated against different bacterial species which shows significant inhibitory action against all the tested bacterial and fungal strain. Methanolic extract was found to be more active than chloroform and ethyl acetate extracts. It reveals that the methanol soluble components of the plant are highly active against the above mentioned microorganism.
Keywords: Iris kashmiriana, Iris ensata, Phytochemical constituent, Total phenolic content, Total flavonoids content, In vitro antimicrobial activity
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Locri, Filippo, Noemi A. Pesce, Monica Aronsson, Maurizio Cammalleri, Mario De Rosa, Vincenzo Pavone, Paola Bagnoli, Anders Kvanta, Massimo Dal Monte, and Helder André. "Gaining insight on mitigation of rubeosis iridis by UPARANT in a mouse model associated with proliferative retinopathy." Journal of Molecular Medicine 98, no. 11 (September 17, 2020): 1629–38. http://dx.doi.org/10.1007/s00109-020-01979-8.
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Abstract Proliferative retinopathies (PR) lead to an increase in neovascularization and inflammation factors, at times culminating in pathologic rubeosis iridis (RI). In mice, uveal puncture combined with injection of hypoxia-conditioned media mimics RI associated with proliferative retinopathies. Here, we investigated the effects of the urokinase plasminogen activator receptor (uPAR) antagonist—UPARANT—on the angiogenic and inflammatory processes that are dysregulated in this model. In addition, the effects of UPARANT were compared with those of anti-vascular endothelial growth factor (VEGF) therapies. Administration of UPARANT promptly decreased iris vasculature, while anti-VEGF effects were slower and less pronounced. Immunoblot and qPCR analysis suggested that UPARANT acts predominantly by reducing the upregulated inflammatory and extracellular matrix degradation responses. UPARANT appears to be more effective in comparison to anti-VEGF in the treatment of RI associated with PR in the murine model, by modulating multiple uPAR-associated signaling pathways. Furthermore, UPARANT effectiveness was maintained when systemically administered, which could open to novel improved therapies for proliferative ocular diseases, particularly those associated with PR. Key messages • Further evidence of UPARANT effectiveness in normalizing pathological iris neovascularization. • Both systemic and local administration of UPARANT reduce iris neovascularization in a model associated with proliferative retinopathies. • In the mouse models of rubeosis iridis associated with proliferative retinopathy, UPARANT displays stronger effects when compared with anti-vascular endothelial growth factor regimen.
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Choudhary, M. Iqbal, S. Naheed, S. Jalil, J. M. Alam, and Atta-ur-Rahman. "Effects of ethanolic extract of Iris germanica on lipid profile of rats fed on a high-fat diet." Journal of Ethnopharmacology 98, no. 1-2 (April 2005): 217–20. http://dx.doi.org/10.1016/j.jep.2005.01.013.
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Pesheva, Ekaterina D., and Valentin V. Fadeev. "Pioglitazone is a forgotten hypoglycemic drug with proven cardioprotective and nephroprotective properties." Consilium Medicum 23, no. 4 (2021): 366–71. http://dx.doi.org/10.26442/20751753.2021.4.200892.
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Considering that type 2 diabetes mellitus is a multicomponent disease and is associated with an extremely high risk of macrovascular complications (myocardial infarction, stroke and death from cardiovascular diseases), at present, much attention is paid to the choice of hypoglycemic drugs, given the individual characteristics of the patient. Preference is given to drugs of those classes that have a positive effect on cardiovascular outcomes. Along with relatively new molecules (inhibitors of the sodium-glucose cotransporter type 2 and agonists of glucagon-like peptide-1 receptors), the well-known drug pioglitazone, which belongs to the thiazolidinediones group, has not left the field of attention of researchers. Importantly, the cardioprotective effect of pioglitazone has been confirmed in several large randomized trials that showed a delay in atherosclerosis and a reduced risk of cardiovascular disease (PERISCOPE, CHICAGO, IRIS and PROactive). As an insulin sensitizer, pioglitazone reduces insulin resistance, has a protective effect on pancreatic β-cells, and also has a beneficial effect on components of insulin resistance syndrome (lowers blood pressure, lipid spectrum parameters) and improves the course of non-alcoholic fatty liver disease. There is evidence of possible side effects (weight gain, fluid retention, fractures), but their severity decreases with decreasing dose of the drug.
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Pan, Xiaolei, Li Wang, Dirk Gründemann, and Douglas H. Sweet. "Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy." Antimicrobial Agents and Chemotherapy 57, no. 10 (August 5, 2013): 5053–59. http://dx.doi.org/10.1128/aac.01255-13.
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ABSTRACTAccording to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2′-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50= 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting thatin vivopharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin).
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DeFronzo, Ralph A., Silvio Inzucchi, Muhammad Abdul-Ghani, and Steven E. Nissen. "Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes." Diabetes and Vascular Disease Research 16, no. 2 (February 1, 2019): 133–43. http://dx.doi.org/10.1177/1479164118825376.
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Type 2 diabetes individuals are at high risk for macrovascular complications: myocardial infarction, stroke and cardiovascular mortality. Recent cardiovascular outcome trials have demonstrated that agents in two antidiabetic classes (SGLT2 inhibitors and GLP-1 receptor agonists) reduce major adverse cardiovascular events. However, there is strong evidence that an older and now generically available medication, the thiazolidinedione, pioglitazone, can retard the atherosclerotic process (PERISCOPE and Chicago) and reduce cardiovascular events in large randomized prospective cardiovascular outcome trials (IRIS and PROactive). Pioglitazone is a potent insulin sensitizer, preserves beta-cell function, causes durable reduction in HbA1c, corrects multiple components of metabolic syndrome and improves nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Adverse effects (weight gain, fluid retention, fractures) must be considered, but are diminished with lower doses and are arguably outweighed by these multiple benefits. With healthcare expenses attributable to diabetes increasing rapidly, this cost-effective drug requires reconsideration in the therapeutic armamentarium for the disease.
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Mataveli, Fábio, Alessandra Calabró, Wellington Mendes, Denizar Vianna, Pedro Dorlhiac-Llacer, Ricardo Bigni, and Vania Hungria. "Cost-Effectiveness of Imatinib Versus Interferon-α in the Treatment of Patients Newly Diagnosed with Chronic Myeloid Leukemia, under the Brazilian Public Healthcare System Perspective." Blood 108, no. 11 (November 16, 2006): 3314. http://dx.doi.org/10.1182/blood.v108.11.3314.3314.
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Abstract The 60-month follow-up data for patients randomized to imatinib in IRIS demonstrated significant clinical improvements in survival rates and QALYs gained (17,09 years;13,58 QALYs) in patients newly diagnosed with chronic myeloid leukemia (CML) and treated with imatinib in comparison to patients under interferon-alpha (INF-α) (9,10 years;6,31 QALYS) as first line therapy. Although reimbursed as second line therapy for chronic phase CML patients who did not respond to INF-α, imatinib was not considered for public reimbursement as first line treatment in Brazil based solely on drug costs. An economic evaluation of imatinib as first line treatment versus INF-α was performed under the Brazilian Public Heathcare System perspective, according to the long-term follow-up data from IRIS, literature recommendations and prior health technology assessment from the National Institute for Clinical Excellence (NICE) to consider long term follow-up survival and adverse events costs. This study was aimed to evaluate the cost-effectiveness of imatinib compared with IFN-α for first-line treatment of chronic myeloid leukemia under the Brazilian public healthcare system perspective. For the economic model, a base case of 100 patients for each treatment option was constructed focused on drug costs and adverse events. Drug costs were estimated based on the Brazilian public healthcare reimbursement payment (APAC-SUS) for chronic phase CML treatment. Febrile neutropenia (grade III and IV), depression, nausea and abnormal liver-function results were considered as adverse events. Clinical guidelines and protocols from two public hematology Brazilian centers, Fundação Pró-Sangue FM-USP and Instituto Nacional do Cancer, were used to estimate adverse events treatment costs. Adverse events frequency for all grades was based on data published by NICE and the Agency for Health Care Research and Quality. Due to the high crossover rate from INF-α to Imatinib group observed in the IRIS study (90% from INF-α to imatinib within a year of study entry) the estimated life time survival for INF-α treatment group was based on the European Study Group on Interferon in Chronic Myeloid Leukemia. Utilities values from the IRIS study were used for both groups. Annual discount rates were of 6% for costs and 1.5% for QALYs. The annual average costs for the treatment of adverse effects in the INF-α were 1.83 higher than the imatinib group. Adverse events lifetime costs for INF-α were 24% higher than imatinib, even tough imatinib granted a projected 6.3 years survival advantage over INF-α. The resulting incremental cost-effectiveness ratio (ICER) of imatinib, compared with IFNα, considering adverse events was US$ 18,637 per QALY gained. Assuming a conservative cost-effectiveness threshold of less than US$ 25,500, which is three times the GDP per capita in Brazil (US$ 8,500 in 2005), the ICER for imatinib compared with INF-α falls within the range considered by the World Heath Organization as a cost-effective fist line treatment for patients newly diagnosed with CML.
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Cui, Yan-Mei, Hui Wang, Quan-Ru Liu, Mei Han, Yang Lu, and Chang-Qi Zhao. "Flavans from Iris tenuifolia and their effects on β-amyloid aggregation and neural stem cells proliferation in vitro." Bioorganic & Medicinal Chemistry Letters 21, no. 15 (August 2011): 4400–4403. http://dx.doi.org/10.1016/j.bmcl.2011.06.039.
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Salukhov, V. V., and E. A. Kovalevskaya. "Rethinking the role of pioglitazone in modern diabetology as a cardiorenoprotective agent." Meditsinskiy sovet = Medical Council, no. 10 (June 18, 2022): 10–21. http://dx.doi.org/10.21518/2079-701x-2022-16-10-10-21.
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Thiazolidinediones are insulin sensitizers – a class of antidiabetic drugs that reducing insulin resistance, convincingly improve glycemic control in patients with type 2 diabetes. In addition to glucose-reducing action, a representative of this class – pioglitazone in studies demonstrates other pleiotropic effects associated with a decrease in blood pressure, a decrease in the level of pro-inflammatory cytokines and prothrombotic factors, correction of dyslipidemia and improving the state of the vascular wall. In accordance with these anti-atherogenic and metabolic effects of pioglitazone in patients with confirmed cardiovascular diseases, he reduced the frequency of development of large atherosclerotic events in prospective randomized clinical studies (studies of PROactive and IRIS), as well as in meta-analyses of all published studies of pioglitazone. Pioglitazone reduces albuminuria and proteinuria, mortality from all causes and cardiovascular events in patients with diabetes and chronic kidney disease. In other studies, the intake of pioglitazone was associated with mobilization of fat from liver in patients with non-alcoholic fatty liver disease with an improvement in its function and a positive effect on fibrosis. This article also provides an analysis of unwanted phenomena that were noted during the study of pioglitazone. The identified weight increase, swelling, bone fractures of the limbs, have a rare frequency of occurrence and dose-dependent nature. Indeed, when using low doses of pioglitazone (7.5–30 mg/day), the ratio of benefit/risk for the drug seems very favorable. At the same time, the benefits of pioglitazone with a significant improvement in cardiovascular and cerebrovascular outcomes are higher with secondary than with primary prevention in patients with both 2TDM and prediabetes/insulin resistance, most likely due to positive effects on atherosclerosis
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Dai, Xiao-Yu, Yong-Ming Yu, Zheng-Fang Kong, Yi-Sheng Cao, Dan-Dan Huang, Xiao-Rong Hu, Zuo-An Huang, Yang-Yang Xie, and Shun Zhang. "Tectorigenin inhibits Caco-2 human colon cells via NF-κB pathway suppression." Bangladesh Journal of Pharmacology 10, no. 4 (November 18, 2015): 948. http://dx.doi.org/10.3329/bjp.v10i4.23833.
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<p class="Abstract">Effective immunomodulator and pro-inflammatory cytokine, Tumor necrosis factor-α (TNF-α) are considered to be responsible for connecting autoimmune pathological process and contagious diseases. TNF-α stimulates the C-X-C motif chemokine 10 (CXCL10) expression that is participated in migration of tumor, metastasis, and invasion. Tectorigenin, an o-methylated isoflavone, is present as a major portion in the Iris tectorum rhizomes. In this study, we investigated the tectorigenin effects as an anticancer drug. The obtained results showed that tectorigenin hinders the invasion of human colon cancer cells (Caco-2). We used reverse transcription PCR, q-PCR and enzyme linked immunosorbent assays to test whether the tectorigenin is involved in the inhibition of TNF-α induced CXCL-10 expression in the Caco-2 cell lines. Further, we tested TNF-α induced NF-κB activity using the tectorigenin. Collective results showed that tectorigenin inhibits the CXCL10 production by using TNF-α via NF-κB inhibition.</p><p> </p>
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Birney, David M., Derek C. Cole, Craig E. Crosson, Brenda F. Kahl, Bart W. Neff, Ted W. Reid, Kaijun Ren, and Robert D. Walkup. "Use of .beta.-Methylphenylalanine (.beta.MeF) Residues To Probe the Nature of the Interaction of Substance P with Its Receptor: Effects of .beta.MeF-Containing Substance P Analogs on Rabbit Iris Smooth Muscle Contraction." Journal of Medicinal Chemistry 38, no. 13 (June 1995): 2478–82. http://dx.doi.org/10.1021/jm00013a024.
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Nosik, Marina, Konstantin Ryzhov, Irina Rymanova, Alexandr Sobkin, Alexey Kravtchenko, Ulyana Kuimova, Vadim Pokrovsky, Vitaly Zverev, and Oxana Svitich. "Dynamics of Plasmatic Levels of Pro- and Anti-Inflammatory Cytokines in HIV-Infected Individuals with M. tuberculosis Co-Infection." Microorganisms 9, no. 11 (November 4, 2021): 2291. http://dx.doi.org/10.3390/microorganisms9112291.
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Tuberculosis (TB) and HIV have profound effects on the immune system, which can lead to the activation of viral replication and negatively regulate the activation of T cells. Dysregulation in the production of cytokines necessary to fight HIV and M. tuberculosis may ultimately affect the results of the treatment and be important in the pathogenesis of HIV infection and TB. This work presents the results of a study of the expression of pro- and anti-inflammatory cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-1RA) in drug-naïve patients with dual infection of HIV/TB at the late stages of HIV-infection, with newly diagnosed HIV and TB, and previously untreated HIV in the process of receiving antiretroviral (ART) and TB treatment vs. a cohort of patients with HIV monoinfection and TB monoinfection. The study revealed that during a double HIV/TB infection, both Th1 and Th2 immune responses are suppressed, and a prolonged dysregulation of the immune response and an increased severity of the disease in pulmonary/extrapulmonary tuberculosis is observed in HIV/TB co-infection. Moreover, it was revealed that a double HIV/TB infection is characterized by delayed and incomplete recovery of immune activity. High levels of IL-6 were detected in patients with HIV/TB co-infection before initiation of dual therapy (2.1-fold increase vs. HIV), which persisted even after 6 months of treatment (8.96-fold increase vs. HIV), unlike other cytokines. The persistent enhanced expression of IL-6 in patients with dual HIV/TB co-infection allows the consideration of it as a potential marker of early detection of M. tuberculosis infection in HIV-infected individuals. The results of multivariate regression analysis showed a statistical trend towards an increase in the incidence of IRIS in patients with high IL-1Ra levels (in the range of 1550–2500 pg/mL): OR = 4.3 (95%CI 3.7–14.12, p = 0.53), which also allows IL-1Ra to be considered as a potential predictive biomarker of the development of TB-IRIS and treatment outcomes.
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Salukhov, Vladimir V., Yurii Sh Khalimov, Sergey B. Shustov, and Dmitriy V. Kadin. "Decrease of cardiovascular risk in patients with type 2 diabetes: review of the common strategies and clinical studies." Diabetes mellitus 21, no. 3 (August 23, 2018): 193–205. http://dx.doi.org/10.14341/dm9570.
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Military Medical Academy of S.M. Kirov, Saint-Petersburg, Russia
Recent clinical trials about the cardiovascular safety of empagliflozin and liraglutide demonstrated a convincing lowering effect on mortality from cardiovascular causes among the patients with type 2 diabetes. These findings resulted in many questions about why this phenomenon was seen in two drugs with widely different mechanisms of functioning. It is important to note that the glucose-lowering effect was moderate, although a feature seen in both empagliflozin and liraglutide was their ability to increase insulin sensitivity. In many fundamental studies, this feature was associated with a reduction of cardiovascular risks. Insulin resistance, which has always been a pathophysiological base for the development of cardiovascular disease in patients with type 2 diabetes, is a topic for this report. Different methods to manage insulin resistance, including lifestyle changes, drug treatment and metabolic surgery, are discussed. Furthermore, the most common features of glucose-lowering drugs are analysed, including protective effects for cardiovascular outcomes in patients with type 2 diabetes presented in randomised clinical trials. Studies include the United Kingdom Prospective Diabetes Study (UKPDS), PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), Insulin Resistance Intervention After Stroke (IRIS), Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). The current study shows that the potential to reduce the risk of cardiovascular disease is determined not only by effective lowering of glucose but also by the ability to lower insulin resistance, which causes a paradigm shift in the management of type 2 diabetes.
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Sarireh, Fawaz Al, Khalid Al Zubi, and Khalil Al Salem. "Role of bevacizumab intraocular injection in the management of neovascular glaucoma." International Journal of Ophthalmology 14, no. 6 (June 18, 2021): 855–59. http://dx.doi.org/10.18240/ijo.2021.06.10.
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AIM: To assess the long-term effects of intraocular bevacizumab (Avastin) injections as an adjunctive drug to manage patients with neovascular glaucoma (NVG). METHODS: A retrospective study was conducted consisting of 34 eyes with secondary NVG caused by proliferative diabetic retinopathy (n=25), ischemic central retinal vein occlusion (n=8), and retinal ischemia resulting from persistent detachment (n=1) were managed by intraocular injections of bevacizumab (1.25 mg/0.05 mL), in addition to other treatments. The main outcome measure was the change in the degree of iris neovascularization. Secondary outcomes included intraocular pressure and the number of additional interventions or antiglaucoma medications administered after injection. RESULTS: All patients were followed-up for at least 12mo. At the last follow-up, complete regression of rubeosis irides was detectable in 13 (38.2%) eyes and incomplete regression in 21 eyes (61.8%). The mean intraocular pressure was 45.32±7.185 mm Hg at baseline and significantly decreased to 26.15±5.679 mm Hg at the last follow-up visit (P=0.000005). Patients received an average of 4.97 injections. As additional treatments, 12 eyes (35%) received laser photocoagulation and 6 eyes (18%) underwent retinocryopexy. No further treatment was needed in 16 eyes (47.1%). CONCLUSION: Intravitreal bevacizumab injection can have a favorable effect in controlling intraocular pressure and pain control in patients with NVG because it decreases the angiogenesis and helps to augment the results of conventional procedures. The primary cause of retinal ischemia should be always targeted.
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Swymer, Cory, and Michael W. Neville. "Tafluprost: The First Preservative-Free Prostaglandin to Treat Open-Angle Glaucoma and Ocular Hypertension." Annals of Pharmacotherapy 46, no. 11 (November 2012): 1506–10. http://dx.doi.org/10.1345/aph.1r229.
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OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, efficacy data, and adverse effect incidence of tafluprost. DATA SOURCES: A literature search was completed using PubMed, Web of Science, and Google Scholar. Tafluprost was the primary search term. Articles published between January 2008 and April 2012 were included in this review. Additional limits placed on the searches were “human” and “English.” Citations in which tafluprost appeared in the title were 36, 29, and more than 300 in PubMed, Web of Science, and Google Scholar, respectively. STUDY SELECTION AND DATA EXTRACTION: Three clinical trials were included in this review. One trial enrolled more than 500 subjects in a randomized fashion. Another also enrolled more than 500 subjects, although the study design was not randomized. The third trial evaluated the effects of tafluprost on subjects who had recently discontinued use of latanoprost, another prostaglandin that is approved to treat glaucoma and ocular hypertension. The duration of all 3 trials was 12 weeks. DATA SYNTHESIS: Tafluprost 0.0015% is the first topical prostaglandin approved by the Food and Drug Administration for treatment of open-angle glaucoma and ocular hypertension that does not contain the widely used preservative, benzalkonium chloride (BAK). Although some controversy surrounds the long-term safety of exposure to BAK, clinical trial data are inconclusive. Tafluprost, like other prostaglandin analogues, exerts its effects on prostaglandin F receptors to reduce intraocular pressure (IOP). Results from 1 trial demonstrated significant reductions in IOP when monotherapy was switched to tafluprost monotherapy. Reductions in IOP with tafluprost use were compared with those seen with use of timolol and latanoprost in 2 trials, and noninferiority was observed. Significant reductions in tear osmolarity were noted in subjects who changed from latanoprost, another prostaglandin analogue, to tafluprost therapy. Conjunctival hyperemia is the most common adverse effect seen in patients receiving drugs from this class. Many have also reported stinging, ocular pruritus, increased darkening or growth of eyelashes, and darkening of eyelids, as well as irreversible brown pigmentation of the iris. CONCLUSIONS: Clinical trial data suggest that tafluprost is as efficacious as other agents used in the management of ocular hypertension and glaucoma. Its use may be especially advantageous in people with allergies, sensitivities to preservatives, or dry or sensitive eyes.
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Kawaguchi, Tatsuya, Akinobu Hamada, Reiko Nakashima, Kentaro Horikawa, Sonoko Ishihara, Hideyuki Saito, and Hiroaki Mitsuya. "Characteristics of Chronic-Phase CML Patients Having Durable Cytogenetic Response to Low-Dose Imatinib." Blood 112, no. 11 (November 16, 2008): 3218. http://dx.doi.org/10.1182/blood.v112.11.3218.3218.
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Abstract Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, has been established as first-line treatment of chronic-phase chronic myeloid leukemia (CML). On the basis of the IRIS study, 400mg/day IM has been recommended as an initial dose for adult CML patients. Although most patients usually tolerate the recommended dose, serious adverse effects such as grade 3 or 4 cytopenia may occur and require dose reduction of IM to 200–300mg/day. In fact, 8% of patients were receiving less than 400mg IM during 5-year follow-up in the IRIS study (Druker et al, New Engl J Med, 2006). In clinical settings, low-dose IM is actually effective for some patients; however, clinical and laboratory features of such patients have not been well investigated. Recently, it was demonstrated that the effective plasma threshold for trough IM levels should be maintained above 1,002 ng/ml to obtain maximal effects in CML patients (Picard et al, Blood, 2007). In this regard, determination of trough IM plasma levels may help to predict efficacy of low-dose IM. To evaluate the association of optimal IM doses with trough IM levels and patients’ basic characteristics such as body surface area (BSA), we assessed trough plasma concentrations of IM using high performance liquid chromatography (Hamada et al, J Pharmacol Exp Ther, 2003) in 31 chronic-phase CML patients, who were treated in Kumamoto University Hospital during 2003 to 2007. An optimal dose of IM was determined by a favorable response to IM achieving complete cytogenetic response and tolerable adverse events. Twenty-seven patients tolerated IM therapy during the observation period: optimal doses of IM were 400mg/day in 13 patients, 300mg/day in 9 patients, and 500 or 600 mg/day in 5 patients. Four patients discontinued IM for some reasons: two for toxicity, one for a concomitant unrelated disease and one for inefficacy due to drug-resistance. The trough plasma concentrations of IM were 1.64±0.68 μg/ml (mean±SD) in patients on the standard dose of 400mg/day IM (standard dose group) and 1.38±0.53 μg/ml in patients on the reduced dose of 300mg/day IM as an optimal dose (reduced dose group). Both mean trough levels of two groups showed no significant difference and exceeded the effective plasma threshold. Interestingly, BSA was significantly smaller in patients of the reduced dose group than those of the standard dose group (1.50± 0.16 vs. 1.75 ± 0.15 m2 (mean± SD), p=0.001). An optimal IM dose was found to be significantly associated with age and gender as well as BSA. These results suggest that the reduced dose of 300mg/day IM may be sufficient for the treatment of CML patients with smaller body sizes. Monitoring of trough IM levels should enable proper management of individual patients in combination with regular monitoring of optimal response to IM.
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Sokolik, Olena Petrivna, and Galina Olexandrivna Prozorova. "Current research opportunities for potential phytotherapeutic agents for the treatment of pathologies of the female reproductive system." European Journal of Clinical and Experimental Medicine 20, no. 1 (2022): 109–16. http://dx.doi.org/10.15584/ejcem.2022.1.15.
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Introduction and aim. Herbal medicine is prescribed for various disorders of the menstrual cycle (uterine bleeding, dysmenorrhea), for the treatment of premenstrual and climacteric syndromes, inflammatory diseases of the genital organs, mastopathy and mastalgia and other pathological conditions. The aim of the study is to analysis and generalization of data from professional literature and own experience in the treatment of patients with pathologies of the female reproductive system by phytotherapeutic methods, taking into account the influence of medicinal plants on various links in the pathogenesis of the disease, as well as making recommendations for improvement and prospects for the use of phytotherapy in the treatment of this pathology. Material and methods. To make an analysis of literary sources of domestic and foreign authors about usage of medicinal plants for the treatment of pathologies of the female reproductive system. Analysis of the literature. In the treatment of primary (spasmodic) dysmenorrhea, herbal remedies with an antispasmodic, analgesic, hormone-mimetic effects are prescribed. It can be Chamomile (Matricaria chamomilla L.), Achillea millefolium, commonly known as yarrow, Viburnum, Shepherd’s purse (Capsella bursa-pastoris), Greater celandine, Atropa belladonna, Hyoscyamus niger, commonly known as henbane, black henbane, or stinking nightshade and Abraham’s tree. Many plants have bactericidal activity, and this property is used in the treatment of inflammatory diseases of the mucous membranes and skin. Such properties are possessed by flowers of Chamomile (Matricaria chamomilla L.), Calendula officinalis, infusion of Medicinal sage (Salvia officinalis L.). For the treatment of functional hyperprolactinemia phytopreparations are also successfully used. It is known that the medicinal plant Vitex agnus castus has dopaminergic properties, selectively blocking prolactin synthesis, and reduces follicle stimulating hormone levels. Strychnos ignatia, Caulophyllum thalictroides, European cyclamen, Lilium tigrinum, Iris versicolor provide a complex effect on the female body, effectively reduces the level of prolactin and the severity of mastalgia, which is confirmed not only by clinical data, but also by mammography data in fibrocystic breast disease. For the treatment of climacteric syndrome, a large number of medicinal plants are used, in particular, the most popular is the Cimicifuga racemose. Conclusion. The effectiveness of phytotherapeutic drugs has been verified by many clinical trials. Modern phytotherapy is becoming more widespread in clinical practice, as an alternative to drug treatment.
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Kantarjian, Hagop M., Richard A. Larson, Francois Guilhot, Stephen G. O’Brien, and Brian J. Druker. "Declining Rates of Adverse Events (AEs), Rare Occurrence of Serious AEs (SAEs), and No Unexpected Long-Term Side Effects at 5 Years in Patients with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Initially Treated with Imatinib (IM) in the International Randomized Study of Interferon vs STI571 (IRIS)." Blood 108, no. 11 (November 1, 2006): 2136. http://dx.doi.org/10.1182/blood.v108.11.2136.2136.
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Abstract The IRIS trial compared interferon alfa + cytarabine (IFN+Ara-C) and imatinib (IM) in patients (pts) with newly diagnosed CML-CP. Among 553 pts randomized to receive 400 mg IM, 157 (28%) discontinued for reasons which included AEs or deaths unrelated to CML and treatment (6%) and unsatisfactory therapeutic effect (11%). Only 2.4% discontinued due to drug-related AEs. The average daily dose was 389±71 mg, suggesting that no major dose modifications were required due to toxicity. In pts still on IM, the average doses was 382±50 mg. Average duration of exposure is 50 mos (median 60 mos). Table 1 summarizes the most frequently reported non-hematologic AEs (regardless of relationship to study drug) in pts who started IM therapy and those who were still on IM at 2 and 4 years (n=456 and 409 respectively). Table 1. AEs (≥ 20%) on First-Line Imatinib Therapy AE All grades N= 551 (%) All grades, after 2 yrs N = 456 (%) All grades, after 4 yrs N = 409 (%) Grades 3/4 N= 551 (%) Fluid retention 61.7 20.2 5.6 2.5 – Superficial edema 59.9 18.2 5.1 1.5 – Other fluid retention events 6.9 2.4 0.7 1.3 Nausea 49.5 15.4 3.4 1.3 Muscle cramps 49.2 22.8 7.3 2.2 Musculoskeletal pain 47.0 20.8 6.1 5.4 Diarrhea 45.4 23.0 5.1 3.3 Rash and related terms 40.1 13.8 2.4 2.9 Fatigue 38.8 11.4 2.9 1.8 Headache 37.0 12.1 3.4 0.5 Abdominal pain 36.5 15.4 3.4 4.2 Joint pain 31.4 9.2 2.0 2.5 Nasopharyngitis 30.5 14.3 3.7 0 Hemorrhage 28.9 14.3 5.1 1.8 Myalgia 24.1 4.6 1.5 1.5 Vomiting 22.5 9.2 3.7 2.0 Upper respiratory tract infection 21.2 11.2 2.7 0.2 Cough 20.0 7.7 3.4 0.2 Hematologic toxicities were the most frequently occurring grade 3/4 AEs (Table 2). Table 2. Grade 3/4 laboratory abnormalities on First-line Imatinib Overall N = 551 (%) After 2 years N= 456 (%) After 4 years N= 409 (%) Hematologic – Neutropenia 16.7 7 1.0 – Thrombocytopenia 8.9 1.5 0.2 – Anemia 4.4 1.8 0.5 Biochemical – ↑ SGOT/SGPT 5.3 0.4 0 – ↑Total bilirubin 1.1 0.4 0.2 The most frequent reported AEs as well as grade 3/4 hematological and biochemical toxicities were observed at decreasing frequencies throughout therapy. After 4 years, 8% of pts experienced an SAE, compared with 14%, 12%, 7.5%, and 9% during year one through four of therapy. Overall, only 6% of pts had SAEs considered related to study drug (1.5% pts after 4 years of IM). Congestive heart failure/cardiac dysfunction (incl. pulmonary edemas) were reported for 3% of pts (<1% grade 3/4) and pleural effusion in 1% (<1% grade 3/4). Despite much shorter average exposure (12 mos), similar % of these AEs were noted for IFN+Ara-C. Although it should be considered that pts more likely to experience grade 3/4 events may have discontinued from the study prematurely, the 5-year data with IM in pts with newly diagnosed CML-CP show declining frequencies of AEs and SAEs over time. Occurrence of SAEs and laboratory abnormalities with long-term follow-up was rare. No unexpected long-term side effects were noted. These results confirm the IM tolerability and safety profile for durations exceeding 4 years.
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Kerimova, G. F., V. A. Rybak, and V. V. Korol. "DETERMINATION OF TOXICOLOGICAL PROPERTIES, ULCEROGENIC AND LOCAL IRRITATING EFFECTS OF DRY EXTRACTS OF LEAVES AND ROOTS OF IRIS HUNGARICA." Fitoterapia 3, no. 3 (2021): 30–36. http://dx.doi.org/10.33617/2522-9680-2021-3-30.
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Key words: acute toxicity, ulcerogenic and local irritating effect, acetylsalicylic acid, extract hungarian iris. In addition to high pharmacological activity, one of the most important requirements for drugs is their safety. The study objective was to the acute toxicity LD50 of dry extract of leaves and rhizomes of Hungarian iris when administered intragastrically and intraperitoneally to mice and intraperitoneally to rats, as well as possible ulcerogenic and local irritating effects. The study of the acute toxicity of dry extract of leaves and rhizomes of Hungarian iris was carried out according to the method of B. M. Shtabsky; a study of a possible ulcerogenic effect on the mucous membrane of the stomach and duodenum was carried out on Wistar rats according to the method of J. Marazzi-Uberti. A study of the effect of dry extract of leaves and rhizomes of Hungarian iris and acetylsalicylic acid on the stomach and intestines of animals under conditions of ethanol-induced gastric ulcers were carried out on rats for 14 days. The study of the local irritating effect of the dry extract of leaves and rhizomes of hungarian iris was carried out on rabbits of the Chinchilla breed. When studying the acute toxicity of the dry extract of leaves and rhizomes of Hungarian iris when administered intragastrically to mice (at doses of 500 mg / kg, 5000 mg / kg, 10000 mg / kg and 15000 mg / kg) and intraperitoneally to rats (at doses of 10 mg / kg, 100 mg / kg, 1000 mg / kg, 3000 mg / kg and 5000 mg / kg) it was found that the death of experimental animals did not occur. Dry extract of leaves and rhizomes of Hungarian iris belongs to the V class of toxicity of substances - practically non-toxic substances, according to the classification of toxicity of substances by K. K. Sidorov. Dry extract of leaves and rhizomes of Hungarian iris does not show ulcerogenic action at doses of 50 mg / kg and 150 mg / kg. An insignificant ulcerogenic effect of dry extract of leaves and rhizomes of Hungarian iris on the gastric mucosa of rats was revealed only at a dose of 200 mg / kg. On the model of ethanol stomach ulcers, dry extract of leaves and rhizomes of Hungarian iris did not potentiate the ulcerogenic effect of ethyl alcohol. Dry extract of leaves and rhizomes of Hungarian iris does not show a local irritating effect on the mucous conjunctiva of the eye of rabbits.
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Baccarani, Michele, Fausto Castagnetti, Kimmo Porkka, Johan L. Nielsen, Henrik Hjorth-Hansen, Ibrahim Haznedaroglu, Arnon Nagler, et al. "A Prospective Study of Imatinib 400 mg vs 800 mg Frontline in High Risk Ph+ Chronic Myeloid Leukemia (CML) Patients." Blood 110, no. 11 (November 16, 2007): 26. http://dx.doi.org/10.1182/blood.v110.11.26.26.
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Abstract Background: imatinib mesylate (IM) is the drug of choice for the front-line treatment of Ph+ CML, at a dose of 400 mg daily (M. Baccarani et al Blood2006;108:1809–1820). Several biological and clinical observations suggest that increasing the dose may improve the results. The cytogenetic response to IM 400 mg daily is significantly related with Sokal relative risk. High risk patients could benefit of a dose increase front-line. Aim: to compare the effects of 400 mg and 800 mg daily in previously untreated, early chronic phase patients, high Sokal risk. The primary efficacy variable of the study is the complete cytogenetic response (CCgR) rate after 12 months, on an intention-to-treat analysis. Patients and Methods: this is a multicentric international study running in Italy, Sweden, Denmark, Finland, Norway, Turkey and Israel, approved by the local Ethic Committees, conducted according to Helsinki Declaration and Good Clinical Practice. 215 patients with confirmed Ph+ CML previously untreated, high risk according to Sokal formulation (J. Sokal et al Blood1984;63:789–799) were enrolled over a 3-year period and were randomized (1:1) to receive IM 400 or 800 mg daily. Cytogenetic response was assessed by conventional cytogenetics and FISH analysis after 3, 6 and 12 months. Molecular response was evaluated every three months. Results: as of August 2007, 137 patients are evaluable for CCgR rate at 12 months (primary efficacy variable). Patients in CCgR at that time were 78/137 (57%). Treatment failures during the study (no complete hematologic response or 100% Ph+ at 6 months, or loss of response) were 24/137 (17%), patients off-treatment for protocol violations or refusal were 10/137 (7%), patients off-treatment for toxicity were 7/137 (5%). Conclusions: the results of this preliminary analysis show that the CCgR rate at 12 months is overall 57%, in line with the results of the IRIS trial (imatinib 400 mg daily - T. Hughes et al, NEJM 2003, 349;15: 1423–1432) in the same risk category (69% all risks, 49% high Sokal risk). At the time of writing is too early to analyze the results by arm: a second analysis will be performed in November (datalock, October 31) and the results will be presented on site.
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Marcon, G., A. Casini, P. Mura, L. Messori, A. Bergamo, and P. Orioli. "Biological Properties of IRIM, the Iridium(III) Analogue of (Imidazolium (Bisimidazole) Tetrachlororuthenate) (ICR)." Metal-Based Drugs 7, no. 4 (January 1, 2000): 195–200. http://dx.doi.org/10.1155/mbd.2000.195.
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Some biological aspects of the new complex imidazolium bisimidazole tetrachloro iridate(III)-IRIM- the iridium(III) analogue of ICR, were considered. More in detail the conformational effects produced by IRIM on DNA and the cytotoxic properties of IRIM on some selected human cell lines were measured. Dialysis experiments and DNA thermal denaturation studies are suggestive of poor binding of IRIM to DNA; formation of interstrand crosslinks is not observed. In any case CD measurements suggest that addition of increasing amounts of IRIM to calf thymus DNA results into significant spectral changes, that are diagnostic of a direct interaction with DNA. A number of experiments carried out on the A2780 human ovarian carcinoma, B16 murine melanoma, MCF7 and TS mammary adenocarcinoma tumor cell lines strongly point out that IRIM does not exhibit significant growth inhibition effects within the concentration range 10-4-10-6 M. It is suggested that the lower biological effects of IRIM compared to ICR are a consequence of the larger kinetic inertness of the iridium(III) center with respect to ruthenium(III).
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Tiwari, Madhurima, Sunita Gupta, and Prachi Bhargava. "Virtual screening and molecular dynamics simulation studies to predict the binding of Sisymbrium irio L. derived phytochemicals against Staphylococcus aureus dihydrofolate reductase (DHFR)." Journal of Applied and Natural Science 14, no. 4 (December 19, 2022): 1297–307. http://dx.doi.org/10.31018/jans.v14i4.3641.
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The discovery of antibiotics initiated the era of drug innovation and implementation for human and animal health. Very soon, antibiotic resistance started evolving due to over-prescription and heavy usage of drugs leading to deleterious side effects. However, using plant extracts or medicinal plants has emerged as a new approach to dealing with the current problem. One such medicinal plant Sisymbrium irio L. is widely used in Unani therapy as an antimicrobial, analgesic, antipyretic, antioxidant, anti-inflammatory, hepatoprotective, bronchoprotective etc. The phytochemicals extracted from the aerial part of the plant have been used as a natural compound library and screened against a well-known anti-bacterial drug target Dihydrofolate reductase (DHFR) enzyme of Staphylococcus aureus. The top two phytochemicals with lower docking score along with the positive control were subjected to molecular dynamics (MD) simulation studies to examine the stabilities of the complexes over 100 ns, followed by binding free energy estimation. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and Radius of Gyration (Rg) yielded established results throughout the MD run. Moreover, the derived phytochemicals exhibited lower binding free energy values than the positive control that can be tested for its in vitro efficacy, followed by further optimization to attain a potent therapeutic against S. aureus. Taken together, the present study suggests two promising phytochemicals derived from the aerial part of the plant S. irio with stable MD simulation results, strong binding affinity and no side effects.
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Persson, W. M. "Microdose effects of drugs and chemicals on the enzymes urease, diastase and trypsin." British Homeopathic Journal 76, no. 03 (July 1987): 150–57. http://dx.doi.org/10.1016/s0007-0785(87)80065-0.
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AbstractTwelve medicinal agents and chemicals were assessed for microdose effects on the enzymes urease, diastase and trypsin. Silver nitrate and mercuric chloride had a slight effect on urease; mercuric chloride, sulphur and after them calcium chloride had marked effect on diastase, microdoses of Iris, phosphoric acid and arsenic on trypsin. Gold chloride had only a slight effect on diastase. The remaining preparations—benzoic acid, platinum chloride and insulin—had no effect.An investigation was made to determine the effect of dynamized dilutions of iodine on starch, and the pH of phosphoric acid dilutions by electrometric methods.It has been empirically shown that colorimetry provides the most sensitive method for assessing microdose effects (dilutions up to 10−100).
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Donadieu, Jean, Blandine Beaupain, Fares bou Mitri, Flore Sicre de Fontbrune, Despina Moushous, Thierry Lamy, Aline Moignet Autrel, Elodie Gouache, Marlène Pasquet, and Christine Bellanne-Chantelot. "Lenograstim and Filgrastim Have a Similar Efficacy and Safety Profile in the Treatment of Chronic Neutropenia. a Study for the French SCN Registry:." Blood 136, Supplement 1 (November 5, 2020): 17–18. http://dx.doi.org/10.1182/blood-2020-138476.
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Introduction: GCSF is a key drug in the medical management of chronic neutropenia (ChrN). Two major marketed forms of G-CSF are used. Filgrastim (F), marketed initially with the brand name Neupogen®;, now available with generic presentation, is a non-glycosylated GCSF. A pegylated (PegF) formulation of F exists too. Lenograstim (L) is the second form of bio-engineering GCSF and is glycosylated and marketed with the brand name Granocyte®. L is distributed in 263 µg and 105 µg vials while F is distributed in 300 and 480 µg vials. L and F have a similar PK profile (1/2 time ~3.7 h), contrary to PegF (1/2 time 42H). Here we compare the efficacy and safety of F and L in ChrN. METHODS The French Severe Chronic Neutropenia Registry (FSCNR) since 1993 prospectively monitors patients with ChrN and collects routinely information about G-CSF therapy (type of product including the Brand names, dose per injection, number of injections, duration of the period of daily treatment, infections, blood counts, side effects..)(1). On 1 October 2019, the FSCNR had enrolled 1068 patients with ChrN (idiopathic neutropenia(2) n=231 and Congenital neutropenia(3) n=837 patients). To take into account individual changes in G-CSF regimens, for a given patient, treatment was divided into elementary periods during which the characteristics of G-CSF treatment remained constant. Several parameters were calculated by summing up the elementary periods: duration of follow-up after G-CSF start, Cumulative duration, Cumulative dose, Time averaged dose (TAD). Three treatment groups were defined according to the type of G-CSF received: "group F" for patients who received only F, "group L" for patients who received only L , "group FL" for patients who received both F and L in succession. As there are no guidelines for GCSF prescription (F or L), even if L is here prescribed off-labelled, treating physician made is own choice. Because PegF have a very specific PK profile, we excluded the Peg F periods from this analysis (only 29 patients have received PegF as part of their therapy). The analysis presented here is limited only to the "L group', the "F group' and the "FL group'. 434 of the 1068 patients with ChrN have received a GCSF therapy: 172 received Lenograstim alone (group L), 148 Filgrastim alone (group F) and 112 received both cytokines consecutively (group FL). RESULTS : The key parameters defining the disease, the severity of the clinical and hematological presentation, the median neutrophil count, the proportion of patients with bone marrow blockage and the number of severe and oral infections was similar between the 3 patient groups (table 1). For group FL and more over the L group the median age at the start of G-CSF was younger (p<0.001). Such differences may be related to the availability, for L, of a smaller vial, more adapted to the prescription of GCSF in infants. At contrary, the TAD received by the patients was similar between the 3 treatment groups (5.5 µg/kg vs 5 and 5 in FL, L and F respectively, p=0.14). With regards to the efficacy, by taking in consideration both hematological parameters like neutrophil count, the rate of failure, as well clinical endpoints like the rate of stomatological and severe infections, we failed to find any differences between L and F groups and among the FL group, between F and L periods. Lastly, rate of side effects, both major side effects like death (mostly not related to GCSF), Myelodysplasia or leukemia, or mild, like bone pains were not different between F and L. Patients from FL have a higher rate of side effects, probably because physicians tried to avoid minor side effects by drug switch. Conclusions: The efficacy profile as well as the safety profile of Lenograstim is indistinguishable from that of Filgrastim in ChrN. The availability of Lenograstim in small vial represent a pragmatic advantage to treat infants as well as patients who are requiring only little amount of GCSF. References J. Donadieu et al., Haematologica90, 45 (2005).F. Sicre De Fontbrune et al., Blood126, 1643 (2015).J. Donadieu, B. Beaupain, O. Fenneteau, C. Bellanne-Chantelot, Br. J. Haematol.179, 557 (2017). Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding.
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Benavides-Serrato, Angelica, Jacquelyn T. Saunders, Brent Holmes, Robert N. Nishimura, Alan Lichtenstein, and Joseph Gera. "Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma." International Journal of Molecular Sciences 21, no. 1 (January 5, 2020): 344. http://dx.doi.org/10.3390/ijms21010344.
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Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek®), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma.
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Roeder, Ingo, Matthias Horn, Ingmar Glauche, Andreas Hochhaus, Martin C. Mueller, and Markus Loeffler. "Modeling BCR-ABL Transcript Dynamics in CML Patients under Imatinib Treatment." Blood 108, no. 11 (November 1, 2006): 2155. http://dx.doi.org/10.1182/blood.v108.11.2155.2155.
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Abstract Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib represents a successful application of a molecularly targeted therapy. A rapid hematologic and cytogenetic response can be induced for the majority of patients even in advanced disease. However, the time course of disappearance of leukemia cells, characterized by the expression of the BCR-ABL fusion protein, varies between patients, and a complete eradication of the malignant cells is a rare event. The reasons for the heterogeneous response and the persistence of the malignant clone in many patients are currently not known. We propose a mathematical model which consistently explains short and long-term dynamics of BCR-ABL transcript levels in populations of CML patients under imatinib monotherapy. The model is based on the concept that normal and malignant cell clones compete for growth environments in which they behave slightly differently with regard to homing and cell cycle activation/deactivation. This concept has been successfully applied for understanding time-dependent chimerism in mice [Roeder et al.: Blood 105(2):609]. Applying the model to data sets from two independent cohorts of imatinib treated CML patients, we demonstrate the potential of our model to quantitatively describe the typical biphasic decline in BCR-ABL transcript levels during the first year of treatment. Besides the median transcript dynamics in the patient population the model is able to represent the heterogeneity in individual transcript time courses. Qualitative differences in the imatinib response are explained by small quantitative differences in the drug effects regarding proliferation inhibition and/or induction of apoptosis for BCR-ABL positive cells. As demonstrated by comparison with five years follow-up data of 69 unselected newly diagnosed CML patients recruited into the IRIS trial in Germany [Mueller et al.: Leukemia 17(12):2392] the model also correctly describes long-term BCR-ABL dynamics. The observed median BCR-ABL transcript levels, including the vanishing decline after year four of treatment, can quantitatively be explained by a decreasing treatment efficiency in a subset of patients, potentially caused by imatinib-resistant clones. Sensitivity analyses show that moderate functional differences of the resistance mutations can lead to remarkable differences in long-term treatment efficiency. On the other hand, in patients not developing resistance mutations our model predicts the general chance of an eradication of the malignant clone in the long run. This is supported by data in a patient subgroup showing a continued decline of BCR-ABL transcript levels over five years of treatment. Beyond the consistent description of the clinically observed BCR-ABL dynamics we provide testable predictions for effects of different combination treatments. Based on the explanation of CML as a clonal competition of malignant and normal hematopoietic stem cells, our model particularly predicts that the therapeutic benefit of imatinib can be augmented by a combination with proliferation stimulating treatment strategies. In addition the model permits to describe the heterogeneity of the effect of resistance mutations with respect to specific treatment strategies. In summary, our model describes CML dynamics under imatinib therapy with potential implications for the design of future treatment strategies.
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Spier, Isabel, Patrick Maier, Stephanie Laufs, Marlon R. Veldwijk, Frederik Wenz, W. Jens Zeller, and Stefan Fruehauf. "Drug Resistance Gene Therapy by Simultaneous Lentiviral Overexpression of MDR1 in Combination with the MGMT P140K Mutant in Human Hematopoietic Stem Cells." Blood 110, no. 11 (November 16, 2007): 5146. http://dx.doi.org/10.1182/blood.v110.11.5146.5146.
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Abstract Background: In this study we cloned a vector based on a self-inactivating lentiviral backbone containing MDR1 (multidrug resistance 1 gene) connected by an ECMV-IRES-element with MGMT P140K (O6-BG-resistant mutant of O6-methylguanine-DNA methyltransferase). The chemoprotective potential of this HR′SIN-MDR-IRES-MGMT combination vector was compared to single vectors (HR′SIN-MDR, HR′SIN-MGMT). Methods: HL60 and CD34+ cells were transduced with the various vectors. After chemotherapeutical treatment MTT assays were used to detect chemoresistance levels in HL60 cells, CD34+ cells were held in liquid culture under differentiation conditions and analysed by FACS for MDR1 expression. Results: HL60 cells transduced with the combination vector showed significant chemoresistance to O6-BG/ACNU (IC50 13x higher compared to untransduced control), the IC50 of cells transduced with HR′SIN-MGMT was 35x higher. The IC50 of paclitaxel (MDR1 substrate) was 24x higher in cells transduced with HR’SIN-MDR and 25x higher with HR’SIN-MDR-IRES-MGMT compared to untransduced control. Combined exposure of cells to O6-BG/ACNU and paclitaxel showed a survival advantage of cells transduced with the combination vector (IC50 6.25x higher), for the single vectors the IC50 was 1.63x higher (MDR1) and 2.08x higher (MGMT) compared to untransduced control. Treatment of CD34+ cells with increasing concentrations of doxorubicin (up to 0.8 μM) resulted in a higher fraction of MDR1-positive cells either with HR′SIN-MDR (26.6x) or with HR′SIN-MDR-IRES-MGMT (30.6x) compared to untreated cells. After combination treatment (20μM O6-BG/16μM BCNU and 0.4μM doxorubicin) the fraction of MDR1-positive cells was higher for HR′SIN-MDR-IRES-MGMT (14x) than HR′SIN-MDR (8x) transduced cells. Conclusion: The protective effect of the combination vector is comparable with the single vectors for monotherapy and superior for combined therapy. The combination vector presents simultaneous protective effects of two drug resistance genes, thus reducing the risk of insertional mutagenesis by one transduction process. Consequently our results might help to reduce myelotoxic side effects and increase the chemotherapeutic efficiency.
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Dermott, S. F., R. S. Gomes, D. D. Durda, B. Å. S. Gustafson, S. Jayaraman, Y. L. Xu, and P. D. Nicholson. "Dynamics of the Zodiacal Cloud." Symposium - International Astronomical Union 152 (1992): 333–47. http://dx.doi.org/10.1017/s007418090009135x.
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Advances in infrared astronomy and in computing power have recently opened up an interesting area of the solar system for dynamical exploration. The survey of the sky made by The Infrared Astronomical Satellite (IRAS) in 1983 revealed the complex structure of the zodiacal dust cloud. We now know the inclination and nodes of the plane of symmetry of the cloud with respect to the ecliptic and we have evidence that the cloud is not rotationally symmetric with respect to the Sun. Of even more interest is the discovery by IRAS of prominent dust bands that circle the Sun in planes near-parallel to the ecliptic. In 1984, we suggested (Dermott et al., Nature, 312, 505-509) that the solar system dust bands discovered by IRAS are produced by the gradual comminution of the asteroids in the major Hirayama asteroid families. The confirmation of this hypothesis has involved: (1) The development of a new secular perturbation theory that includes the effects of Poynting-Robertson light drag on the evolution of the dust particle orbits; (2) The production of a new high resolution Zodiacal History File by IPAC (the Infrared Processing and Analysis Center at Caltech); (3) The development of the SIMUL code: a three-dimensional numerical model that allows the calculation of the thermal flux produced by any particular distribution of dust particle orbits. SIMUL includes the effects of planetary perturbations and PR drag on the dust particle orbits and reproduces the exact viewing geometry of the IRAS telescope. We report that these tools allow us to account in detail for the observed structure of the dust bands. They also allow us to show that there is evidence in the IRAS data for the transport of asteroidal dust from the main belt to the Earth by Poynting-Robertson light drag.
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Tsai, Becky Pinjou, Judith Jimenez, Sharon Lim, Kerry D. Fitzgerald, Min Zhang, Charles T. H. Chuah, Haley Axelrod, et al. "A novel Bcr-Abl–mTOR–eIF4A axis regulates IRES-mediated translation of LEF-1." Open Biology 4, no. 11 (November 2014): 140180. http://dx.doi.org/10.1098/rsob.140180.
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Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that LEF1 expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the LEF1 5′ untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl–mTOR–eIF4A axis in CML cell lines and primary patient leukaemias. We found that LEF1 and other IRESs are uniquely sensitive to the activities of Bcr-Abl/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the LEF1 IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML.
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Dmitrieva, N. A., Yu V. Lukina, N. P. Kutishenko, and S. Yu Martsevich. "New approaches in drug safety assessment based on information provided by doctors and patients in the register “PROFILE”." Clinician 13, no. 3-4 (January 30, 2020): 29–35. http://dx.doi.org/10.17650/1818-8338-2019-13-3-4-29-35.
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The aim to compare various sources of the pharmacotherapy safety information in the outpatient register.Materials and methods. The original questionnaire included several questions for assessing information about patients’ knowledge of the concept of AEs of drug therapy, awareness of the possibility of drugs’ AEs, how often patients read the instructions for drugs and actions of patients in cases of AEs occurrence. Adverse events appearance were noted by the patients themselves in questionnaire and by doctors when completing the IRCs for the period from September 1. 2017 to May 31. 2018 are compared.Results. Of the 162 patients who answered the questions in the original questionnaire, there were 80 women and 82 men. 112 patients were observed by doctors regularly (at least 1 time per year), 16 people visited doctors 1 time in 1–2 years, 14 people were with a doctor more than 2 years ago, in 18 patients information on the regularity of observation by doctors is not indicated were. According to the questionnaire, the majority of patients (145 (89.5 %)) were familiar with information about the possibility of developing side effects of drugs, and 125 (86.2 %) people received this information from their doctor, 19 (13.1 %) noted that the doctor did not inform them about this. Only 6 patients did not know anything about AE pharmacotherapy. As the questionnaire showed, most patients get acquainted with the instructions for the prescribed medications. Comparison of data from the IRCs and questionnaires revealed more frequent registration of AE by doctors; however, there was an incomplete coincidence of information about the presence of AE from different sources.Conclusion. Using data from the retrospective-prospective registry with obtaining information about adverse events from doctors in combination with simultaneous patients questionare could get more complete information about safety of pharmacotherapy. At the same time solution to the problem of farmacotherapy safety lives in optimizing the doctor–patient relationship.
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YORIO, THOMAS, GEORGE DeLOACH, and NIMMAN SATUMTIRA. "Effects of Antiglaucoma Drugs on [32P]Orthophosphate Incorporation into Phospholipids of Cat Iris and Ciliary Process." Journal of Ocular Pharmacology and Therapeutics 1, no. 3 (January 1985): 245–54. http://dx.doi.org/10.1089/jop.1985.1.245.
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Berry, Katherine E., Betty Peng, David Koditek, Douglas Beeman, Nikos Pagratis, Jason K. Perry, Jay Parrish, Weidong Zhong, Jennifer A. Doudna, and I.-hung Shih. "Optimized High-Throughput Screen for Hepatitis C Virus Translation Inhibitors." Journal of Biomolecular Screening 16, no. 2 (February 2011): 211–20. http://dx.doi.org/10.1177/1087057110391665.
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Hepatitis C virus (HCV) is a considerable global health problem for which new classes of therapeutics are needed. The authors developed a high-throughput assay to identify compounds that selectively block translation initiation from the HCV internal ribosome entry site (HCV IRES). Rabbit reticulocyte lysate conditions were optimized to faithfully report on authentic HCV IRES-dependent translation relative to a 5′ capped mRNA control. The authors screened a library of ~430,000 small molecules for IRES inhibition, leading to ~1700 initial hits. After secondary counterscreening, the vast majority of hits proved to be luciferase and general translation inhibitors. Despite well-optimized in vitro translation conditions, in the end, the authors found no selective HCV IRES inhibitors but did discover a new scaffold of general translation inhibitor. The analysis of these molecules, as well we the finding that a large fraction of false positives resulted from off-target effects, highlights the challenges inherent in screens for RNA-specific inhibitors.
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Wang, Xingling, Jing Wang, and Mingxin Yu. "Immune Subtype Profiling and Establishment of Prognostic Immune-Related lncRNA Pairs in Human Ovarian Cancer." Computational and Mathematical Methods in Medicine 2022 (May 5, 2022): 1–26. http://dx.doi.org/10.1155/2022/8338137.
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This study collected immune-related genes (IRGs) and used gene expression data from TCGA database to construct a molecular subtype of ovarian cancer (OV) based on immune-related lncRNA gene pairs (IRLnc_GPs). The relationships between molecular subtypes and prognosis and clinical characteristics were further explored. IRGs were acquired from the ImmPort database, and round-robin pairing of immune-related lncRNAs was performed. The NMF algorithm was used to identify molecular subtypes, and the immune score of a single sample was calculated through ESTIMATE, TIMER, ssGSEA, MCPcounter, and CIBERSORT. The relationship between molecular subtypes and immune microenvironments was identified. A hypergeometric test was used to test the lncRNA pairs among the OV molecular subtypes (C1 and C2 subtypes). The BH method was used to screen the different lncRNA pairs, and a predictive risk model was constructed and verified. Finally, correlation analysis between the risk model, immune checkpoint genes, and chemotherapy drugs was carried out. Based on IRLnc_GP to classify 373 OV samples of TCGA, the samples were divided into two subtypes, and the prognosis between the subtypes showed significant differences. The C1 subtype with a poor prognosis was more related to the pathways of tumor occurrence and development. We identified 180 differential lncRNA pairs between subtypes and constructed a prognostic risk model based on 8 IRLnc_GPs. In the independent dataset, the distribution of subtypes in functional modules was different and highly repeatable. There were significant differences in the molecular and clinical characteristics of the subtypes and the drug sensitivity of immunotherapy/chemotherapy. In conclusion, the risk model established based on IRLnc_GP can better evaluate the prognosis of OV samples and can also assess the effects of different drug treatments in the high- and low-risk groups, providing new insights and ideas for the treatment of OV.
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Jamal, Rahima, Danielle Desmarais, John Chapdelaine, Yvan Côté, and Lambert Busque. "Retrospective Study of Trough Imatinib Plasma Levels Conducted as Part of the Follow-up of Patients with Chronic Myeloid Leukemia in a Canadian Cohort." Blood 112, no. 11 (November 16, 2008): 4258. http://dx.doi.org/10.1182/blood.v112.11.4258.4258.
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Abstract While imatinib biodisponibility is excellent, trough imatinib plasma levels associated with standard dose imatinib are variable and cannot be predicted by the age, the body surface area or the weight of the patient. Imatinib trough levels have recently been associated with both cytogenetic and molecular responses, making imatinib pharmacokinetics a possible target in optimisation of the treatment of patients with chronic myeloid leukemia. We retrospectively analysed trough imatinib plasma levels prescribed as part of the longitudinal follow-up of a cohort of patients with chronic myeloid leukemia in Canada. Indications for testing were inadequate response, important side effects or suspicion of non compliance. The objectives of the study were to evaluate the variability of trough imatinib plasma levels in our cohort and determine the impact a first result had on the subsequent plasma level in patients with more than one imatinib plasma determination. Analyses of trough plasma levels in 278 patients were conducted in a central canadian laboratory from April 2007 to April 2008. Trough imatinib plasma levels were measured using liquid chromatography and tandem mass spectrometry (LC/MS/MS) with deuterated imatinib as the internal standard. Distribution of trough imatinib plasma levels according to the established IRIS quartiles (Q1–Q4; BLOOD. 2008, vol 11, p4022)) showed an important variability, with plasma levels distributed between less than 100 ng/ml and more than 4500 ng/ml. Sixty-two (22.3%) patients in our cohort had plasma levels below 647 ng/ml (Q1), 101(36.3%) patients had levels between 647–1170 ng/ml (Q2–Q3) and 115 (41.3%) patients had trough levels above 1170 ng/ml (Q4). There were 31 patients (11.2%) with levels above 2000 ng/ml, all of whom were included in the Q4. Thirty seven patients in our cohort had more than one analysis of trough imatinib plasma levels done during the one year follow-up for a total of 82 analyses. Sub-group analysis of trough imatinib plasma levels was conducted in the 13 patients in the Q1 and the six patients in the Q4 who had 2 analyses done. Mean trough imatinib plasma levels went from 401ng/ml to 665 ng/ml in the Q1 patients and from 2845 ng/ml to 1065 ng/ml in the Q4 patients. These results confirm the feasibility of imatinib plasma levels testing in the community and the important variability of trough imatinib plasma concentrations in individual patients, as described by other groups. A significant portion of patients in our cohort had trough levels below 647 ng/ml, which has been associated with less favourable cytogenetic and molecular responses in studies. These results also suggest that physicians act on the information procured by the determination of imatinib plasma levels as second level determination was improved for patients initially in Q1 or Q4. Further follow up analyses are needed to document if optimisation of dosing leads to better response or improvement in tolerability of the drug.
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Webber, Kath, Andrew Neil Davies, Charlotte Leach, and Anna Bradley. "Alcohol and drug use disorders in patients with cancer and caregivers: effects on caregiver burden." BMJ Supportive & Palliative Care 10, no. 2 (January 29, 2020): 242–47. http://dx.doi.org/10.1136/bmjspcare-2019-002127.
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BackgroundThe estimated prevalence of alcohol use disorders in patients with advanced cancer is reported as 4%–38%. There are limited data regarding alcohol and drug use disorders in caregivers of patients with cancer and the effects on other issues.AimTo establish the prevalence of alcohol and drug use disorders in a large cohort of patients with advanced cancer and their caregivers.To evaluate the relationship between alcohol and drug use disorders and patient symptoms and caregiver burden.DesignThe patient with cancer and caregiver completed the Alcohol Use Disorders Identification Tool, CAGE questionnaire and Drug Abuse Screening Test. The patient completed the Memorial Symptom Assessment Scale–Short Form, and the caregiver completed the Zarit Burden Questionnaire.Statistical analysis compared cases and non-cases of alcohol and drug use disorders with symptom and burden score.Setting/participantsPatients with cancer, and their caregivers, were recruited from 11 UK sites, 6 hospices and 5 hospitals.ResultsFive hundred and seven patients and their caregivers were recruited. Twenty-seven patients (5%) and 44 caregivers (9%) screened positively for alcohol use disorders on the Alcohol Use Disorders Identification Tool. Thirty patients (6%), and 16 caregivers (3%), screened positively for drug abuse problems on the Drug Abuse Screening Test.There was a significantly higher carer burden score in caregivers screening positively for alcohol and drug abuse problems.ConclusionsThe prevalence of alcohol use disorders in patients with cancer and caregivers was lower than reported in previous studies. Caregiver burden scores were significantly higher in carers screening positively for alcohol and drug use disorders.Trial registration numberTrial registered National Institute for Health Research Clinical Research Network Portfolio (CPMS ID 30723) IRAS ID 198753.
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Yousufzai, S. Y., and A. A. Abdel-Latif. "Effects of platelet-activating factor on the release of arachidonic acid and prostaglandins by rabbit iris smooth muscle. Inhibition by calcium channel antagonists." Biochemical Journal 228, no. 3 (June 15, 1985): 697–706. http://dx.doi.org/10.1042/bj2280697.
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Addition of physiological concentrations (10(-12)-10(-8)M) of platelet-activating factor (PAF) to rabbit iris muscle induced a rapid release (in 15s) of prostaglandin (PG)E2 and 6-oxo-PGF1 alpha, measured by radioimmunoassay and rapid release of 14C-labelled arachidonate and PGE2 in muscle prelabelled with [14C]arachidonic acid, measured by radiochromatography. These PAF actions are concentration- and time-dependent. The effect of PAF on PG release is not mediated through the cyclo-oxygenase pathway. The studies on the properties and mechanism of arachidonate release from phosphatidylinositol and other phospholipids in prelabelled irides by PAF suggest the involvement of a phospholipase A2. This conclusion is supported by the findings: (a) that both the removal of arachidonate and formation of lysophosphatidylinositol, from phosphatidylinositol, by PAF occur concomitantly in a time-dependent manner, (b) that Ca2+ is required for the agonist-induced release of arachidonate and PGE2, and (c) that in contrast to the rapid release of [3H]myo-inositol phosphates by carbachol and other Ca2+-mobilizing agonists previously reported in the iris muscle [Akhtar & Abdel-Latif (1984) Biochem. J. 224, 291-300], PAF (10(-12)-10(-8)M) did not appreciably enhance the release of [14C]myo-inositol phosphates and 32P labelling of phosphatidate and phosphatidylinositol in this tissue. Ca2+-channel antagonists, such as nifedipine, verapamil, diltiazem and manganese inhibited PAF-induced arachidonate and PGE2 release in a dose-dependent manner. K+ depolarization, which causes influx of extracellular Ca2+ in smooth muscle, did not increase the release of arachidonate and PGE2. The ability of Ca2+ antagonists to inhibit arachidonate release by PAF in this tissue probably reflects interference with PAF binding to its receptor. The PAF-induced release of arachidonate and PGE2 occur independently of the cyclo-oxygenase and lipoxygenase pathways. Whether the PAF-induced release of arachidonate and PG in the iris muscle is involved in the pathogenesis of inflammatory and/or physiological reactions in the eye, and how much the inhibitory effects of Ca2+-entry blockers on the PAF actions contribute to the therapeutic use of these drugs, remain to be established.
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Park, Jimin, Hyun Soo Kim, Seung Min Lee, Kanghyun Yoon, Woo-shik Kim, Jong Shin Woo, Sanghoon Lee, Jin-Bae Kim, and Weon Kim. "Acupuncture Antiarrhythmic Effects on Drug Refractory Persistent Atrial Fibrillation: Study Protocol for a Randomized, Controlled Trial." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/613970.
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Background.Atrial fibrillation (AF) is the most common form of arrhythmia. Several trials have suggested that acupuncture may prevent AF. However, the efficacy of acupuncture for AF prevention has not been well investigated. Therefore, we designed a prospective, two-parallel-armed, participant and assessor blinded, randomized, sham-controlled clinical trial to investigate acupuncture in persistent AF (ACU-AF).Methods.A total of 80 participants will be randomly assigned to active acupuncture or sham acupuncture groups in a 1 : 1 ratio. Both groups will take the same antiarrhythmic medication during the study period. Patients will receive 10 sessions of acupuncture treatment once a week for 10 weeks. The primary endpoint is AF recurrence rate. Secondary endpoints are left atrium (LA) and left atrial appendage (LAA) changes in function and volume, and inflammatory biomarker changes.Ethics.This study protocol was approved by the institutional review boards (IRBs) of Kyung Hee University Hospital (number 1335-04). This trial is registered with clinicaltrials.govNCT02110537.
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Weijers, Julia M., Wieland D. Müskens, and Piet L. C. M. van Riel. "Effect of significant weight loss on disease activity: reason to implement this non-pharmaceutical intervention in daily clinical practice." RMD Open 7, no. 1 (January 2021): e001498. http://dx.doi.org/10.1136/rmdopen-2020-001498.
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Obesity is very common in patients with inflammatory rheumatic diseases (IRDs), of which between 27% and 37% of patients have a body mass index ≥30 kg/m2. In addition to further increasing the risk of developing cardiovascular diseases (CVDs) in this group of patients, obesity is associated with higher disease activity and a lower response to drug therapy. This case series showed that in those patients with rheumatoid arthritis or psoriatic arthritis with a substantial weight loss of >10% of body mass, median Disease Activity Score 28 joints score decreased with 0.9. This reduction in disease activity resulted in an increase in the percentage of patients achieving remission from 6% to 63%. This reduction in disease activity was obtained without intensification of medical treatment in 87% of the patients. This case series supports the current evidence that weight reduction has positive effects on the course of the disease and thus also on the CVD risk profile in these patients. Therefore, weight loss can serve as a non-pharmacological treatment option in obese patients with IRDs.
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Soler, Muriel, John G. McHutchison, T. Jesse Kwoh, F. Andrew Dorr, and Jean-Michel Pawlotsky. "Virological Effects of Isis 14803, An Antisense Oligonucleotide Inhibitor of Hepatitis C Virus (HCV) Internal Ribosome Entry Site (IRES), on HCV Ires in Chronic Hepatitis C Patients and Examination of the Potential Role of Primary and Secondary HCV Resistance in the Outcome of Treatment." Antiviral Therapy 9, no. 6 (August 2004): 953–68. http://dx.doi.org/10.1177/135965350400900612.
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Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor (<1.0 log10) viral load reductions that were difficult to definitively distinguish from assay or patient variations. The aims of this study were to examine the effect of ISIS 14803 on its target site and neighbouring region quasispecies evolution, and to determine whether primary and secondary HCV resistance contributed to the observed virological response rate. The HCV internal ribosome entry site (IRES), including the ISIS 14803 target site in virus specimens collected from patients at baseline and end-of-treatment, was sequenced. An extensive IRES quasispecies analysis was performed in 10 of the patients at various time points before, during and after ISIS 14803 treatment. A significant IRES genetic evolution was found in three out of 10 patients through quasispecies analysis suggesting that treatment with ISIS 14803, a drug designed to bind to HCV RNA, exerted a selective pressure on HCV IRES. However, no mutations in the ISIS 14803 target site, which would inhibit binding of the oligonucleotide to HCV RNA, were detected before (primary resistance) or after treatment (secondary resistance) with the oligonucleotide. Furthermore, no obvious nucleotide changes in the surrounding IRES region that might possibly affect oligonucleotide binding were detected.
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Takahashi, Naoto, Yoshihiro Kameoka, Hirofumi Saitoh, Naohito Fujishima, Makoto Hirokawa, and Kenichi Sawada. "Low Dose and Standard Dose of Imatinib Therapy for Patients with Chronic Myeloid Leukemia in Akita Prefecture, Japan." Blood 110, no. 11 (November 16, 2007): 4575. http://dx.doi.org/10.1182/blood.v110.11.4575.4575.
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Abstract The IRIS study for CML patients demonstrated the excellent clinical and cytogenetic/molecular effects of imatinib. Patients participating in the IRIS trial were selected according to strict eligibility criteria. The clinical features of patients are usually much more heterogeneous in practical situations than in clinical trials. Sometimes, patients cannot be treated with the standard dose of imatinib because of severe toxicity, especially older patients or patients who had already been treated with the other drugs. In this study, we analyzed whether patients could still be effectively treated using lower doses. Our study analyzed 86 CML patients from 17 hospitals in Akita prefecture. 80 patients were in CP, one patient was in AP, 4 patients were in BC, and one patient had cytogenetic relapse after allo-SCT. All patients were treated with imatinib between December 2001 and July 2007. Initially a dose of 400mg/day was given to almost all patients. Later the dose was decreased in a subset of patients experiencing imatinib-induced side effects. We classified patients into two groups according to the imatinib dosage and analyzed their clinical characteristics [Table 1] and the accumulation of CCR/MMR [Figure 1, 2]. In Group 1, we analyzed 55 patients received 300mg or more of imantiib per day. In Group 2, we analyzed 31 patients received less than 300mg of imatinib per day. Patients in Group 2 were older and had more histories of pretreatment and showed a higher frequency of adverse effects of imatinib than in Group 1. There were no significant differences of CCR/MMR rate between Group 1 and Group 2. This study reproduces the imatinib efficacy results described in the IRIS study, not only for patients treated with standard dose imatinib and for patients who could not take 400mg/day because of imatinib toxicity or other complications. We did not observe an increase in frequency of BCR-ABL point mutations in patients receiving a lower dose of imatinib, suggesting that the low dose imatinib treatment analyzed in our study does not enhance imatinib resistance by increasing BCR-ABL point mutations. In conclusion, we provide data supporting the use of lower doses of imatinib for CML patients that cannot be given sufficient dosage of imatinib for reasons such as severe hematological or non-hematological side effects or other complication. Clinical Characteristics of Patients in Group I and II Group 1(n=55) Group 2(n=31) P Average doseage 380 mg/day 185 mg/day Average age (% of over 70 yrs) 57.7 yrs (22 %) 68.0 yrs (58 %) .001 (.007) History of treatment with IFN/HU before imatinib therapy 16% 55%. 002 Adverse effect (Grade3/4) 16% 42% .009 PFS to AP/BC at 60 Mo 97.8% 89.6% .28 CCR /MMR rate 78% / 51% 61% / 39% .09 / .27 Point mutation of bcr-abl in patients without MMR 4/17 2/13 .99 Figure Figure Figure Figure
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Varikkodan, Muhammed Muhsin, Chun-Chung Chen, and Tzong-Yuan Wu. "Recombinant Baculovirus: A Flexible Drug Screening Platform for Chikungunya Virus." International Journal of Molecular Sciences 22, no. 15 (July 23, 2021): 7891. http://dx.doi.org/10.3390/ijms22157891.
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Chikungunya virus (CHIKV) is a mosquito-transmitted infectious agent that causes an endemic or epidemic outbreak(s) of Chikungunya fever that is reported in almost all countries. This virus is an intense global threat, due to its high rate of contagion and the lack of effective remedies. In this study, we developed two baculovirus expression vector system (BEVS)-based approaches for the screening of anti-CHIKV drugs in Spodoptera frugiperda insect (Sf21) cells and U-2OS cells. First, structural protein of CHIKV was co-expressed through BEVS and thereby induced cell fusion in Sf21 cells. We used an internal ribosome entry site (IRES) to co-express the green fluorescent protein (EGFP) for identifying these fusion events. The EGFP-positive Sf21 cells fused with each other and with uninfected cells to form syncytia. We identified that ursolic acid has potential anti-CHIKV activity in vitro, by using this approach. Second, BacMam virus-based gene delivery has been successfully applied for the transient expression of non-structural proteins with a subgenomic promoter-EGFP (SP-EGFP) cassette in U-2OS cells to act as an in vitro CHIKV replicon system. Our BacMam-based screening system has identified that the potential effects of baicalin and baicalein phytocompounds can inhibit the replicon activity of CHIKV in U-2OS cells. In conclusion, our results suggested that BEVS can be a potential tool for screening drugs against CHIKV.
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Zhang, Hong, Ronnie Hanecak, Vickie Brown-Driver, Raana Azad, Boyd Conklin, Maureen C. Fox, and Kevin P. Anderson. "Antisense Oligonucleotide Inhibition of Hepatitis C Virus (HCV) Gene Expression in Livers of Mice Infected with an HCV-Vaccinia Virus Recombinant." Antimicrobial Agents and Chemotherapy 43, no. 2 (February 1, 1999): 347–53. http://dx.doi.org/10.1128/aac.43.2.347.
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ABSTRACT Hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis worldwide. Current treatments are not curative for most infected individuals, and there is an urgent need for both novel therapeutic agents and small-animal models which can be used to evaluate candidate drugs. A small-animal model of HCV gene expression was developed with recombinant vaccinia virus vectors. VHCV-IRES (internal ribosome entry site) is a recombinant vaccinia viral vector containing the HCV 5′ nontranslated region (5′-NTR) and a portion of the HCV core coding region fused to the firefly luciferase gene. Intraperitoneal injection of VHCV-IRES produced high levels of luciferase activity in the livers of BALB/c mice. Antisense oligonucleotides complementary to the HCV 5′-NTR and translation initiation codon regions were then evaluated for their effects on the expression of these target HCV sequences in BALB/c mice infected with the vaccinia virus vector. Treatment of VHCV-IRES-infected mice with 20-base phosphorothioate oligonucleotides complementary to the sequence surrounding the HCV initiation codon (nucleotides 330 to 349) specifically reduced luciferase expression in the livers in a dose-dependent manner. Inhibition of HCV reporter gene expression in this small-animal model suggests that antisense oligonucleotides may provide a novel therapy for treatment of chronic HCV infection.
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Krombholz, Sophia, Andreas Thomas, and Mario Thevis. "Investigations into the In Vitro Metabolism of hGH and IGF-I Employing Stable-Isotope-Labelled Drugs and Monitoring Diagnostic Immonium Ions by High-Resolution/High-Accuracy Mass Spectrometry." Metabolites 12, no. 2 (February 4, 2022): 146. http://dx.doi.org/10.3390/metabo12020146.
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Studying the metabolism of prohibited substances is an essential element in anti-doping research in order to facilitate and improve detectability. Whilst pharmacokinetic studies on healthy volunteers are valuable, they are often difficult, not least due to safety reasons and ethical constraints, especially concerning peptidic substances, which must be administered parenterally. Hence, there is a growing need for suitable in vitro models and sophisticated analytical strategies to investigate the metabolism of protein- and peptide-derived drugs. These include human growth hormone (hGH) and its main mediator insulin-like growth factor-I (IGF-I), both prohibited in professional sports for their anabolic and lipolytic effects, while challenging in their detection, as they occur naturally in the human body.Within this study, the in vitro metabolism of hGH and IGF-I was investigated using a stable-isotope-labelled reporter ion screening strategy (IRIS). A combination of liquid chromatography, high-resolution mass spectrometry, and characteristic immonium ions generated by internal dissociation of the stable-isotope-labelled peptidic metabolites enabled the detection of specific fragments. Several degradation products for hGH and IGF-I were identified within this study. These metabolites, potentially even indicative for subcutaneous administration of the drugs, could serve as promising targets for the detection of hGH and IGF-I misuse in future anti-doping applications.
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Fan, Fengjuan, Sonia Vallet, Martin Sattler, Giovanni Tonon, Muhammad Hasan Bashari, Latifa Bakiri, Hartmut Goldschmidt, Erwin F. Wagner, Dirk Jaeger, and Klaus Podar. "The AP-1 Transcription Factor JunB Promotes Multiple Myeloma (MM) Cell Proliferation, Survival and Drug Resistance in the Bone Marrow Microenvironment." Blood 124, no. 21 (December 6, 2014): 3446. http://dx.doi.org/10.1182/blood.v124.21.3446.3446.
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Abstract MEK/ERK and NF-kB signaling pathways have been reported to play a key role in multiple myeloma (MM) survival, proliferation and drug resistance. These pathways regulate the activity of numerous transcription factors. For example, the activator protein-1 (AP-1) transcription factor has been implicated in a multitude of physiologic processes, but also tumorigenesis. However, the function of AP-1 in MM is largely unknown. Our data show a vast variety of AP-1 (c-Jun, JunB, JunD, c-Maf and c-Fos) expression levels in MM cells. Importantly, co-culture of MM cells with bone marrow stromal cells (BMSCs), i.e. isotypic primary BMSCs as well as BMSC lines KM-105 and HS-27A, rapidly and strongly induces expression of JunB, but not other AP-1 members. Previous studies have shown that JunB exerts opposite functions depending on the cellular origin and the physiopathological context. For example, it serves as a gatekeeper in acute and chronic myeloid leukemia, but as a positive regulator in Hodgkin's lymphomas and anaplastic large cell lymphomas. The relevance of JunB activity in MM growth, survival and drug resistance is elusive. First, our data demonstrate that induction of JunB is predominantly mediated by soluble factors secreted by BMSCs rather than direct MM-BMSC contact. Indeed, using cytokine arrays, we identified IL-6 among the most potent factors that trigger JunB expression. Mechanistically, JunB upregulation occurs at both transcriptional as well as translational level. Pharmacologic inhibition was used next in order to identify upstream signaling pathways, which mediate BMSC- induced JunB upregulation in MM cells. Our data show that activation of MEK/ERK or NF-kB is required for induction of JunB expression and AP-1 transcriptional activity. To delineate the specific functional role of JunB in MM pathogenesis, we transduced MM cells with pLKO.1-JunB shRNA or pLKO.1-scrambled shRNA (SCR). After puromycin- selection, effects of JunB knockdown on MM proliferation, survival and drug resistance were analyzed by 3H-thymidine incorporation, flow cytometry and western blot. Indeed, we observed significant inhibition of proliferation in MM/ JunB shRNA (decreased to ~ 25 – 40 %, p < 0.01) compared with MM/ SCR control cells, when co-cultured with BMSCs in particular. Moreover, our preliminary data show that knockdown of JunB overcomes resistance of MM cells against doxorubicin as well as melphalan. Furthermore, 4-hydroxytamoxifen (4-OHT) treatment of MM cell lines stably transduced with pMSCV-JunB-ER-IRES-GFP but not pMSCV-IRES-GFP induced significant AP-1 luciferase activity (~ 3.3 fold, p < 0.01) as well as MM cell proliferation. In ongoing experiments, the in vivo relevance of our in vitro data is evaluated in a xenograft mouse model inoculated with MM /JunB-ER-IRES-GFP and MM/ IRES-GFP cells. Finally, gene expression profiles on > 1000 MM patient samples of different prognostic groups were compared to samples from healthy donors using the gene set enrichment analysis (GSEA). Our results further support a key role for JunB in MM pathogenesis. In summary, our data demonstrate for the first time an important role of JunB/AP-1 in MM tumorigenesis and strongly propose it as a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.
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Claudiani, Simone, Nikhita Gupta, Ji Soo Baik, Simona Deplano, Renuka Palanicawander, Gareth Gerrard, Alistair G. Reid, et al. "Excellent Outcome and Good Tolerability of Long-Term Imatinib in Patients with Chronic Myeloid Leukemia (CML)." Blood 126, no. 23 (December 3, 2015): 2794. http://dx.doi.org/10.1182/blood.v126.23.2794.2794.
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Abstract Introduction: The introduction of the tyrosine kinase inhibitors (TKIs) into clinical practice in the late 1990s has considerably improved both survival and quality of life for patients with CML. Imatinib was the only TKI available for several years with no useful drug treatment for patients with resistance and/or intolerance. Despite the lack of alternative agents the 8-year follow-up of the IRIS trialshowed that only 55% of patients were still on imatinib. The majority of those who discontinued did so for lack or loss of response rather than intolerance, suggesting that imatinib is very well tolerated in the long-term. This is particularly pertinent today as controversy persists as to the best agent for newly diagnosed patients. There is not only increasing evidence that the second and third generation TKIs are associated with more severe adverse events, but generic imatinib is now available in many countries at considerably less expense. We report our experience of treating 45 patients with continuous imatinib for more than 10 years. Methods: We interrogated our single centre database of all patients treated with TKIs for CML at our centre from June 2000 to March 2015. From a total of 832 patients we identified 188 CML who had received only imatinib. Of these, 45 patients had received treatment for more than 10 years. Results: The median duration of imatinib therapy was 6 years in the total cohort of imatinib only patients and 11 years (range 10-14.7) in the study group. All 45 patients were in chronic phase at diagnosis: the median age was 45.4 years (range 26-72). Forty patients were evaluable for Sokal scoring, with 19, 13 and 8 identified as low, intermediate and high risk respectively. The median imatinib starting dose was 400 mg daily. The proportions of patients who achieved optimal responses (OR), as defined by the ELN at 3, 6 and 12 months from start of imatinib, were 88.2%, 78.8 and 56.1% respectively. At 10 years the probabilities of CCyR, MR3, MR4, MR4,5 and MR5 were 100%, 100%, 100%, 100%, 75.6% respectively. The 10 year probability of obtaining a sustained (at least 2 years) molecular response was 100%, 64.4%, 35.6% and 15.6% for MR3, MR4, MR4.5 and MR5 respectively. In patients who were not optimal responders at one or more time points (n=21), the median dose of imatinib was ≥400 mg in the first 12 months of treatment; for 13/21 higher dosages (range 600-800 mg daily) were prescribed. We found a significant correlation between a low or intermediate Sokal score at diagnosis and OR at 3 months (p=0.012). No correlation was found between Sokal score and OR at 6 or 12 months. No statistically significant association was found between an optimal response at 6 or 12 months and the future depth of responses. In fact, the overall rates of sustained MR4.5 for patients optimal responders at 6 and 12 months were 52% and 52% versus 41.6% and 50% for non optimal responders at the same time points. Grade 4 toxicities and secondary malignancies were not observed during the follow-up. Seven pts (15.5%) experienced grade 3 events, including 1 each of supraventricular tachycardia and anemia, and neutropenia, fatigue and hypophosphataemia were each seen in 2 patients. The most frequent adverse event of any grade was fatigue (36% of pts), followed by anemia (27%) and neutropenia (18%). The cumulative probability of common side effects increased over the time. Cardiovascular events were mostly grade 1-2 palpitations and hypertension. At last follow-up, all pts were alive. Conclusions: Our patient cohort analysis confirms long term safety and tolerability of imatinib after 10 years of therapy. The majority of side effects were grade 1-2 and some increased in incidence over the time. The most frequent adverse events were hematological. Imatinib continues to provide an excellent therapeutic outcome granting deep molecular responses even in some patients deemed to be poor risk at diagnosis. ELN optimal response status at 6 and 12 months was not associated with prediction of the future depth of response, in this very good risk population (majority of patients in optimal response at 3 months). Disclosures Milojkovic: BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Apperley:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Slaby, Jiri, Jordan Johnson, Paola Neri, K. Gratton, Li Ren, Douglas A. Stewart, Peter Duggan, and Nizar J. Bahlis. "Lenalidomide Suppresses 5′-Cap-Independent C-MYC Translation in Multiple Myeloma Cells." Blood 120, no. 21 (November 16, 2012): 3943. http://dx.doi.org/10.1182/blood.v120.21.3943.3943.
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Abstract Abstract 3943 Background: Immunomodulatory drugs (IMiDs) are highly active in the treatment of multiple myeloma (MM). Blockade of the Wnt-GSK3β-beta catenin axis and suppression of eIF4E-C/EBPβ-dependent IRF4 expression were previously shown to mediate some of the IMiDs cytotoxic effects. In particular, cereblon (CRBN), an adaptor protein of the Cul4A-DDB1-ROC1 ubiquitin E3 ligase complex, was recently identified as an essential requirement for IMiDs anti-MM activity. In the present study, we examined how lenalidomide treatment modifies MM cells ubiquitome downstream of the Cul4A-DDB1-CRBN E3 ligase complex with the intent to identify novel molecular targets mediating IMiDs anti-MM effects. Methods and Results: Ubiquitin-proteome pull-down using Tandem Ubiquitin Binding Entity (TUBE, Lifesensors) coupled with quantitative mass-spectroscopy based proteomics (iTRAQ) was performed to identify modification to OPM2 cells ubiquitin-proteome induced by lenalidomide (10 μM for 24 hours) versus vehicle control treatment. Among the differentially modified ubiquitilated targets, histone family members H4, H2A.Z, H2B (known substrates of the Cullin-Ring Ub E3 ligases) and the 40S ribosomal proteins RPS25 and RPS26 were more than 2 fold increased in lenalidomide treated samples. Ribosomal protein RPS25 is required for internal ribosomal entry site (IRES) and 5′-cap-independent proteosynthesis. To examine the function of RPS25 in MM, siRNA-KD experiments were carried out in 2 human MM cell lines (OPM2 and MM1S). RPS25 silencing significantly (30–40%) reduced MM cells viability (MTT assay) when compared to non-targeting siRNA controls. Of interest, MM cells surviving RPS25 silencing were more resistant to IMIDs with approximately 20 to 30% reduction in lenalidomide induced cells death (Annexin V staining and MTT assay). Since, the 5′ UTR of c-myc is known to contain an IRES segement and c-myc translation can therefore be initiated by internal ribosome entry (RPS25 mediated) as well as by cap-dependent mechanisms, we next examined whether lenalidomide may downregulate c-myc through an IRF4-independent and rather RPS25-IRES dependent mechanism. Following 4 hours exposure to lenalidomide, C-MYC protein was significantly downregulated (western blot analysis) in OPM2 and MM1S cells, with no changes to IRF4 (protein or mRNA) or c-myc mRNA (qRT-PCR) at this early time point. No changes were observed in IRF4 until 24–48 hours of treatment with lenalidomide, findings consistent with an IRF4-independent C-MYC downregulation. Using the bicistronic (pRMF) luciferase reporter plasmid in which the upstream cistron encodes a Renilla luciferase translated in a cap-dependent manner, and the downstream cistron encoding a firefly luciferase translated in a cap-independent manner because of c-myc IRES insertion between the two cistrons, we examined whether treatment with lenalidomide modifies c-myc IRES ribosomal entry and translation. Following lenalidomide treatment, MM1S-pRMF transfected cells had a significant reduction in c-myc cap-independent translation as indicated by the reduction in the firely/renilla luminescence ratio. These findings were further supported by the use of the m-TOR inhibitor Rapamycin, an inhibitor of cap-dependent protein translation. Co-treatment of MM1S and OPM2 cells for 4 hours with the combination of Rapamycin (10 nM) and lenalidomide (10 μM) resulted in further reduction in C-MYC protein levels compared to either drugs alone. These results are consistent with an independent and additive (5′-cap-dependent with Rapamycin and independent with lenalidomide) rather than epistatic (both 5′-cap dependent) effects on c-myc translation. Conclusions: Taken together our data indicate that treatment with lenalidomide suppresses c-myc translation in an IRF4/5′-cap-translation independent mechanism (early time point), an effect possibly resulting from a Cul4a-CRBN regulation of RPS25, a key protein-mediating ribosomal entry. Disclosures: Neri: Johnson ans Johnson: Research Funding. Bahlis:Johnson and Johnson: Honoraria, Research Funding; Celgene: Honoraria.
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Pavlovic, Marijana, Marija Ostojic, Kristina Zivic, Aleksandar Pavic, Tatjana Srdic-Rajic, and Jelena Grahovac. "Abstract 3463: Nischarin agonist rilmenidine inhibits pancreatic ductal adenocarcinoma cell migration and invasion." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3463. http://dx.doi.org/10.1158/1538-7445.am2022-3463.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy due to the lack of early diagnosis and limited response to all treatment modalities. Early metastatic dissemination, rich desmoplastic stroma and immunosuppressive infiltrate are some of the features contributing to the poor prognosis of PDAC patients (5-year survival rate of less than 10%). Despite scientific progress in the development of new therapeutic regimes, PDAC patients in low- and middle-income countries have restricted access to high-cost innovative drugs. Recently, attention has been given to the concept of drug repurposing that could meet the need for novel but affordable and widely accessible therapies. Imidazoline receptor 1 Nischarin (NISCH, IR1, IRAS) is an integrin α5-interacting protein that acts as a tumor suppressor in breast cancer through modulation of cancer cell motility and survival. Importantly, NISCH has several clinically approved agonists that are used for the treatment of hypertension and are shown to modulate autophagy and reduce inflammation and fibrosis, which makes NISCH a potentially good therapeutic target for defying PDAC progression. Based on our GSEA analysis of NISCH expression in PDAC patient samples, NISCH was predicted to have an effect on cancer cell focal adhesion assembly and cytoskeletal organization. Therefore, we examined the effects of NISCH agonists on PDAC cells fitness in vitro. A panel of PDAC cell lines was tested in MTT assay to determine the effects of NISCH agonists rilmenidine, clonidine and moxonidine on cell viability. Flow cytometry, western blot and immunofluorescence were used to examine the effects of NISCH agonists on PDAC cell metabolism, migration and cytoskeletal organization. Tg(fli1:EGFP) zebrafish model was used to examine the effects of NISCH agonists on PDAC cell growth and invasion. We found that NISCH was expressed in PDAC cell lines, and that out of the three tested agonists, rilmenidine most potently inhibited cancer cell viability. Treatment with rilmenidine significantly reduced PANC-1, MIA PaCa-2 and BxPC-3 cell attachment to extracellular matrix (collagen type I and fibronectin) and migratory potential in wound healing and transwell assays. Furthermore, treatment with rilmenidine altered the organization of actin cytoskeleton and focal adhesion assembly, potentially through the reduction of intracellular reactive oxygen species (ROS) levels. Importantly, treatment with rilmenidine inhibited invasion of PANC-1 cells in Tg(fli1:EGFP) zebrafish model. With these antimigratory and potentially antimetastatic effects of rilmenidine, our study lays the ground for a more extensive examination of the biological role of NISCH in PDAC progression and implies that its agonists may be good candidates for drug repurposing in this type of cancer. Citation Format: Marijana Pavlovic, Marija Ostojic, Kristina Zivic, Aleksandar Pavic, Tatjana Srdic-Rajic, Jelena Grahovac. Nischarin agonist rilmenidine inhibits pancreatic ductal adenocarcinoma cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3463.
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Drozhdina, M. B., and E. V. Suslova. "Immune response in atopic dermatitis: main pathogenetic mechanisms and stage-dependent correlations with age in regard to dermatological and non-dermatological systemic processes." Medical Immunology (Russia) 23, no. 2 (May 3, 2021): 237–44. http://dx.doi.org/10.15789/1563-0625-iri-2138.
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Atopic dermatitis is one of the most common chronic inflammatory skin diseases caused by both terminal defects in keratinocyte differentiation, and pronounced type 2 immune responses. Atopic dermatitis is a fairly heterogenous disease, depending on the age subtype caused by activation of the Th22, Th17/IL-23 and Th1 cytokine pathway. Clinical studies using classical and targeted therapies have helped to determine contribution of various immune axes to the disease phenotype.We present the modern activation theory mediated by Th2 reactions, due to congenital lymphoid cells of the 2nd group. Correlations between immune response in acute (IL-4, IL-5, IL-13, IL-31, CCL18, IL-22, S100A proteins) and chronic (IFNγ, CXCL9, and CXCL10) manifestations of atopic dermatitis are described. The theory of relationship between clinical manifestations and overexpression of some cytokines (IL-4, IL-13) is discussed. The correlation was shown between peripheral blood phenotype in atopic dermatitis of early childhood and in adult patients and individual production of serum biomarkers. In addition to excess Th17 production, early onset of atopic dermatitis in children correlated with elevated levels of antimicrobial peptides, which may serve as a signaling marker that triggers the disease. The article provides information about relationship between atopic dermatitis and other systemic non-allergic processes and diseases (psoriasis, atherosclerosis, cardiovascular diseases, obesity). Despite different polarity of T cells in atopic dermatitis and psoriasis, and different groups of cytokines produced in these diseases. Psoriasis is most of all due to Th17 associated with activation of IL-17, whereas atopic dermatitis is a consequence of Th2 dominance and associated excessive production of IL-4 and IL-13. The both diseases show activation of Th1 and Th22 with increased production of interferon-γ and IL-22, respectively. The article also concerns an interesting hypothesis on effects of the TWEAK protein upon clinical course of atopic dermatitis and psoriasis. In response to increased TWEAK activity, keratinocytes and skin fibroblasts produce a number of chemoattractant and pro-inflammatory factors commonly found in atopic dermatitis and psoriasis, in particular IL-13 and IL-17. TWEAK is not a single etiological factor for atopic dermatitis or psoriasis, but it causes the production of chemokines that promote chemotaxis of pathogenic inflammatory cells into the skin. With further studies of this pathogenetic factor, it will be possible to synthesize a new targeted drug for the treatment of atopic dermatitis and psoriasis.
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Cheng, Yuan-Lung, Keng-Hsueh Lan, Wei-Ping Lee, Szu-Han Tseng, Li-Rong Hung, Han-Chieh Lin, Fa-Yauh Lee, Shou-Dong Lee, and Keng-Hsin Lan. "Amiodarone inhibits the entry and assembly steps of hepatitis C virus life cycle." Clinical Science 125, no. 9 (July 8, 2013): 439–48. http://dx.doi.org/10.1042/cs20120594.
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HCV (hepatitis C virus) infection affects an estimated 180 million people in the world's population. Adverse effects occur frequently with current standard treatment of interferon and ribavirin, while resistance of new direct anti-viral agents, NS3 protease inhibitors, is a major concern because of their single anti-HCV mechanism against the viral factor. New anti-viral agents are needed to resolve the problems. Amiodarone, an anti-arrhythmic drug, has recently been shown to inhibit HCV infection in vitro. The detailed mechanism has yet to be clarified. The aim of the present study was to elucidate the molecular mechanism of the inhibitory effect of amiodarone on HCV life cycle. The effect of amiodarone on HCV life cycle was investigated in Huh-7.5.1 cells with HCVcc (cell culture-derived HCV), HCVpp (HCV pseudoviral particles), sub-genomic replicons, IRES (internal ribosomal entry site)-mediated translation assay, and intracellular and extracellular infectivity assays. The administration of amiodarone appeared to inhibit HCV entry independent of genotypes, which was attributed to the down-regulation of CD81 receptor expression. The inhibitory effect of amiodarone also manifested in the HCV assembly step, via the suppression of MTP (microsomal triacylglycerol transfer protein) activity. Amiodarone revealed no effects on HCV replication and translation. With the host factor-targeting characteristics, amiodarone may be an attractive agent for the treatment of HCV infection.
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Juan, Chenxia, Ye Zhu, Yan Zhou, Weiwei Zhu, Xufang Wang, Weiming He, and Yan Chen. "Exploration of Prognostic Immune-Related Genes and lncRNAs Biomarkers in Kidney Renal Clear Cell Carcinoma and Its Crosstalk with Acute Kidney Injury." Journal of Oncology 2022 (February 8, 2022): 1–17. http://dx.doi.org/10.1155/2022/6100187.
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Kidney renal clear cell carcinoma (KIRC) has a poor prognosis and a high death rate globally. Cancer prognosis is strongly linked to immune-related genes (IRGs), according to numerous research. We utilized KIRC RNA-seq data from the TCGA database to build a prognostic model incorporating seven immune-related (IR) lncRNAs, and we constructed the model using LASSO regression. Additionally, we calculated a risk score for each patient using a prognostic model that divided patients into high-risk and low-risk groups. The ESTIMATE and CIBERSORT methodologies were then used to analyze the differences in the tumor microenvironment of the two groups of patients. Finally, we predicted three small molecule drugs that may have potential therapeutic effects for high-risk patients. We combined the acute kidney injury dataset to obtain differential genes that may serve standard biological functions with two risk groups. Our study shows that the model we constructed for IR-lncRNAs has reliable predictive efficacy for patients with KIRC.