scholarly journals Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with The Novel Antibody NZ-16 for Malignant Mesothelioma

2021 ◽  
Author(s):  
Hitomi Sudo ◽  
Atsushi B Tsuji ◽  
Aya Sugyo ◽  
Mika K. Kaneko ◽  
Yukinari Kato ◽  
...  
Keyword(s):  
Malignant Mesothelioma ◽  
Competitive Inhibition ◽  
Therapeutic Option ◽  
Body Weight Loss ◽  
The Novel ◽  
Ki 67 ◽  
Absorbed Doses ◽  
Biodistribution Studies ◽  
Biodistribution Data

Abstract Purpose This study aimed to evaluate the potential of podoplanin (PDPN)-targeted alpharadiotherapy (RIT) for treating malignant mesothelioma.Methods A newly developed anti-PDPN antibody, NZ-16, and a previous anti-PDPN antibody, NZ-12, were assessed. The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing NCI-H226 (H226) mesothelioma cells. The biodistribution of 111 In-labeled antibodies was studied in tumorbearing mice. Tumor volumes and body weights of mice treated with 90 Y- and 225 Ac-labeled NZ-16 were measured for 56 days. The absorbed doses were estimated on the basis of the biodistribution data. Pathologic analysis of tumors and organs was conducted.Results The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12. RIT with 225 Ac-labeled NZ-16 (11.1 and 18.5 kBq) had a significantly higher antitumor effect than RIT with 90 Y-labeled NZ-16 (3.7 MBq; P < 0.01). 225 Ac-labeled NZ-16 induced more necrosis compared with 90 Y-labeled NZ-16, but the Ki-67 index and apoptosis rate were similar. The estimated absorbed doses were expected to be tolerable in mice. Temporary body weight loss occurred, but recovered within several days. No visible damage to major organs was detected.Conclusion The novel anti-PDPN antibody NZ-16 was a more effective RIT agent than NZ12. Radiolabeled NZ-16, especially 225 Ac-labeled NZ-16, markedly suppressed tumor growth and prolonged survival without inducing severe adverse effects. RIT with radiolabeled NZ-16 is a promising therapeutic option for malignant mesothelioma.

scholarly journals Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2503
Author(s):  
Hitomi Sudo ◽  
Atsushi B. Tsuji ◽  
Aya Sugyo ◽  
Mika K. Kaneko ◽  
Yukinari Kato ◽  
...  
Keyword(s):  
Malignant Mesothelioma ◽  
Competitive Inhibition ◽  
Therapeutic Option ◽  
The Novel ◽  
Absorbed Doses ◽  
Biodistribution Studies ◽  
Biodistribution Data ◽  
Body Weights ◽  
Necrotic Change

The prognosis of advanced mesothelioma is poor. Podoplanin (PDPN) is highly expressed in most malignant mesothelioma. This study aimed to evaluate the potential alpha-radioimmunotherapy (RIT) with a newly developed anti-PDPN antibody, NZ-16, compared with a previous antibody, NZ-12. Methods: The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. The absorbed doses were estimated based on biodistribution data. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. Histologic analysis was conducted. Results: The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12, providing higher absorbed doses to tumors. RIT with 225Ac- and 90Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-12. 225Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than 90Y-labeled NZ-16. There is no obvious adverse effect. Conclusions: Alpha-RIT with the newly developed NZ-16 is a promising therapeutic option for malignant mesothelioma.

Synthetic and semi-synthetic drugs as promising therapeutic option for the treatment of COVID-19

2020 ◽  
Vol 20 ◽  
Author(s):  
Ekta Shirbhate ◽  
Preeti Patel ◽  
Vijay K Patel ◽  
Ravichandran Veerasamy ◽  
Prabodh C Sharma ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Antiviral Treatment ◽  
The Novel ◽  
Clinical Experiences ◽  
Synthetic Compounds ◽  
Synthetic Drugs ◽  
Global Pandemic ◽  
The World ◽  
Novel Coronavirus

: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.

Abstract P233: Inhibition Of Aldosterone Synthesis In Non-human Primates By PB6440, The Novel Highly Selective And Potent CYP11B2 Inhibitor

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Bertram Pitt ◽  
Deepak L Bhatt ◽  
Karen Morris ◽  
J. David Becherer ◽  
William Hoekstra ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Multiple Dose ◽  
Therapeutic Option ◽  
Dependent Manner ◽  
The Novel ◽  
Aldosterone Synthase ◽  
Acth Challenge ◽  
High Doses ◽  
Synthase Inhibitor

Aldosterone is an important mineralocorticoid responsible for fluid and electrolyte homeostasis produced by aldosterone synthase (CYP11B2). An aldosterone synthase inhibitor (ASI) may be a therapeutic option for primary aldosteronism-related conditions such as resistant hypertension. An ASI with sufficient selectivity for CYP11B2 versus the similar cortisol-producing enzyme CYP11B1 has remained elusive. PB6440 is a novel ASI that is potent and highly selective for CYP11B2. In vitro studies demonstrated 200-300-fold selectivity of PB6440 for human CYP11B2 compared to human CYP11B1. In single and multiple dose cynomolgus monkey studies of orally administered PB6440, dose-and concentration-dependent reduction of plasma aldosterone after ACTH challenge was observed with >90% reduction at higher doses. Consistent with its high selectivity, PB6440 had little effect on the CYP11B1 cortisol pathway. Plasma levels of cortisol, 11-deoxycortisol, and deoxycorticosterone, remained unchanged even at high doses of PB6440. Systolic and diastolic blood pressure was reduced in a dose-dependent manner. Circulating half-life of PB6440 was approximately 17 hours with high oral bioavailability. In summary, PB6440 is a highly selective ASI that demonstrated sustained aldosterone suppression for 14 days with no effect on the CYP11B1 pathway in non-human primates. In single and multiple dose studies, PB6440 appeared well tolerated, demonstrating good oral bioavailability, and a PK profile supportive of once daily dosing. These results suggest that PB6440 may be useful in humans as a novel therapeutic for treating hypertension or other conditions caused by excess aldosterone.

scholarly journals Therapeutic Evaluation of Palbociclib and Its Compatibility with Other Chemotherapies in Primary and Recurrent Nasopharyngeal Carcinoma

2020 ◽  
Author(s):  
Zhichao Xue ◽  
Vivian Wai Yan Lui ◽  
Yongshu Li ◽  
Jia Lin ◽  
Chanping You ◽  
...  
Keyword(s):  
Cell Death ◽  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Therapeutic Option ◽  
Substantial Reduction ◽  
Inhibitory Effect ◽  
High Dose ◽  
Ki 67

Abstract Background: Recent genomic analyses revealed that druggable molecule targets could only be detected in around 6% of nasopharyngeal carcinoma (NPC) patients. Yet, an addiction to dysregulated CDK4/6-cyclinD1 signalling pathway is an essential event in the pathogenesis of NPC. Using our newly established xenografts and cell lines derived from primary, recurrent and metastatic NPC, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemodrugs in treating NPC.Methods: The efficacy of single treatment of palbociclib on NPC models was first evaluated, followed by concurrent treatment with cisplatin or suberanilohydroxamic acid (SAHA). RNA sequencing was used to profile the related pathways in governing the drug response. Palbociclib-resistant NPC cell lines were also established to demonstrate if cisplatin could be used as a second-line treatment once the cells developed resistance to palbociclib. The efficacy of palbociclib treatment on cisplatin-resistant NPC cells was also examined. Results: Palbociclib single drug treatment was confirmed to have a cell cycle arresting effect of NPC cells in G1 phase in vitro. It also had a significant inhibitory effect in all the 6 NPC tumor models in vivo, with a substantial reduction in total tumor volume and proliferation marker Ki-67. Concurrent use of palbociclib dampened the cytotoxic effect of cisplatin in NPC cells in vitro. Notably, combination of palbociclib with SAHA resulted in synergistic cell death of NPC both in vitro and in vivo. Autophagy-associated cell death was found to be involved in the enhanced tumor growth inhibitory effect in the combined palbociclib+SAHA treatment. NPC cell lines trained to sustain growth in high dose of palbociclib and cisplatin remained sensitive in subsequent treatment of cisplatin or palbociclib respectively.Conclusions: This study provides essential evidences to position palbociclib as an alternative therapeutic option to NPC treatment, and to aware the effective administrative timing of palbociclib with other chemodrugs. The findings give the basis for planning of the first-in-human clinical trials of palbociclib regimens in NPC patients.

scholarly journals Treatment of Darier’s disease with oral magnesium: a case report

2018 ◽  
Vol 6 ◽  
pp. 2050313X1879507
Author(s):  
Heidi Oi-Yee Li ◽  
Sophia Colantonio ◽  
Nordau Kanigsberg
Keyword(s):  
Endoplasmic Reticulum ◽  
Magnesium Chloride ◽  
Therapeutic Option ◽  
The Novel ◽  
Darier’S Disease ◽  
Darier Disease ◽  
Darier's Disease ◽  
Effective Therapeutic Option ◽  
Oral Magnesium

Darier’s disease, an autosomal dominant genodermatosis, arises from a mutation in the ATP2A2 gene that codes for sarco/endoplasmic reticulum Ca2+-ATPase in the endoplasmic reticulum and is characterized by greasy keratotic papules commonly found in seborrheic regions. Conventional treatments, including topical corticosteroids, antibiotics, antifungals and retinoids, often have limited efficacy. The present article reports the novel use of oral magnesium chloride supplementation (300 mg daily) in the treatment of Darier disease. After 5 years of limited improvement using conventional therapies, significant improvements in neck lesions were observed within 1 month of starting oral magnesium chloride. This suggests that oral magnesium chloride may be an effective therapeutic option for Darier disease, although further in vitro and clinical trials are necessary to evaluate its clinical efficacy.

scholarly journals Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting

2013 ◽  
Vol 118 (6) ◽  
pp. 1466-1474 ◽  
Author(s):  
Jerrold H. Levy ◽  
David Faraoni ◽  
Jenna L. Spring ◽  
James D. Douketis ◽  
Charles M. Samama
Keyword(s):  
Oral Anticoagulation ◽  
Elective Surgery ◽  
Therapeutic Option ◽  
Oral Anticoagulants ◽  
Thrombin Inhibitor ◽  
Renal Elimination ◽  
The Novel ◽  
Bleeding Management ◽  
Anticoagulation Agents

Abstract Managing patients in the perioperative setting receiving novel oral anticoagulation agents for thromboprophylaxis or stroke prevention with atrial fibrillation is an important consideration for clinicians. The novel oral anticoagulation agents include direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran. In elective surgery, discontinuing their use is important, but renal function must also be considered because elimination is highly dependent on renal elimination. If bleeding occurs in patients who have received these agents, common principles of bleeding management as with any anticoagulant (including the known principles for warfarin) should be considered. This review summarizes the available data regarding the management of bleeding with novel oral anticoagulation agents. Hemodialysis is a therapeutic option for dabigatran-related bleeding, while in vitro studies showed that prothrombin complex concentrates are reported to be useful for rivaroxaban-related bleeding. Additional clinical studies are needed to determine the best method for reversal of the novel oral anticoagulation agents when bleeding occurs.

scholarly journals The therapeutic potential of the novel ribonuclease ranpirnase (Onconase®) in the treatment of malignant mesothelioma

2011 ◽  
pp. 61-65
Author(s):  
Luciano Mutti ◽  
Giovanni Gaudino
Keyword(s):  
Malignant Mesothelioma ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Phase Iii ◽  
The Novel ◽  
Phase Iii Study ◽  
Large Phase ◽  
Tumor Types

Ribonucleases are a superfamily of RNA-cleaving enzymes that can be cytotoxic since the cleavage of RNA makes its information indecipherable. Ranpirnase is a novel ribonuclease which preferentially degrades tRNA, thus leading to an inhibition of protein synthesis and, ultimately, to cytostasis and cytotoxicity. Ranpirnase has demonstrated antitumor activity both in vitro and in vivo in several tumor models, including malignant mesothelioma. A large phase II trial showed that ranpirnase has diseasemodifying activity against mesothelioma. A first phase III study demonstrated that rampirnase may be combined with doxorubicin and that such an association is more active than Ranpirnase alone against mesothelioma. At present, another large, phase III trial in combination with doxorubicin has completed enrollment and its results are awaited. In all the above studies, ranpirnase died not demonstrate conventional anticancer activity, stabilizing progressive disease and potentially prolonging patients’ survival. Finally, a better understanding of its mechanism of action, coupled with its favorable toxicity profile, especially characterized by the lack of major hematologic toxicities, makes ranpirnase an attractive drug to test in combination with other anticancer agents, in MMe as well as in other tumor types.

Effects of Dipyrone on Prostaglandin Production by Human Platelets and Cultured Bovine Aortic Endothelial Cells

1983 ◽  
Vol 49 (02) ◽  
pp. 132-137 ◽  
Author(s):  
A Eldor ◽  
G Polliack ◽  
I Vlodavsky ◽  
M Levy
Keyword(s):  
Endothelial Cells ◽  
Arachidonic Acid ◽  
Competitive Inhibition ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Ionophore A23187 ◽  
Aortic Endothelial Cells ◽  
Bovine Aortic Endothelial Cells ◽  
Aortic Endothelial

SummaryDipyrone and its metabolites 4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoan- tipyrine inhibited the formation of thromboxane A2 (TXA2) during in vitro platelet aggregation induced by ADP, epinephrine, collagen, ionophore A23187 and arachidonic acid. Inhibition occurred after a short incubation (30–40 sec) and depended on the concentration of the drug or its metabolites and the aggregating agents. The minimal inhibitory concentration of dipyrone needed to completely block aggregation varied between individual donors, and related directly to the inherent capacity of their platelets to synthesize TXA2.Incubation of dipyrone with cultured bovine aortic endothelial cells resulted in a time and dose dependent inhibition of the release of prostacyclin (PGI2) into the culture medium. However, inhibition was abolished when the drug was removed from the culture, or when the cells were stimulated to produce PGI2 with either arachidonic acid or ionophore A23187.These results indicate that dipyrone exerts its inhibitory effect on prostaglandins synthesis by platelets or endothelial cells through a competitive inhibition of the cyclooxygenase system.

Molecular iodine synergized and sensitized neuroblastoma cells to the antineoplastic effect of ATRA

2020 ◽  
Vol 27 (12) ◽  
pp. 699-710
Author(s):  
Irasema Mendieta ◽  
Gabriel Rodríguez-Gómez ◽  
Bertha Rueda-Zarazúa ◽  
Julia Rodríguez-Castelán ◽  
Winniberg Álvarez-León ◽  
...  
Keyword(s):  
Residual Disease ◽  
Neuroblastoma Cells ◽  
Survivin Expression ◽  
Body Weight Loss ◽  
Immunohistochemical Analysis ◽  
Molecular Iodine ◽  
Tyrosine Kinase Receptor ◽  
Adjuvant Effect

Neuroblastoma (NB) is the most common solid childhood tumor, and all-trans retinoic acid (ATRA) is used as a treatment to decrease minimal residual disease. Molecular iodine (I2) induces differentiation and/or apoptosis in several neoplastic cells through activation of PPARγ nuclear receptors. Here, we analyzed whether the coadministration of I2 and ATRA increases the efficacy of NB treatment. ATRA-sensitive (SH-SY5Y), partially-sensitive (SK-N-BE(2)), and non-sensitive (SK-N-AS) NB cells were used to analyze the effect of I2 and ATRA in vitro and in xenografts (Foxn1 nu/nu mice), exploring actions on cellular viability, differentiation, and molecular responses. In the SH-SY5Y cells, 200 μM I2 caused a 100-fold (0.01 µM) reduction in the antiproliferative dose of ATRA and promoted neurite extension and neural marker expression (tyrosine hydroxylase (TH) and tyrosine kinase receptor alpha (Trk-A)). In SK-N-AS, the I2 supplement sensitized these cells to 0.1 μM ATRA, increasing the ATRA-receptor (RARα) and PPARγ expression, and decreasing the Survivin expression. The I2 supplement increased the mitochondrial membrane potential in SK-N-AS suggesting the participation of mitochondrial-mediated mechanisms involved in the sensibilization to ATRA. In vivo, oral I2 supplementation (0.025%) synergized the antitumor effect of ATRA (1.5 mg/kg BW) and prevented side effects (body weight loss and diarrhea episodes). The immunohistochemical analysis showed that I2 supplementation decreased the intratumoral vasculature (CD34). We suggest that the I2 + ATRA combination should be studied in preclinical and clinical trials to evaluate its potential adjuvant effect in addition to conventional treatments.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

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