Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2

Since the first cases the coronavirus disease caused by SARS-CoV-2 (COVID-19) reported in December 2019, worldwide continuous efforts have been placed both for the prevention and treatment of this infectious disease. As new variants of the virus emerge, the need for an effective antiviral treatment continues. The concept of preventing SARS-CoV-2 on both pre-entry and post-entry stages has not been much studied. Therefore, we compared the antiviral activities of three antiviral drugs which have been currently used in the clinic. In silico docking analyses and in vitro viral infection in Vero E6 cells were performed to delineate their antiviral effectivity when used alone or in combination. Both in silico and in vitro results suggest that the combinatorial treatment by favipiravir and umifenovir or camostat mesylate has more antiviral activity against SARS-CoV-2 rather than single drug treatment. These results suggest that inhibiting both viral entry and viral replication at the same time is much more effective for the antiviral treatment of SARS-CoV-2.

A Pilot Basket Study to Evaluate Multi-Analyte Liquid Biopsies for Personalized Treatments in Advanced Refractory Cancers

Prior attempts at personalizing anticancer treatments based on univariate tumor profiling (single gene variant) for selection of monotherapy with targeted agents (single drug) have generally yielded poor response rates. We report findings from the LIQUID IMPACT pilot trial where Multi-analyte Liquid Biopsy (MLB) profiling of circulating tumor analytes in peripheral blood was used to inform selection of personalized combination regimens in advanced refractory cancers. Among the 43 patients evaluable as per study protocol, 34 had targetable pathway activations. Partial Response (PR) was observed in 14 (41.1%) of the 34 patients with signaling pathway activation, including 5 (50%) of 10 cases with mTOR activation, 8 (44.4%) of 18 cases with activation of angiogenesis and 4 (50.0%) of 8 cases with EGFR / ERBB2 activation. PR was not reported among the 9 cases with no detectable pathway activation. Toxicities were manageable and there were no treatment related deaths. The study findings suggest that MLB may be able to inform safe and efficacious combination regimens in patients with advanced refractory cancers.

A Review on Contaminants of Emerging Concern in the Environment: A Focus on Active Chemicals in Sub-Saharan Africa

Active chemicals are among the contaminants of emerging concern that are rarely covered in regulatory documents in sub-Saharan Africa. These substances are neither in the list of routinely monitored substances nor in the guidelines for routine environmental monitoring activities. This has been of concern to public health officials, toxicologists, communities, and governments, hence the need for risk assessment and regulation of these substances. In this review article, the presence of active chemicals in the sub-Saharan African environment was investigated. The results indicate the availability of few studies in some countries, while in other countries no reports of active chemicals were found, hence the need for further research targeting such countries. It was further observed that mixtures of active chemicals from different therapeutic categories—such as antibiotics and analgesics—were reported. The natural environment is increasingly at risk due to the presence of these substances, their metabolites, and their transformation byproducts. These substances are characterized by persistence as a result of their non-biodegradable nature; hence, they circulate from one environmental compartment to another through the food chain, causing harm along the way. Most studies that evaluated the toxicity of these substances considered the effects of a single drug, but observations indicated the presence of drug mixtures, hence the need for further evaluation of the effects of drug–drug interactions—including synergistic and additive effects—for environmental sustainability. The presence of ACs in several environmental compartments at quantifiable quantities was discovered in this investigation, indicating the potential for ecosystem injury as a result of bioaccumulation, bioconcentration, and biomagnification through the food chain. This necessitates further research on the subject in order to ensure a healthier environment.

VISHAHARA DRAVYAS IN MADANAPALA NIGHANTU – A REVIEW ARTICLE

Background: Ayurveda is the science of life that deals with the protection of the health of the healthy and pacify- ing the disease of the diseased. Agada tantra is one of the branches of Ayurveda that deals with the signs and symptoms with treatment of visha of all types. Madanapala Nighantu is one of the ancient Nighantu written by King Madanapala. A total of 13 chapters are explained in Madanapala Nighantu and there are many vishahara dravyas explained throughout these chapters. Materials and Method: Here an attempt is made to collect and re- view the Vishahara dravya mentioned in the various vargas of Madanapala Nighantu with its botanical name, family and indication and is presented in the table. Observations and results: Among 13 Chapters of Mada- napala Nighantu 105 dravyas are vishahara in nature. Conclusion: Either a single drug preparation or their com- binations can give great results in the management of various poisoning. Keywords: Agada tantra, Madanapala Nighantu, Visha, Vishahara.

Clinical Study of Gefitinib for Non-Small Cell Lung Cancer

Objective: To evaluate the clinical efficacy of gefitinib in non-small cell lung cancer. Methods: A total of 45 patients with non-small cell lung cancer who received treatment in Taizhou Second People’s Hospital from January 2018 to January 2020 were selected as the subjects in this study, in which all of them were treated with gefitinib. Its efficacy and safety were evaluated. Results: The objective response rate was 53.33% and the disease control rate was 84.44%. After treatment, the levels of tumor markers were measured again, of which the levels of CA125 and CEA were significantly lower than before (P < 0.05). After treatment, the patients’ CD3+, CD4+, and CD4+/CD8+ were significantly lower than those before treatment, and CD8+ was significantly higher (P < 0.05). Conclusion: Gefitinib, which is a targeted therapy for non-small cell lung cancer, can reduce the level of serum tumor markers and improve the immune function. The curative effect is good, but more emphasis should be on the adverse reactions caused by a single drug use.

Effect and Mechanism of Lidocaine Pretreatment Combined with Dexmedetomidine on Oxidative Stress in Patients with Intracranial Aneurysm Clipping

This study aimed to explore the effect and mechanism of lidocaine pretreatment combined with dexmedetomidine on oxidative stress in patients with intracranial aneurysm clipping. Many studies have used various drugs such as lidocaine to explore the effect and mechanism of lidocaine pretreatment. A total of 80 patients with intracranial aneurysm clipping surgery were randomly divided into 4 groups: the single lidocaine group, single dexmedetomidine group, lidocaine combined with dexmedetomidine group, and control group. The thread embolism method was used to establish a stable intracranial aneurysm model of Hashimoto rats. Fifty adult rats were randomly divided into a sham operation group, ligation of the left common carotid artery and bilateral posterior branch of renal artery, lidocaine group, dexmedetomidine group, and lidocaine combined with dexmedetomidine group. The colorimetric method was used to determine the oxidative stress indicators in brain tissue: MDA content, SOD activity, and T-AOC content. The western blot method characterized the protein levels related to oxidative stress: nNOS, iNOS, and NADPH oxidase subunits p22phox, gp91phox, and p47phox. The differences in each index between the groups were statistically significant ( P < 0.05 ). Animal experiment results revealed that the content of MDA in the brain tissue of rats in the LD group was significantly lower than that in the single-drug group and sham group. The T-AOC and SOD concentrations in the LD group were significantly higher than those in the single-drug group and sham group, and the differences between the groups were statistically significant ( P < 0.05 ). The protein expression of the LD group was significantly lower than that of the drug-alone group and model group, and the difference between groups was statistically significant ( P < 0.05 ). To sum up, lidocaine pretreatment combined with dexmedetomidine can effectively maintain the hemodynamic stability of patients with intracranial aneurysm clipping and reduce postoperative oxidative stress response. Its mechanism of action may be related to the inhibition of oxidative stress damage mediated by nNOS, iNOS, and p22phox, gp91phox, and p47phox in the hippocampus. Our study has significant and applicable medical aspects in lidocaine pretreatment combined with dexmedetomidine on oxidative stress in patients.

Targeting EZH2 Promotes Chemosensitivity of BCL-2 Inhibitor through PIK3IP1-PI3K/AKT Axis in Acute Myeloid Leukemia

Introduction Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which plays critical roles in transcription repressions.[1] PRC2 is required for acute Myeloid Leukemia (AML) cell survival, and EZH2 is overexpressed and related to worse prognosis in AML, therefore, EZH2 may involve in leukemogenesis through inhibition of the tumor suppressor genes in AML. [2, 3] BCL-2, one of the key anti-apoptosis proteins is dysregulated in AML. Venetoclax (Ven, ABT-199), a BCL-2 selective inhibitor has anti-tumor activity in AML but its overall response rate of monotherapy was unsatisfied owing to the clinical resistance to the inhibitor. [4] In this study, we examined the effect of targeting EZH2 on chemosensitivity of BCL-2 inhibitor in AML and the underlying mechanisms. Methods Cell Counting Kit-8 assay was used for cell proliferation and cytotoxicity in U937 and MV-4-11 AML cells treated with vehicle control, EZH2 inhibitor (DZNeP), Ven and Combination (Combo, Ven+DZNeP) for 48 hours. Synergistic effect was analyzed with Calcusyn. RNA-seq was performed with total RNA isolated from U937 cells treated with 2μM DZNeP, 7.5μM Ven or vehicle for 48 hours. Apoptosis was measured by cell staining with Annexin V+propidium iodide (PI) following flow cytometry analysis. EZH2 mRNA level was examined by qPCR in 39 newly-diagnosed AML patients from February 1, 2016 to February 28, 2019 at our institute with an approval of the Ethics Committee. Level of the apoptotic effectors was detected by western blot. GEPIA (Gene Expression Profiling Interactive Analysis) and R2 genomics analysis and visualization application were utilized for survival analysis. Results Both Ven and DZNeP had a dose-dependent and time-dependent effect on cell proliferation arrest in U937 and MV4-11 cells. DZNeP significantly sensitized the effect of Ven on cell proliferation arrest compared to single drug only (P&lt;0.001) (Fig.1a). CalcuSyn analysis showed the synergistic effect of the Ven+DZNeP on cell proliferation arrest (Fig.1b). Total apoptosis rate increased significantly in the Ven +DZNeP group in U937(32.04%±2.83) and MV-4-11 (25.73%±0.34) cells compared to single drug controls (Fig.1c). Also, level of the apoptotic effectors, PARP, Cleaved caspase-3 and Cleaved caspase-9 were significantly increased in Ven+DZNeP group compared to single drug and vehicle control (Fig.1d). Moreover, 1727 significantly regulated genes were identified by RNA-seq in U937 cells upon Ven treatment compared to vehicle control, and 1376 upon DZNeP treatment, in which 333 were overlapped (104 genes changed in the same direction but 228 changed in the opposite) (Fig 2a). The overlapped regulated genes upon the two drugs treatment are mainly involved in PIK3/AKT/mTOR, G1/S transition of mitotic cell cycle, apoptosis, et al. PIK3AP1, PIK3C2B and PIK3R3, the activators of PI3K signaling are up-regulated upon Ven treatment; and PI3KIP1, the suppressor of PI3K/AKT/mTOR signaling pathway is down-regulated by Ven but up-regulated by DZNeP. qPCR data showed that Ven+DZNeP significantly upregulated PIK3IP1 and down-regulated the expression of PI3K activators in the cells (Fig 2b). It is reported that the PI3K/AKT/mTOR signaling pathway is related to the clinical resistance of Ven in AML patients. Thus, our data not only showed the synergistic effect of Ven+DZNeP but also revealed a model that targeting EZH2 by DZNeP might conquer the Ven-induced bypass-effect through upregulation of PIK3IP1 to repression of PI3K/AKT signaling pathway. In addition, EZH2 mRNA level was quantified in 39 newly diagnosis patients with AML and 20 health control, and data showed EZH2 is increased in AML (p&lt;0.05). Metadata analysis support our results, and EZH2 overexpression is associated with short overall survival (p&lt;0.05) (Fig 2c). Database analysis assured that the expression of PIK3IP1 in patients with AML is lower than normal control. High PIK3IP1 showed a trend to a better outcome, which further supports that PIK3IP is a tumor suppressor in AML (Fig 2d). Conclusions Our data demonstrate the DZNeP sensitizes the effect of Ven in AML. Our results also reveal a novel mechanism that accounts for the synergistic effect of the two drugs and the fact that DZNeP may increase the chemosensitivity of BCL-2 inhibitor through PIK3IP1-PI3K/AKT axis in AML. Our findings suggest the potential combined therapy of Ven+DZNeP for AML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Refunds If a Drug Doesn’t Work

No abstract available. Article truncated after 150 words. One aspect of the high cost of healthcare is the cost of new drugs. Cancer drugs have received much of the attention because of their extremely high price (1). For example, crizotinib, used to treat non-small cell lung cancer (NSCLC), costs $19,144 for each month's supply. Pfizer, the manufacturer of crizotinib, has just announced that they are offering a refund if its drug "doesn't work" (2). If crizotinib use is discontinued and documentation of ineffectiveness is provided, Pfizer will refund the out-of-pocket amount that was paid for up to the first three bottles (30-day supply) of crizotinib, up to a maximum of $19,144 for each month's supply, or a total of $57,432. Of course, the cost of care includes more than just a single drug and can be much higher and Pfizer is reimbursing only the drug cost. Although Pfizer claims that its pilot program is a first in the …

Recent Herbal Proprietary Preparations for Liver Diseases: A Comparative Study

Liver is considered to be one of the most vital organs that functions as a centre of metabolism and excretion of waste metabolites. A number of risk factors predispose an individual to hepatic injury and thus liver diseases. Total death worldwide due to liver diseases raised by 50 million per year over two decades, according first ever WHO Study of Liver Disease Mortality. In recent years Indian Traditional Medicines like Ayurveda, Siddha and Unani have gained importance and popularity because of their safety and efficacy in liver diseases. Several Ayurvedic proprietary liver preparations are being extensively used in Ayurveda for the management of liver diseases. About 600 commercial herbal formulations with claimed hepato protective activity are being sold all over the world. In India more than 93 medicinal plants are used in different combinations in the preparation of 40 patented herbal formulations in the form of liquid and tablet. But very little is known when and how these formulations are to be used in present practice. Out of this easily available most commonly used liver preparations Adliv, Amlicure DS, Arkaliv, Ayuliv, Hepjaun, Kamilari, Kamilari plus, Liv Aid, Livercure, Livergen, Liv 52, Livobell, Livokin, Livomyn, Livpar, Nirocil, Stimuliv, Strongliv, Terfoliv and Vasuliv are taken for the study. These preparations are classified on various basis like available market form, Herbo-Herbomineral preparations etc. Kutaki is most commonly used single drug in maximum number of preparations followed by Bhringraj, Bhui Aamalaki, and Kalmegh. Individual drugs of the preparations are studied according to Rasa, Virya and Vipaka. Uses of individual drugs as well as of liver preparations are also studied in relations with liver diseases. Present study will definitely give a clue for standard herbal formulations based on physiopathology of liver disease which is a need of a day Keywords: Liver, Hepato protective, Herbal, Formulations.