Analysis of novel antineoplastic drugs treatment impact on the federal project «cancer control» goals achievement

The Federal project “Cancer Control” was launched in 2019. Its main objective is to reduce mortality from malignant neoplasms in Russia. The main goal of this research is to develop a methodology for assessment of innovative drugs treatment impact on reducing mortality from neoplasms (including malignant) and testing it in the case of some novel drugs. Materials and methods. Firstly, we assessed the number of patients, who annually can start a novel drug treatment. Afterwards we estimated the number of deaths, which could be avoided due to the efficacy differences between innovative drugs compared to the standard of care in terms of overall survival. Obtained results were than correlated to the reduction in malignant mortality ratio needed to achieve annually (comparing to the basis 2020). For the approbation of the model, we chose durvalumab, osimertinib and olaparib, which are indicated for lung and ovarian cancer treatment. Results. Annually 6 746 patients can start the treatment: 2 391 with durvalumab, 2 334 with osimertinib, 2 021 with olaparib. In the 2021-2023 frame durvalumab treatment can help to avoid 779 deaths, osimertinib treatment can help to avoid 723 deaths, olaparib treatment can help to avoid 679 deaths (totally 10,8% of reduction in deaths needed to achieve 2021-2023 goals). Conclusion. Novel antineoplastic drugs treatment leads to a quantifiable reduction in mortality from malignant neoplasms in Russia.

Trends of Phase I Clinical Trials of New Drugs in Mainland China Over the Past 10 Years (2011–2020)

Background: In recent years, the number of clinical trials initiated in China has increased rapidly. The aim of this study was to overview the changing landscape of phase I clinical trials in mainland China from 2011 to 2020.Methods: We analyzed phase I clinical trials registered on 3 websites including the Chinese Clinical Trial Registry, ClinicalTrials.gov, and the China National Medical Products Administration Center for Drug Evaluation platform.Findings: A total of 2,842 phase I clinical trials were posted from January 1, 2011, to December 31, 2020. The overall number of clinical trials for innovative drugs was 1,497, accounting for half of all the phase I clinical trials (53%). Among these 1,486 innovative drug clinical trials, 924 were newly tested drugs with an average annual growth rate of 59%. Biological drug research increased significantly from 22.6% during 2011–2015 to 33.3% during 2016–2020. These principal investigators (PIs) of these clinical trials were mainly from Beijing (n = 871), followed by Shanghai (n = 496) and Jiangsu (n = 281). As for the therapeutic area of phase I clinical trials, cancer took up the most percentage of all the clinical trials (35%), followed by infectious disease (9%), nervous system disease (9%), etc. Most phase I clinical trials are conducted on healthy volunteers (n = 1,642, 57.8%), some cancer drugs are conducted in patients with cancer (n = 846, 29.8%), and only a few clinical trials were conducted in the elderly (n = 7). Among these clinical trials of the newly tested innovative drugs, the first in human (FIH) clinical trials accounted for 82% (744), and the First in Chinese (FIC) clinical trials only took up 18% (167). Only a small number of drugs could be made the transition to phase II (n = 207, 22%). In addition, despite the number of newly tested drugs during 2011–2015 (n = 163) was much less than that in 2016–2020 (n = 761), the percentage of drugs that could enter into phase II clinical trials in 2011–2015 (34%) was higher than that in 2016–2020 (20%).Conclusion: In the past 10 years, the development of phase I clinical trials has achieved great progress in mainland China due to the novel design and drug innovation policy. Nevertheless, future efforts are needed to make for improving the phase transition success rate of innovative drugs.

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.

Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide

Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternatives. Dermaseptin-B2, a natural multifunctional antimicrobial peptide isolated from Amazonian frog skin, has been reported to possess antitumor activity. To improve its pharmacological properties and to decrease its peripheral toxicity and lethality we developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys6-LHRH to target the LHRH receptor. This hormonotoxin has a significant antiproliferative effect on the PC3 tumor cell line, with an IC50 value close to that of dermaseptin-B2. Its antitumor activity has been confirmed in vivo in a xenograft mouse model with PC3 tumors and appears to be better tolerated than dermaseptin-B2. Biophysical experiments showed that the addition of LHRH to dermaseptin-B2 did not alter its secondary structure or biological activity. The combination of different experimental approaches indicated that this hormonotoxin induces cell death by an apoptotic mechanism instead of necrosis, as observed for dermaseptin-B2. These results could explain the lower toxicity observed for this hormonotoxin compared to dermaseptin-B2 and may represent a promising targeting approach for cancer therapy.

Surprises in cardiology: efficacy of gliflozines in heart failure even in the absence of diabetes

It is now well-established that the therapy of type II diabetes mellitus has undergone a radical change in the past 15 years: countless innovative drugs, such as SGLT2I, able to guarantee an optimization of glycaemic control without causing hypoglycaemia, today represent real therapeutic cornerstones not only for the intrinsic ability of these molecules to ensure better glycaemic control but also for the effects they exert on the cardiovascular system. Several pioneering clinical trials, such as EMPA-REG, CANVAS, and DECLARE-TIMI-58, have demonstrated clear benefits of empagliflozin, canagliflozin, and dapagliflozin, respectively, in reducing cardiovascular risk and diabetes-associated macrovascular complications in the diabetic population. The promising results that emerged from these trials represent the spark that triggered a series of studies aimed at evaluating the efficacy of gliflozines in the treatment of patients with heart failure even in the absence of diabetes. Preliminary results confirm the efficacy of SGLT2I in the treatment of this population, representing a real therapeutic revolution.

The evolution of COVID-19 pandemic wave and optimal levels of vaccination to reduce negative effects in society

Coronavirus disease 2019 (COVID-19) continues to be a pandemic threat with new mutations of the viral agent (SARS-CoV 2) that are generating a constant state of attention in manifold countries. Innovative drugs, such as vaccines can sustain, as far as possible, immunity of people and decrease negative effects in society. The study here, using data of vaccines and confirmed cases of COVID-19 between countries from March to May 2021, clarifies different optimal levels of vaccination associated with the growth of pandemic wave for reducing infected individuals in society. Findings reveal that a vaccination campaign in the initial phase of pandemic wave has a lower optimal level of doses administered per 100 inhabitants, but the growth of pandemic wave moves up the optimal level of vaccines from 58.5 in March to more than 86 doses per 100 people in May 2021. This study suggests that the optimal strategy and response to pandemic crisis is a rapid vaccination rollout, before the takeoff of pandemic wave, for an effective response to reduce numbers of COVID-19 related infected individuals and deaths and negative effects of pandemic crisis on environment and socioeconomic systems.

Polyphenolic Flavonoid Compound Quercetin Effects in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Flavonoids are ubiquitous groups of polyphenolic compounds present in most natural products and plants. These substances have been shown to have promising chemopreventive and chemotherapeutic properties with multiple target interactions and multiple pathway regulations against various human cancers. Polyphenolic flavonoid compounds can block the initiation or reverse the promotion stage of multistep carcinogenesis. Quercetin is one of the most abundant flavonoids found in fruits and vegetables and has been shown to have multiple properties capable of reducing cell growth in cancer cells. Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) therapy remains a challenge for hematologists worldwide, and the outcomes for patients with both disorders continue to be poor. This scenario indicates the increasing demand for innovative drugs and rational combinative therapies. Herein, we discuss the multitarget effects of the flavonoid quercetin, a naturally occurring flavonol, on AML and MDS.