Improvement of a pharmaceutical enterprise’s business processes at the stage of preclinical development of new drugs

The authors consider the impact of financial innovations on the macroeconomic situation. The increasing complexity of financial market instruments is the way to decrease its transparency and, consequently, the overall economic stability. The global crisis of 2008-2009 demonstrated the relevance of this problem. However, the authors believe that the nations can take advantage of new financial products, technologies and business processes if the regulators manage to fully track and timely offset the accompanying risks. It is important that execution of the financial innovations correspond with the structure of the funding companies and banks. It is concluded that adequate regulation of financial innovation will allow better use of their potential in order to address a number of important economic issues. In particular, it may help to accelerate the development and introduction of new drugs, to the implementation of environmental projects, the financing of social progress in the developing countries for achieving the Millennium Goals proclaimed by the UN in 2000.

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Studying the peculiarities of project and program management in the pharmaceutical companies on Russian market

Scientific Research and Development Russian Journal of Project Management ◽

10.12737/article_5ac5d8dc3cd9a3.66220138 ◽

2018 ◽

Vol 7 (1) ◽

pp. 19-33

Author(s):

Екатерина Фролкина ◽

Ekaterina Frolkina

Keyword(s):

Life Cycle ◽

Research And Development ◽

Business Processes ◽

Program Management ◽

New Drugs ◽

Pharmaceutical Companies ◽

Development Projects ◽

Russian Market ◽

Key Features ◽

A Company

The author singled out a typology of projects in pharmaceutical companies for the life cycle of the creation and commercializing of a new drug on the market, including research and development projects, production projects and implementation projects. In the framework of the study, the author examined only implementation projects, namely: projects for introducing new drugs to the market, projects to maintain existing drugs on the market and projects to optimize business processes. The purpose of this study was to identify key features of managing projects and programs in pharmaceutical companies operating on the Russian market, to form an approach to managing a company that increases its competitiveness.

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Drug Repurposing: A Review

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i31b31704 ◽

2021 ◽

pp. 161-169

Author(s):

Rani Teksinh Bhagat ◽

Santosh Ramarao Butle

Keyword(s):

Drug Development ◽

Research And Development ◽

Development Process ◽

Drug Repositioning ◽

Drug Repurposing ◽

New Drugs ◽

Preclinical Development ◽

Therapeutic Uses ◽

Original Application ◽

Approved Drugs

The drug development is a very time consuming and complex process. Drug development Process is Expensive. Success rate for the new drug development is very small. In recent years, decreases the new drugs development. The powerful tools are developed to support the research and development (R&D) process is essential. The Drug repurposing are helpful for research and development process. The drug re-purposing as an approach finds new therapeutic uses for current candidates or existing candidates or approved drugs, different from its original application. The main aimed of Drug repurposing is to reduce costs and research time investments in Research & Development. It is used for the diagnosis and treatment of various diseases. Repositioning is important over traditional approaches and need for effective therapies. Drug re-purposing identifies new application for already banned or existing drugs from market. In drug design, drug repurposing plays important role, because it helps to preclinical development. It reducing time eﬀorts, expenses and failures in drug discovery process. It is also called as drug repositioning, drug redirecting, drug reprofiling.

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Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species

Antioxidants ◽

10.3390/antiox10121883 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1883

Author(s):

Yen-Po Chen ◽

Po-Chang Shih ◽

Chien-Wei Feng ◽

Chang-Cheng Wu ◽

Kuan-Hao Tsui ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Ovarian Cancer ◽

Reactive Oxygen ◽

New Drugs ◽

Oxygen Species ◽

Preclinical Development ◽

Skov3 Cells ◽

Ic50 Values ◽

Induced Apoptosis ◽

Related Proteins

Most ovarian cancer (OC) patients are diagnosed with stage III or higher disease, resulting in a poor prognosis. Currently, paclitaxel combined with carboplatin shows the best treatment outcome for OC. However, no effective drug is available for patients that do not respond to treatment; thus, new drugs for OC are needed. We evaluated the antimicrobial peptide, pardaxin, in PA-1 and SKOV3 cells. Pardaxin induced apoptosis as determined by MTT and TUNEL assays, as well as activation of caspases-9/3, Bid, t-Bid, and Bax, whereas Bcl-2 was downregulated. The IC50 values for pardaxin were 4.6–3.0 μM at 24 and 48 h. Mitochondrial and intracellular reactive oxygen species (ROS) were overproduced and associated with disrupted mitochondrial membrane potential and respiratory capacity. Additionally, the mitochondrial network was fragmented with downregulated fusogenic proteins, MFN1/2 and L-/S-OPA1, and upregulated fission-related proteins, DRP1 and FIS1. Autophagy was also activated as evidenced by increased expression of autophagosome formation-related proteins, Beclin, p62, and LC3. Enhanced mitochondrial fragmentation and autophagy indicate that mitophagy was activated. ROS-induced cytotoxicity was reversed by the addition of N-acetylcysteine, confirming ROS overproduction as a contributor. Taken together, pardaxin demonstrated promising anticancer activity in OC cells, which warrants further preclinical development of this compound.

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P6342Subcutaneous delivery of NPA7, first-in-class novel bispecific designer peptide: enhances cardiorenal function and suppresses renin and aldosterone in vivo and in vitro

European Heart Journal ◽

10.1093/eurheartj/ehz746.0939 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Sugihara ◽

T Ichiki ◽

Y Chen ◽

G J Harty ◽

D M Heublen ◽

...

Keyword(s):

Therapeutic Potential ◽

Ex Vivo ◽

Plasma Renin ◽

New Drugs ◽

Preclinical Development ◽

Effective Delivery ◽

Canine Serum ◽

Canine Plasma

Abstract Introduction The rapid increase of patients of heart failure (HF) is a major health burden worldwide. Most importantly is the need to develop innovative new drugs for treatment of HF, such as sacubitril/valsartan which in part functions by enhancing the natriuretic peptides (NPs). We engineered NPA7 as a novel 30 amino acid bispecific designer peptide which activates the particulate guanylyl cyclase A receptor (pGC-A)/cGMP and for which the NPs both ANP and BNP are ligands and the Mas-receptor (MasR)/cAMP pathways for Angiotensin 1–7 (Ang1–7) is the endogenous ligand. We previously reported that acute intravenous (IV) administration of NPA7 shows cardiorenal protective and renin-aldosterone suppressing actions that go beyond the native peptides, BNP or Ang 1–7, which may have therapeutic potential for HF. Purpose To support the clinical development of NPA7 as a potential therapy in HF which promotes NP and MasR pathways, we investigated the actions and stability of subcutaneous (SQ) administration of NPA7 in normal canines. We also defined NPA7's peptide stability and metabolites in canine plasma. Methods Plasma and urinary cGMP, cardiorenal and renin-aldosterone responses to SQ injection (10μg/kg) were determined over 4 hours in normal canines (n=5) in vivo. Ex vivo, we established stability of NPA7 and key metabolites in canine serum using liquid chromatography-mass spectrometry (LC-MS). Data are expressed as mean ± SEM. * P<0.05 vs. BL. Results In vivo, SQ NPA7 resulted in a sustained increase at 2 hours in plasma (BL: 10±3; 120 min: 30±6* pmol/ml) and urinary (BL: 1033±198; 120 min: 5792±857* pmol/min) cGMP, GFR (BL: 29±6; 120 min: 70±12* ml/min) and sodium excretion (BL: 18±10; 120 min: 144±33* ueq/min). We observed a gradual reduction in BP at 60 min (BL: 109±4; 60 min: 99±7* mmHg) with a sustained decrease in PCWP at 4 hours (BL: 5±0.9; 240 min: 3.1±0.6* mmHg). SQ NPA7 also suppressed plasma renin and aldosterone up to 3 hours after SQ injection. LC-MS revealed that NPA7 was highly stable with both the pGC-A and MasR activating moieties intact ex vivo in canine serum with a disappearance time of 2 hours. We also identified 2 major NPA7 metabolites NPA71–27 and NPA71–28. Conclusions SQ NPA7 possesses cGMP activating, cardiac unloading, diuretic, natriuretic, and renin-aldosterone suppressing actions in normal canines. NPA7 is also highly stable in serum. These studies support SQ administration as an effective delivery strategy for NPA7, a first-in-class innovative bispecific dual pGC-A/MasR activator now in preclinical development for HF.

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Trace incorporation of heavy water reveals slow and heterogeneous pathogen growth rates in cystic fibrosis sputum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512057112 ◽

2015 ◽

Vol 113 (2) ◽

pp. E110-E116 ◽

Cited By ~ 72

Author(s):

Sebastian H. Kopf ◽

Alex L. Sessions ◽

Elise S. Cowley ◽

Carmen Reyes ◽

Lindsey Van Sambeek ◽

...

Keyword(s):

Cystic Fibrosis ◽

Heavy Water ◽

Growth Rates ◽

Physiological State ◽

Full Range ◽

New Drugs ◽

Chronic Infections ◽

Preclinical Development ◽

Laboratory Models

Effective treatment for chronic infections is undermined by a significant gap in understanding of the physiological state of pathogens at the site of infection. Chronic pulmonary infections are responsible for the morbidity and mortality of millions of immunocompromised individuals worldwide, yet drugs that are successful in laboratory culture are far less effective against pathogen populations persisting in vivo. Laboratory models, upon which preclinical development of new drugs is based, can only replicate host conditions when we understand the metabolic state of the pathogens and the degree of heterogeneity within the population. In this study, we measured the anabolic activity of the pathogenStaphylococcus aureusdirectly in the sputum of pediatric patients with cystic fibrosis (CF), by combining the high sensitivity of isotope ratio mass spectrometry with a heavy water labeling approach to capture the full range of in situ growth rates. Our results revealS. aureusgeneration times with a median of 2.1 d, with extensive growth rate heterogeneity at the single-cell level. These growth rates are far below the detection limit of previous estimates of CF pathogen growth rates, and the rates are slowest in acutely sick patients undergoing pulmonary exacerbations; nevertheless, they are accessible to experimental replication within laboratory models. Treatment regimens that include specific antibiotics (vancomycin, piperacillin/tazobactam, tobramycin) further appear to correlate with slow growth ofS. aureuson average, but follow-up longitudinal studies must be performed to determine whether this effect holds for individual patients.

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Preclinical Development of New Drugs that Enhance Thyroid Hormone Metabolism and Clearance: Inadequacy of Using Rats as an Animal Model for Predicting Human Risks in an IND and NDA

American Journal of Therapeutics ◽

10.1097/01.mjt.0000209673.01885.b0 ◽

2006 ◽

Vol 13 (2) ◽

pp. 141-144 ◽

Cited By ~ 33

Author(s):

Kuei-Meng Wu ◽

James G. Farrelly

Keyword(s):

Animal Model ◽

Thyroid Hormone ◽

New Drugs ◽

Hormone Metabolism ◽

Preclinical Development ◽

Thyroid Hormone Metabolism

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Two isoprenylated flavonoids from Dorstenia psilurus activate AMPK, stimulate glucose uptake, inhibit glucose production and lower glycemia

Biochemical Journal ◽

10.1042/bcj20190326 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3687-3704 ◽

Cited By ~ 2

Author(s):

Aphrodite T. Choumessi ◽

Manuel Johanns ◽

Claire Beaufay ◽

Marie-France Herent ◽

Vincent Stroobant ◽

...

Keyword(s):

Glucose Uptake ◽

Human Cancer ◽

Glucose Production ◽

Liver Mitochondria ◽

New Drugs ◽

Structural Isomer ◽

Rat Liver Mitochondria ◽

Ionization Mass ◽

Ampk Activation ◽

Starting Point

Root extracts of a Cameroon medicinal plant, Dorstenia psilurus, were purified by screening for AMP-activated protein kinase (AMPK) activation in incubated mouse embryo fibroblasts (MEFs). Two isoprenylated flavones that activated AMPK were isolated. Compound 1 was identified as artelasticin by high-resolution electrospray ionization mass spectrometry and 2D-NMR while its structural isomer, compound 2, was isolated for the first time and differed only by the position of one double bond on one isoprenyl substituent. Treatment of MEFs with purified compound 1 or compound 2 led to rapid and robust AMPK activation at low micromolar concentrations and increased the intracellular AMP:ATP ratio. In oxygen consumption experiments on isolated rat liver mitochondria, compound 1 and compound 2 inhibited complex II of the electron transport chain and in freeze–thawed mitochondria succinate dehydrogenase was inhibited. In incubated rat skeletal muscles, both compounds activated AMPK and stimulated glucose uptake. Moreover, these effects were lost in muscles pre-incubated with AMPK inhibitor SBI-0206965, suggesting AMPK dependency. Incubation of mouse hepatocytes with compound 1 or compound 2 led to AMPK activation, but glucose production was decreased in hepatocytes from both wild-type and AMPKβ1−/− mice, suggesting that this effect was not AMPK-dependent. However, when administered intraperitoneally to high-fat diet-induced insulin-resistant mice, compound 1 and compound 2 had blood glucose-lowering effects. In addition, compound 1 and compound 2 reduced the viability of several human cancer cells in culture. The flavonoids we have identified could be a starting point for the development of new drugs to treat type 2 diabetes.

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