Prodrugs of NSAIDs: A Review

Intoroduction:Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action.Methods & Materials:The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects.Results:As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs.Conclusion:This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding).

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Lead Molecule Prediction and Characterization for Designing MERS-CoV 3C-like Protease Inhibitors: An In silico Approach

Current Computer - Aided Drug Design ◽

10.2174/1573409914666180629151906 ◽

2018 ◽

Vol 15 (1) ◽

pp. 82-88 ◽

Cited By ~ 1

Author(s):

Md. Mostafijur Rahman ◽

Md. Bayejid Hosen ◽

M. Zakir Hossain Howlader ◽

Yearul Kabir

Keyword(s):

Binding Energy ◽

Middle East ◽

Virtual Screening ◽

In Silico ◽

Screening Method ◽

Middle East Respiratory Syndrome ◽

Cytochrome P450 Enzymes ◽

Drug Molecules ◽

Essential Enzyme ◽

Reduced Toxicity

Background: 3C-like protease also called the main protease is an essential enzyme for the completion of the life cycle of Middle East Respiratory Syndrome Coronavirus. In our study we predicted compounds which are capable of inhibiting 3C-like protease, and thus inhibit the lifecycle of Middle East Respiratory Syndrome Coronavirus using in silico methods. </P><P> Methods: Lead like compounds and drug molecules which are capable of inhibiting 3C-like protease was identified by structure-based virtual screening and ligand-based virtual screening method. Further, the compounds were validated through absorption, distribution, metabolism and excretion filtering. Results: Based on binding energy, ADME properties, and toxicology analysis, we finally selected 3 compounds from structure-based virtual screening (ZINC ID: 75121653, 41131653, and 67266079) having binding energy -7.12, -7.1 and -7.08 Kcal/mol, respectively and 5 compounds from ligandbased virtual screening (ZINC ID: 05576502, 47654332, 04829153, 86434515 and 25626324) having binding energy -49.8, -54.9, -65.6, -61.1 and -66.7 Kcal/mol respectively. All these compounds have good ADME profile and reduced toxicity. Among eight compounds, one is soluble in water and remaining 7 compounds are highly soluble in water. All compounds have bioavailability 0.55 on the scale of 0 to 1. Among the 5 compounds from structure-based virtual screening, 2 compounds showed leadlikeness. All the compounds showed no inhibition of cytochrome P450 enzymes, no blood-brain barrier permeability and no toxic structure in medicinal chemistry profile. All the compounds are not a substrate of P-glycoprotein. Our predicted compounds may be capable of inhibiting 3C-like protease but need some further validation in wet lab.

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Identification of novel antiviral drug combinations in vitro and tracking their development

10.1101/2020.09.17.299933 ◽

2020 ◽

Author(s):

Aleksandr Ianevski ◽

Rouan Yao ◽

Svetlana Biza ◽

Eva Zusinaite ◽

Andres Männik ◽

...

Keyword(s):

Viral Infections ◽

Human Lung ◽

Antiviral Drug ◽

A549 Cells ◽

Drug Combinations ◽

Investigational Drug ◽

Synergistic Activity ◽

Lung Epithelial ◽

Reduced Toxicity

AbstractCombination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

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CURRENTLY USED ANTI-TUBERCULAR AGENTS, THEIR ANALOGUES AND RECENTLY DEVELOPED DRUGS

INDIAN DRUGS ◽

10.53879/id.49.07.p0005 ◽

2012 ◽

Vol 49 (07) ◽

pp. 5-19

Author(s):

A Mohammad ◽

Keyword(s):

Antimicrobial Activity ◽

Side Effects ◽

Multidrug Resistant ◽

Drug Resistant ◽

Duration Of Treatment ◽

Duration Of Therapy ◽

Drug Molecules ◽

Prolonged Duration ◽

Resistant Strains ◽

Reduced Toxicity

Tuberculosis (TB) is one of most prevailing diseases, responsible for the morbidity and mortality of a large number of populations worldwide. Traditionally, it has relied on a limited number of drugs such as isoniazid, rifampicin, ethambutol, streptomycin, ethionamide and pyrazinamide. However, many of these drugs have different disadvantages such as prolonged duration of treatment, host toxicity and ineffectiveness against resistant strains. This has motivated the search of newer drug molecules, capable of rapid mycobactericidal action with shortened duration of therapy, reduced toxicity and enhanced activity against multidrug resistant strains. These observations have been guiding for the currently used and newly developed anti-tubercular agents that possess potent antimicrobial activity and their side effects, activity against multi drug resistant Mycobacterium, and also in patients co-infected with HIV/AIDS.

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Vesicular Drug Delivery Systems

Advances in Medical Technologies and Clinical Practice - Novel Approaches for Drug Delivery ◽

10.4018/978-1-5225-0751-2.ch005 ◽

2017 ◽

pp. 121-147

Author(s):

Preeti Khulbe

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Colloidal Dispersions ◽

Polyphenolic Compounds ◽

Future Prospects ◽

Lipid Complex ◽

Research Experiences ◽

Drug Molecules ◽

Pass Through ◽

Drug Incorporation

Pharmacosomes are the colloidal dispersions of drugs covalently bound to lipids and may exist as ultrafine vesicular, micellar or hexagonal aggregates, depending on the chemical structure of the drug lipid complex. The term pharmacosomes is explicitly used to describe the zwitterion, amphiphilic stoichiometric complexes of polyphenolic compounds with phospholipids. The system is formed by linking a drug (pharmakon) to a carrier (soma), they are called pharmacosomes. Pharmacosomes can pass through biomembranes efficiently and possess advantages over the use of other vesicular systems such as transferosomes liposomes and noisome. Pharmacososmes are design to avoid the unusual problems associated with the liposomal entrapment of polar drug molecules like low drug incorporation, leakage and solubility. This chapter includes the basic introduction, applications, method of preparation, characterisation, advantages, some research experiences and future prospects of pharmacosomes.

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Poly(ε-caprolactone) (PCL) Hollow Nanoparticles with Surface Sealability and On-Demand Pore Generability for Easy Loading and NIR Light-Triggered Release of Drug

Pharmaceutics ◽

10.3390/pharmaceutics11100528 ◽

2019 ◽

Vol 11 (10) ◽

pp. 528 ◽

Cited By ~ 1

Author(s):

Ju Hyang Park ◽

Da In Kim ◽

Sang Gi Hong ◽

Hojun Seo ◽

Jongbok Kim ◽

...

Keyword(s):

Fatty Acid ◽

Synergistic Activity ◽

Triggered Release ◽

Hollow Nanoparticles ◽

Anticancer Efficacy ◽

Hollow Particles ◽

On Demand ◽

Drug Molecules ◽

Nir Light ◽

New System

A new system for the easy loading and NIR light-triggered release of drugs is introduced. It consists of poly(ε-caprolactone) (PCL) hollow nanoparticles with surface openings containing a biodegradable fatty acid with phase-change ability and a biocompatible photothermal agent. These openings, which can enhance the connectivity between the interior and the exterior, enable the easy loading of drug molecules into the interior voids, and their successive sealing ensures a stable encapsulation of the drug. Upon exposure to an external NIR light irradiation, the photothermal agent generates heat that raises the local temperature of the hollow particles above the melting point of the fatty acid, leading to the formation of nanopores on their shells, and consequently, the instant release of the encapsulated drug molecules through the pores. The synergistic activity of the hyperthermia effect from the photothermal agent and the NIR-triggered release of the drug molecules results in noticeable anticancer efficacy.

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Accessing the Blood-Brain Barrier to Treat Brain Disorders

Current Nanomedicine ◽

10.2174/2468187309666190823154318 ◽

2019 ◽

Vol 9 (3) ◽

pp. 198-209

Author(s):

M. Sureshkumar ◽

A. Pandian

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Low Molecular Weight ◽

Brain Disorders ◽

Permeable Membrane ◽

Drug Molecules ◽

Blood Brain ◽

Therapeutic Molecules ◽

Pass Through ◽

The Brain

: Crossing the blood-brain barrier (BBB) and treating brain disorders by delivering therapeutic agents to specific regions of the brain is a challenge. The BBB, naturally evolved, protective physiological barrier acts as a selective permeable membrane in such a way that it allows only nonionic molecules and molecules of low molecular weight to pass through. Treating brain tumor has become a great challenge as the drug molecules of larger size are not able to cross the BBB and reach the target site. The incompetence of techniques for brain-specific delivery of therapeutic molecules has led researchers to increasingly explore the diagnosis and treatment of disorders incurable with present techniques. This article is to discuss the various techniques or methods to deliver drugs to the brain crossing the BBB.

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‘Mutual Prodrug’ and approach to increase the effectiveness of Non-Steroidal Anti-inflammatory Drugs

10.53346/wjbpr.2021.1.1.0011 ◽

2021 ◽

Vol 1 (1) ◽

pp. 035-045

Author(s):

Manish S. Junagade ◽

Anju Goyal

Keyword(s):

Pharmacokinetic Parameters ◽

Formulation Development ◽

Duration Of Action ◽

Drug Molecules ◽

Carrier Molecule ◽

Inflammatory Drugs ◽

Development Approach ◽

Pharmacologically Active ◽

Mutual Prodrug ◽

Poor Absorption

A clinically useful drug may have limitations in practice because of undesirable side effects, poor solubility, and poor bioavailability, short duration of action, first-pass effect, poor absorption & adverse effects. There are increased efforts in research to increase the therapeutic efficacy of drugs by eliminating or minimizing the undesirable properties of drug molecules. Some of the problems can be solved using a formulation development approach but in some cases, chemical modification in the molecule is necessary to correct the pharmacokinetic parameters. One of the approaches to convert the existing molecule to a more efficient molecule is prodrug design. Mutual Prodrug is the molecule in which an active drug molecule is attached to a carrier molecule having pharmacological activity. So a mutual prodrug consists of two pharmacologically active molecules connected by a bio labile linkage. Both molecules in this act as a pro moiety of each other. The design of mutual prodrug is very fruitful in the area of research & has given successful results in increasing the clinical & therapeutic effectiveness of the drugs. The present article takes a review of various applications of mutual prodrugs & development in this field in the last few decades.

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Formulation and Nanotechnology-Based Approaches for Solubility and Bioavailability Enhancement of Zerumbone

Medicina ◽

10.3390/medicina56110557 ◽

2020 ◽

Vol 56 (11) ◽

pp. 557

Author(s):

Siddharth S. Kesharwani ◽

G. Jayarama Bhat

Keyword(s):

Aqueous Solubility ◽

Clinical Development ◽

World Population ◽

Formulation Development ◽

Volatile Oils ◽

Bioavailability Enhancement ◽

Drug Molecules ◽

Development Pipeline ◽

Traditional Therapies ◽

Poor Absorption

About 40–70% of drug molecules in the clinical development pipeline suffer from one of either low aqueous solubility, poor absorption, or extremely low bioavailability. Approximately 75% of the world population relies on traditional therapies and therefore there has been a growing interest in the utilization of natural compounds. Zerumbone is one such natural compound, classified as a sesquiterpenoid that is extracted from the essential volatile oils of rhizomes from Zingiber zerumbet. It possesses strong antitumor, antioxidant, antimicrobial, and anti-inflammatory activity. However, despite promising preclinical studies demonstrating the therapeutic utility of zerumbone, its clinical development has been limited due to its low aqueous solubility, poor absorption, or associated low bioavailability. Multiple reviews demonstrating the pharmacological effects of zerumbone for various diseases have been published. However, to our knowledge, no review demonstrates the various formulation strategies developed to overcome the biopharmaceutical challenges of zerumbone. The purpose of this review is to provide a comprehensive perspective on zerumbone as a molecule for formulation development. A section related to pharmacokinetics, toxicity, and patents of zerumbone is included. This review provides the importance of developing novel formulations of zerumbone to overcome its biopharmaceutical challenges thereby advance its potential in the treatment of various diseases.

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EMERGING TRENDS IN ORAL BIOAVAILABILITY ENHANCEMENT

International Journal of Drug Regulatory Affairs ◽

10.22270/ijdra.v1i2.108 ◽

2018 ◽

Vol 1 (2) ◽

pp. 20-38 ◽

Cited By ~ 2

Author(s):

S Talegaonkar ◽

A Ahmad ◽

M Tariq ◽

Z.I. Khan ◽

L.M. Negi ◽

...

Keyword(s):

Oral Bioavailability ◽

Active Form ◽

Oral Route ◽

Low Permeability ◽

Bioavailability Enhancement ◽

Physiological Factors ◽

Drug Molecules ◽

Emerging Trends ◽

Therapeutic Molecules ◽

Low Solubility

Oral route is one of the most accepted and convenient mode of drug administration, however low oral bioavailability of many drugs is a major concern which limits their oral administration. Optimum solubility and permeation of a drug across the intestinal epithelium is a prerequisite to reach the systematic circulation in the active form for effective action at the desired site. Physicochemical properties of the drug, physiological factors and pharmacokinetic factors are mainly responsible for their low solubility, low permeability and high metabolism which in turn into low oral bioavailability of the drug molecules. In this review, various factors which affect bioavailability of drugs and possible approaches to overcome this problem have been discussed. The review identifies various areas for research that can be focused for improving oral bioavailability of therapeutic molecules for different classes of drugs, thus making the oral route of administration of the drugs more effective and useful.

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Untargeted Metabolic Profiling of Extracellular Vesicles of SARS-CoV-2-Infected Patients Shows Presence of Potent Anti-Inflammatory Metabolites

International Journal of Molecular Sciences ◽

10.3390/ijms221910467 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10467

Author(s):

Faisal A. Alzahrani ◽

Mohammed Razeeth Shait Mohammed ◽

Saleh Alkarim ◽

Esam I. Azhar ◽

Mohammed A. El-Magd ◽

...

Keyword(s):

Extracellular Vesicles ◽

Elaidic Acid ◽

Metabolic Profiling ◽

Crucial Role ◽

Active Drug ◽

Viral Infections ◽

Limited Data ◽

Drug Molecules ◽

Anti Inflammatory ◽

Metabolite Content

Extracellular vesicles (EVs) carry important biomolecules, including metabolites, and contribute to the spread and pathogenesis of some viruses. However, to date, limited data are available on EV metabolite content that might play a crucial role during infection with the SARS-CoV-2 virus. Therefore, this study aimed to perform untargeted metabolomics to identify key metabolites and associated pathways that are present in EVs, isolated from the serum of COVID-19 patients. The results showed the presence of antivirals and antibiotics such as Foscarnet, Indinavir, and lymecycline in EVs from patients treated with these drugs. Moreover, increased levels of anti-inflammatory metabolites such as LysoPS, 7-α,25-Dihydroxycholesterol, and 15-d-PGJ2 were detected in EVs from COVID-19 patients when compared with controls. Further, we found decreased levels of metabolites associated with coagulation, such as thromboxane and elaidic acid, in EVs from COVID-19 patients. These findings suggest that EVs not only carry active drug molecules but also anti-inflammatory metabolites, clearly suggesting that exosomes might play a crucial role in negotiating with heightened inflammation during COVID-19 infection. These preliminary results could also pave the way for the identification of novel metabolites that might act as critical regulators of inflammatory pathways during viral infections.

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