\r\n\t• As a consequence of the pandemic spread of obesity, NAFLD is one of the most important causes of liver disease worldwide in adults and children. The large volume of patients sets NAFLD apart from other liver diseases, meaning the major focus of clinical care is discerning those at the highest risk of progressive liver disease \r\n\t• Because the overweighting in childhood and adolescence is associated with an increased risk of NAFLD later in life, the threshold of liver-related morbidity and/or mortality is reached at a younger age. Patients with NAFLD have a high risk of liver-related morbidity and mortality along with metabolic comorbidities and might place a growing strain on healthcare systems \r\n\t• Whereas animal studies have demonstrated a potential causal role of gut microbiota in NAFLD, human studies have only just started to describe microbiome signatures in NAFLD. \r\n\t• Proteobacteria are consistently enriched in steatosis and non-alcoholic steatohepatitis. \r\n\t• Discrepant microbiome signatures across studies could be linked to the heterogeneity of geographical regions, ethnicity, population characteristics, microbiome sequencing tools, NAFLD diagnostic tools, disease spectrum, drug consumption, and circadian rhythm. \r\n\t• The composition of the diet, in particular the types of lipids and carbohydrates, have an important role in the progression of NAFLD to NASH and fibrosis \r\n\t• A complex interplay between the environment (especially diet), host genetics, and the gut microflora is crucial for the development and progression of NAFLD \r\n\t• Activation of the innate immune system has an essential role in maintaining homeostasis and liver regeneration, as well as disease pathogenesis, acting in a cooperative rather than independent fashion \r\n\t• Discoveries that characterized the importance of cell death in NAFLD progression triggered the development of novel therapeutic and diagnostic approaches for NAFLD \r\n\t• Various types of cell death contribute to the development of NAFLD; extensive crosstalk and biochemical cooperation exists between these cell death pathways to drive disease progression \r\n\t• Chronic hepatic inflammation represents the driving force in the evolution of nonalcoholic steatohepatitis (NASH) to liver fibrosis and/or cirrhosis. \r\n\t• In both humans and rodents, NASH is characterized by B cell and T cell infiltration of the liver as well as by the presence of circulating antibodies targeting antigens originating from oxidative stress. \r\n\t• Alterations in regulatory T cell and hepatic dendritic cell homeostasis have a role in triggering immune responses during the progression of NASH. \r\n\t• While NAFLD progression to non-alcoholic steatohepatitis is becoming the leading cause of end-stage liver failure, the leading causes of death in patients with NAFLD are complications of cardiometabolic disease and a tight relationship exists between NAFLD, insulin resistance, and type II diabetes mellitus. \r\n\t• A NAFLD has become the most common liver disease globally, yet there are currently no approved therapies and It is likely that developing therapeutics that target both NAFLD and cardiometabolic risk factors might be extremely beneficial. \r\n\t
",isbn:"978-1-83968-091-5",printIsbn:"978-1-83968-090-8",pdfIsbn:"978-1-83968-102-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"b86853fe2ec412149e127824b249b061",bookSignature:"Prof. Ju-Seop Kang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11716.jpg",keywords:"Immunity in NAFLD, Immunologic Targets in NAFLD, Hepatic Lymphocyte in NAFLD, Metabolomics in NAFLD, Hepatic Lipid Homeostasis in NAFLD, NAFLD and Hyperlipidemia, Gut Microbiota in NAFLD, Diet Manipulation in Control of NAFLD, Obesity and NAFLD, Lifestyle and Diet Control in NAFLD Control, Novel Therapeutic and Diagnostic Approaches for NAFLD",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 14th 2022",dateEndSecondStepPublish:"May 12th 2022",dateEndThirdStepPublish:"July 11th 2022",dateEndFourthStepPublish:"September 29th 2022",dateEndFifthStepPublish:"November 28th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"13 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr.Kang is a pioneering researcher and contributor to new drug development & research and clinical pharmacology. 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1. Introduction
The chapter discusses the procedure for using the Green’s function for the analytical description of electromagnetic and acoustic fields in a stationary isotropic and arbitrarily inhomogeneous medium. In the case of the electromagnetic field, the wave equation for the electric vector of the electromagnetic field in the inhomogeneous medium with conductivity, dielectric and magnetic permeability is used. In the case of the acoustic field, the wave equation proposed by the author for the vector of particle velocity and the well-known equation for acoustic pressure in an inhomogeneous stationary medium are used. Using the Green’s function and the method of successive approximations makes it possible to achieve the required accuracy of calculating the electric and magnetic vectors of the electromagnetic field, as well as to calculate the vectors of complex intensity and intensity, density of energy, acoustic pressure and the particle velocity vector of the acoustic field in media with arbitrary spatial variability of the parameters. The approach used allows one to reduce the problem of solving differential wave equations in an arbitrarily inhomogeneous medium to integration. The chapter is divided into two parts. At the beginning of each part, the corresponding wave equations are derived and next, a method of using the Green’s function is described and analytical expressions describing the fields are formulated. At the beginning we will describe the method as applied to the electromagnetic field, and then as applied to the acoustic field.
Research and modeling of the electromagnetic field in spatially inhomogeneous natural and composite media are actively developing in various fields of science and technology, ranging from systems of underground and underwater electromagnetic communication to photonics, metamaterials and metasurfaces [1]. Such a wide field of scientific research requires methods of mathematical modeling of the properties of the electromagnetic field in media with different spatial scales of conductivity, magnetic and dielectric permittivity. At present, analytical methods are applicable in a very limited range of environments. Among the methods of mathematical modeling of the electromagnetic field in the frequency range from fractions of the hertz to optical, various numerical methods and technologies are used [2, 3]. Numerical modeling uses a variety of methods and technologies, for example, parallel computing which are used in electrodynamic modeling programs. Among them, there are also direct and universal methods for solving boundary problems. The drawback of these methods is a large expenditure of computer resources, which leads to a significant simplification of physical models of the environment and mathematical approximations. There is a third class of methods, in which, at the initial stage, analytical methods are used, for example, the Green’s function method, which brings the problem to a form that can be solved by fairly simple numerical methods. Below we will use exactly this approach using the Green’s function. Green’s function is actively used in a wide range of problems [4, 5, 6] of describing electromagnetic and other physical fields in various multilayer, chiral and anisotropic media, including inhomogeneous ones. The proposed procedure is also applicable to media with boundaries and arbitrary dependence on the coordinates of conductivity, magnetic and dielectric permittivity. The source of the field in the environment can be the electric current or an external field. The electric current can be located also inside the medium and outside it. The problem of descriptions the electric vector in an inhomogeneous medium by using the Green’s function is formulated as the integral equation with its subsequent solution by the method of successive approximations. This procedure uses the equation for the vector of electric field strength in an inhomogeneous medium, with a certain conductivity, magnetic permeability, and dielectric constant.
The acoustic energy flux density vector (intensity vector), basically, until the beginning of the second half of the 20th century was only of theoretical interest. The second half of the 20th century brought about reliable means of synchronous measurement, practically at a single point, of the acoustic pressure and the components of particle velocity vector necessary to determine the intensity vector of acoustic field [7, 8, 9, 10, 11, 12, 13, 14]. However, this did not lead to a significant increase in the number and quality of theoretical research methods and modeling of the intensity vector in an inhomogeneous medium. For the complete theoretical description of the acoustic field, knowledge of its acoustic pressure and the particle velocity vector is required. These two quantities make it possible to find the field of the acoustic intensity vector, to describe the energy and phase structure of the acoustic field. Knowledge of these quantities is useful for solving fundamental and applied problems of acoustic tomography and sounding of the geosphere, applied and fundamental hydroacoustics, creation of acoustic metamaterials, technical and architectural acoustics, noise control, etc. [15, 16, 17]. The acoustic pressure P→ar→t and the particle velocity vector V→r→t are interrelated. This connection is obvious for a plane wave and, in the approximation of a continuous medium, has the following form: V→r→t=−1ρ0r→∫P→ar→tdt , where ρ0r→ is the density of the medium unperturbed by the acoustic field at the point r→ and t is time, and ∇ is the Nabla operator. This relationship largely determined the development of the theory of sound as a scalar field of acoustic pressure. Currently, there are several directions for the development of methods of calculation and theoretical analysis of the characteristics of the intensity vector. In the first direction, the relationship between the acoustic pressure and the particle velocity vector is used. This approach is applicable when there are mathematical expressions for the acoustic pressure field. As a rule, this is only possible in a homogeneous medium or for simple waveguides [18]. The second direction requires the use of the continuity equation and the equation of state of the inhomogeneous medium, as well as dynamic equations of motion of elementary volumes or particles of the inhomogeneous medium, for example: the Euler or Navier-Stokes equations. These equations are viewed as a system of equations for determining the pressure and the particle velocity vector. This approach is used to model the propagation of waves in various environments, including plasma and stellar atmospheres [19, 20, 21, 22]. These equations are widely known, but to find analytical wave solutions of such systems given an arbitrary dependence of the density and speed of sound on the coordinates is a very difficult task. The use of the acoustic energy transfer equation is the third approach [9]. This approach allows one to describe the energy structure of the acoustic field which makes it possible to study the statistical characteristics of the complex intensity vector in a Gaussian delta-correlated inhomogeneous medium with refraction [9]. It is a very difficult task to find solutions to the transport equation in an inhomogeneous media. In turn, numerical methods for modeling metamaterials and propagation of acoustic waves in a medium are usually limited to specific problems [23, 24, 25]. None of the listed approaches, including numerical ones, provides the possibility of a complete theoretical description of the characteristics of the acoustic field and their evolution during field propagation in an arbitrary inhomogeneous medium. One of the promising directions is to use two wave equations in an inhomogeneous medium: equations for the acoustic pressure and equations for the particle velocity vector. We use this very approach. It is based on the proposed by authors wave equation for the particle velocity vector and the well-known equation for acoustic pressure in an inhomogeneous stationary medium. The proposed wave equation for the vector of the particle velocity of the acoustic field in a stationary inhomogeneous and isotropic medium is much more complicated than for the acoustic pressure. This makes it difficult to find the analytical solution for inhomogeneous media with an arbitrary spatial dependence of the density of the medium and the speed of sound in it. However, in an inhomogeneous medium, in which the field of the acoustic intensity vector is weakly vortex, the use of the Green’s tensor together with the method of successive approximations makes it possible to find analytical solutions for an arbitrary spatial dependence of the speed of sound and density of the inhomogeneous medium.
2. Electromagnetic field
By an inhomogeneous medium, we mean a medium in which the conductivity σr→, dielectric εr→ and magnetic μr→ permittivity, and the current density J→r→ have an arbitrary, but differentiable, in the ordinary and in the generalized sense, dependence on coordinates points of the medium. Below we will not point out the explicit dependence of these and other quantities on time and coordinates, where this will not lead to misunderstanding. In an isotropic inhomogeneous medium, ε, μ, σ are scalar functions of coordinates. To derive the wave equation of the electromagnetic field in such a medium, we use the following well known fundamental and material Maxwell equations in a continuous isotropic and stationary medium:
where ρf is the density of free charges of the medium, and ρext is the density of external charges introduced into the medium, εr and μr are the relative dielectric and magnetic permeability of the medium, and J→ext is the current density created by free and external charges. The wave equation for the electric vector in an inhomogeneous medium can be obtained, as for a homogeneous medium, excluding the vector of magnetic field strength from the system of Maxwell’s equations. For this, we use the well-known vector analysis formulas [26] and take the rotor from the 2nd equation in system (Eq. (1)):
∇×∇×E→=∇⋅∇⋅E→−Δ⋅E→=−∂∂t∇×B→E2
In this case, the source of electromagnetic field is the electric current density J→, so the divergence of the vector ∇⋅E→ , we need to associate with a current density in the medium. For this, we use (Eq. (5)) of the Maxwell system of equations (Eq. (1)) and obtain ∇⋅E→=1σ∇⋅J→−E→∇⋅σ. Using the vector analysis formulas, we find the following expression:
The expression for the rotor of the magnetic field induction vector has the form
∇×B→=∇×μH→=μ∇×H→+∇⋅μ×H→E4
Using equations 1 and 2 of the system of Maxwell equations and expressions (Eq. (2)) and (Eq. (3)), we find that −∂∂t∇×B→=−μσ∂∂tE→−μ∂∂tJ→−εμ∂2∂t2E→+∇⋅lnμ×∇×E→ , and the desired equation for an electric vector with a field source, in which the charge flux from the volume occupied by the current is not equal to zero, has the following form:
If there is no injection of external charges into the medium, the value ∇⋅J→ is equal to zero and ∇J→=∇J→ext=−∂∂tρext otherwise. When deriving (Eq. (5)), no conditions on the field frequency were used. Therefore, the equation is valid up to frequencies that correspond to wavelengths λ larger than the sizes of atoms or molecules. The smallness of the ratio of the first and second terms of equation (Eq. (5)) corresponds to the condition of quasi-stationarity of the electromagnetic field. For a monochromatic field with the angular frequency ω, the modulus of their ratio is equal εσω and small under conditions of high conductivity, low dielectric constant, or low the angular frequency. In this case, the propagation of the field in the medium will have a predominantly diffusion character and will be described by the following equation:
When εσω>>1 the field propagation in the media is of the wave-type mainly. At the present time, there are no methods for finding exact solutions of equations of the type (Eq. (5)) and (Eq. (6)). Solutions satisfying a given accuracy can be obtained in two ways. The first is to use numerical methods. The second, which we will follow, consists in passing from the differential equation (5) to the integral equation using the tensor Green’s function of the Helmholtz equation for the Fourier - the spectrum of the vector of the electric field strength. The solution to an integral equation can be written in the form of a sequence of approximate solutions, in which each subsequent term is more accurate. It is important that such a procedure for finding a solution is applicable for arbitrary differentiable, both in the usual and in the generalized sense, dependences of σ, ε, and μ on coordinates. For this, we express the vector of the electric field E→r→t and the current density J→r→t through their Fourier spectra E→r→ω and J→r→ω
For high frequencies, when the dependence of ε and μ from the field frequency cannot be neglected, but spatial dispersion and nonlinear effects can be neglected, J→r→ω=σωr→E→ωr→, D→ωr→=εωr→E→ωr→ и B→ωr→=μωr→H→ωr→. Spatial dispersion plays a minor role in comparison with temporal dispersion and is significant in media with the mean free path of the charge or its diffusion much longer than the field wavelength. Below we will not indicate the dependence of the conductivity and permeability on frequency. Let’s consider conductivity and permittivity as a sum of a constant and a space-dependent variable:
f→→ωr→=−∇μ1r→μr→+∇σ1r→σr→×∇×E→r→ω−∇σ1r→σr→∇E→r→ω−E→r→ω⋅∇∇σ1r→σr→. Substituting expressions (Eq. (8)) and (Eq. (9)) into equation (Eq. (5)), we arrive at the following equation:
ΔE→r→ω+k2r→ωE→r→ω=f→r→ω+f→extr→ωE10
Eq. (10) must be supplemented with boundary conditions. In an inhomogeneous medium, the interface between the media can be considered as an inhomogeneity with its dependence on coordinates, described by the corresponding functions, for example: Heaviside step function, etc. Therefore, the boundary conditions will be the conditions at infinity, where the field and its divergence must be equal to zero. In Eq. (10) the field source is not only the external currents (term f→extωr→ but also the heterogeneity of the environment). These sources are described by f→ωr→. At present, there are no methods for the analytical solution of equations similar to (10) with an arbitrary dependence of the term f→ωr→on coordinates. Nevertheless, using the Green’s functions of the vector Helmholtz equation in a homogeneous isotropic medium we can reformulate (10) into the integral with respect to the vector E→r→ω, the solution of which can be found in an iterative way, for example, by the method of successive approximations.
Using (Eq. (8)) one can formulate k2r→ωas the sum of independent on coordinates kc2 function on coordinates and k12r→ω
Formally, we can consider Eq. (12) as an inhomogeneous Helmholtz equation and using the Green’s function for it, we can rewrite Eq. (12) in the form of an integral equation. For vector fields, the Green’s function [7, 8, 9, 10] is a tensor of the second rank. In an orthogonal coordinate system, Eq. (5) decomposes into a system of three scalar equations for the projections of the field E (r, ω) on the coordinate axis. This simplifies the form of the Green’s tensor and it has only diagonal elements that are not equal to zero. It can be represented as the vector
G→r→−r→1=∑i=13n→iGir→−r→1, where Gir→−r→1 is the components of which are the Green’s functions of the one-dimensional Helmholtz equation and ni are the unit vectors of the coordinate axes. Let the area Ω in which we describe the field be large enough so that on its borders the field and its derivatives can be equated to zero. Using the Green tensor, we can rewrite Eq. (5) for the electric vector at the point r→∈Ω of the in the form of the following integral equation
E→r→ω=∑i=13ni∫ΩGir→−r→1fiextωr→1+fi1ωr→1dr→1E13
where r→r→1∈Ω, fiextωr1 and fi1ωr1 are the projections of vectors f→extωr→ and f→1ωr→ on to the coordinate axes. Integration is performed over the volume occupied by inhomogeneities, which are secondary sources of the field. In practice, the volume should be chosen such that secondary and higher order sources make a noticeable contribution to the field. Due to the rapid decrease in the amplitude of the Green’s function and, especially with a strong absorption of the electromagnetic field by the medium, the region of integration can be about 1/α where α is the absorption coefficient of the field.
The steps for finding E→r→ω by the method of successive approximations can be as follows. We find the zeroth approximation E→0r→ω for the field, which is valid in a homogeneous medium with parameters σc, μc, εc
E→0r→ω=∑i−13n→i∫Ω1Gr→−r→1n→i⋅f→extωr→1dr→1.E14
Integration is performed over the volume Ω1 occupied by the external current (primary source of the field). This solution describes the primary field created by an external current. Using obtained by Eq. (14) expression E→0r→ω and expression (9), we find fi1ωr→1. Using (Eq. (13)) and integrating, we obtain a more accurate first E→1r→ω approximation for E→r→ω, which takes into account the influence of medium inhomogeneities on the field. To find the second approximation, it is necessary to substitute E→1r→ω into fi1ωr→1 and using (Eq. (13)) to obtain the second more accurate approximation. Similarly, more accurate solutions are obtained that take into account multiple field scattering by medium inhomogeneities. At these stages, the integration is performed over the volume occupied by inhomogeneities, which are secondary sources of the field. If the source of the field in an inhomogeneous medium is an external field with an electric vector E→extr→ω it should be used as the vector E→0r→ω.
For determining the magnetic field component one uses Maxwell’s equations and writes them in terms of magnetic and electric fields Fourier spectrums: ∇×E→r→ω=−ωB→r→ω. Substituting (Eq. (13)) in this equation one obtains
Using the Green’s function, as the experience of its use shows (e.g. [7]) in such tasks, significantly reduces the requirements for computing resources and reduces the computation time. Note that the proposed procedure can be effective in simulating the optical properties of metamaterials, nanocomposites, and nanostructures.
3. Acoustic field
The wave equation for acoustic pressure Par→t in a continuous inhomogeneous motionless and stationary medium is well known [16, 17]
where f→r→t is the density of volumetric external forces that are the source of the acoustic field.
Eq. (1) is obtained by excluding the particle velocity vector from the linearized Euler equations, continuity and state of the medium. If we exclude acoustic pressure from these equations, then we get the equation for the vector of the particle velocity of the acoustic field. For this, we differentiate the equation of state in taking into account the smallness of the acoustic pressure, perturbation of the density of the medium by the ρar→t in comparison with the background values ρ0r→ and P0r→ the medium. In the inhomogeneous medium, the equation of state Pcρr→t describes the relationship of the instantaneous local value of pressure and density of the medium. Therefore, it is necessary to use the total time derivative when differentiating the equation of state. Using it, we find in the linear approximation
ddtPcρr→t=c2r→∂∂tρar→t+∇ρ0r→V→r→t,E16
where Cr→=∂Pcρr→t∂ρr→t is the local phase speed of sound for the acoustic pressure wave. We used the expansion ρr→t=ρ0r→t+ρar→t and the condition ∇ρar→tVr→t<<∇ρ0r→Vr→t. With the help of expression (2) and representation, Pcρr→t=P0r→+Par→t the equation of continuity∂∂tρr→t+∇ρr→tV→r→t=0 is reduced to a linearized form
1ρ0r→c2r→∂∂tPr→t+∇Vr→t=0E17
In the inhomogeneity of the medium ∇V→r→t≠0 , even in the approximation of an incompressible medium. Let us Take the time derivative on the linearized Euler equation ρ0r→∂∂tV→r→t+∇Pr→t+f→r→t=0 and take the gradient of the equation of continuity (Eq. (17)). We exclude the acoustic pressure from the obtained expressions and find the equation for the particle velocity vector
When f→r→t=0 then ∇×∇×V→r→t=−∇×∇lnρ0r→×V→r→t and can transformed equation (Eq. (18)) to the following form, which is valid in the absence of external forces
In areas of the medium where this ratio is greater than unity, the fourth term in equations (Eqs. (18) and (19)) can be neglected. As a rule, these are media with a large relative gradient of the speed of sound. One of the examples of such media can be the marine environment, in which the local gradient of the speed of sound is determined less by the change in water density than salinity and temperature [12, 24]. Directly near the surface and the ocean floor or the interface between the media, the relative density gradient of the medium can be large. In these regions, the field of the particle velocity vector and acoustic intensity can have a significant rotational (vortex) component.
At present, the solution of these equations is possible only by numerical methods. If the fourth term in the equations is small, the equations for the vector of particle velocity and acoustic pressure allows one to find analytical expressions connecting the phases and moduli of vector of complex intensity and particle velocity vector, pressure, density of acoustic energy with the density of the medium and the speed of sound in it. Let us do it for equation 19. Using both scalar function Ψr→t and vector U→r→t
Pr→t=Zpr→Zp0Ψr→tV→r→t=Zvr→Zv0U→r′→t,E21
we rewrite equations (Eqs. (15) and (19)) in the following form:
where Zpr→=ρ0r→ and Zvr→=1ρ0r→c2r→, and Zp0=ρ0r→0, Zv0=1ρ0r→0c2r→0 are values Zpr→ and Zvr→ at some point in space r→0. For the spectral components Ψr→ω and U→r→ω using the Fourier transform of equations (Eqs. (22) and (23)) with respect to the time variable, we obtain the following equations
From expressions (Eq. (26)) it follows that the gradient of the speed of sound affects only the vibrational speed in a medium with a small swirl of the particle velocity field. The acoustic pressure depends only on the gradient of the density of the medium and does not depend on the gradient of the speed of sound. This situation is valid for media in which the density gradient of the medium is less than the gradient of the speed of sound. These differences form the phase difference between the acoustic pressure and the vibrational velocity vector during the propagation of an acoustic wave in an inhomogeneous medium. Different field reactions V→r→t and Pr→t to the density gradient of the medium and the gradient of the sound speed form the phase difference between the acoustic pressure Φpr→t and the particle velocity Φvr→t vector during the propagation of an acoustic wave in an inhomogeneous medium. Solutions to equations (Eqs. (24) and (25)) can be found using the method of successive approximations. For this, we represent these equations in the following form:
ΔΨr→ω+k02Ψr→ω=k1Ψ2r→Ψr→ωE27
ΔU→r→ω+k02U→r→ω=k1v2r→U←r→ωE28
where k02=ω2c2r→0, k1Ψ2r→=k02−kψ2r→ and k1U2r→=k02−kU2r→
Similarly to the case of an electromagnetic field in the inhomogeneous medium, using the scalar Gr→−r→1 and vector G→r→−r→1 Green’s functions of the Helmholtz equation for a homogeneous unbounded medium. Eqs. (2) and (13) and Eq. (2.14) can be rewritten in the form of the following integral equations:
Ψr→ω=Ψ0r→ω+∫ΩGr→−r→1k1Ψ2r→1Ψr→1ωdr→1E29
Uir→ω=U0ir→ω+∫ΩGir→−r→1k1U2r→1Uir→1ωdr→1E30
Here Uir→1ω is the projections of the vector onto the coordinate axes and Ψ0r→ω and U0ir→ω are the solutions of equations (Eq. (27)) and (Eq. (28)) with the right-hand side equal to zero, and Gir→−r→1 are the components of the vector Green’s function. The steps for finding a solution to equations (2.15) and (2.16) by the method of successive refinements can be as follows:
We find Ψ0r→ω and U0ir→ω which are the zeroth approximation for the field, valid in a homogeneous medium
We find an explicit form of dependence k1Ψ2r→=k02−kψ2r→ and k1U2r→=k02−kU2r→ on coordinates
Using Ψ0r→ω and U0ir→ω and expressions for k1Ψ2r→ and k1U2r→with the help of (Eqs. (29) and (30)), we obtain more accurate first approximations that take into account single scattering of the primary field.
To obtain the second more accurate approximation, it is necessary to substitute the first approximations in expressions (Eqs. (29) and (30)) and obtain the second more accurate approximation of the solution.
Similarly, you can get solutions that are more accurate. Integration is performed over the volume of the inhomogeneous medium, the inhomogeneities of which will be secondary, etc. field sources. In a real situation, the volume should be chosen such that its secondary sources make a noticeable contribution to the field.
Let us consider an example that shows how the parameters of an inhomogeneous medium affect the characteristics of the acoustic field. We represent the acoustic pressure, and the vector of the particle velocity of the monochromatic acoustic field by the frequency ω in the following form
Pr→t=P0r→expiωt−Φpr→ and V→r→t=V→0r→expiωt−Φvr→. Complex intensity vector will be written as I→r→=Pr→tV→∗r→t=I→0r→expiΦvr→−Φpr→. In a medium without absorption of the acoustic energy, the phases Φpr→ and Φvr→, respectively are equal to the phases Ψr→t and U→r→t. The wave vector of a wave is normal to its phase surface and is determined by the wave phase gradient and the wave number by the modulus of this gradient. For the wavenumbers of the pressure kpr→ and the particle velocity vector kvr→, we can take, respectively, the quantities kψr→ and kUr→ if the inequalities Δψ0r→ψ0r→<<kψ2r→−∇Φpr→2 and ΔU→0r→U0r→<<kU2r→−∇Φvr→2. The refractive indices of the medium for the acoustic pressure and the particle velocity relative to the point r→0 are different and accordingly, equal npr→=kpr→k0 and nvr→=kvr→k0, where k0=ωcr→0 and Cr→0 is the phase velocity of sound for the acoustic pressure wave at the point r→0. The phase velocities of the acoustic pressure wave and the particle velocity vector become different, which leads to the inequality of the phases of the acoustic pressure and the particle velocity vector when the acoustic wave propagates in an inhomogeneous medium. The absorption of acoustic energy by the medium is taken into account by assuming the speed of sound and the density of the medium to be complex quantities, in which the imaginary part is responsible for the absorption of the energy of the acoustic field. In this case, the phases and acquire an additive equal to the phases of the values Zpr→Zp0 and Zvr→Zv0. To avoid cumbersome expressions, we restrict ourselves to the first approximation. The proposed example is often implemented in real measurements of the characteristics of the acoustic field. In practice, as a rule, the projections of the vibrational velocity vector and, accordingly, the intensity vector are measured in an orthogonal coordinate system, for example, in a Cartesian one. Consider the projection of a vector U→r→ω on the OX axis. In this case, the projection will be a function of only the x coordinate, and the Y and Z coordinates will act as parameters and determine the straight line parallel to the OX axis, along which the observation point x changes. The wave numbers k1Ψ2r→ and k1U2r→, accordingly, the solutions of equations (Eqs. (29) and (30)) depend on the values of these parameters. In fact, we turn to the case of one-dimensional propagation of acoustic radiation along the OX axis passing through the point r0X0Y0Z0. Let us choose Ψ0r→ω and U→0r→ω both in the form of plane waves and propagating along the X axis. We can put the moduli of these plane waves Ψ0ω and U→0ω equal to the moduli of the acoustic pressure P0 and the component v→x of the particle velocity vector on the OX axis. In this case, the component of the vector Green’s function will be equal to the one-dimensional Green’s function
Gx−x1=12ik0expik0x−x1 we find the solution corresponding to the first approximation at the point X
Here P0expik0x и U→0expik0x represent the primary radiation, the second terms are the radiation scattered forward in the region −∞≤x1≤x, and the third terms are the radiation scattered back. Solutions (Eqs. (31) and (32)) and the relations (Eq. (21)) allow us, in the first approximation, to find an expression for the projection of the complex intensity vector on the on the OX axis
In this expression, the first term describes the complex intensity vector of the primary radiation, the fifth term corresponds to the forward propagating secondary radiation, and the ninth term corresponds to the backscattered radiation. The other terms describe the mutual energy of the primary and scattered radiation. If the field is measured arriving at a point x only from the region, x1≤x then the dependence of the projection of the complex intensity vector on the OX axis takes the following form:
In this expression αpx=∫−∞xk1Ψ2x1dx1 and αvx=∫−∞xk1U2x1dx1. The modulus I0xy0z0ω and phase Фxy0z0ω of the complex of acoustic intensity vector are respectively equal:
From expressions (Eqs. (22) and (23)) it is seen that the inhomogeneous nature of the speed of sound will have a more significant effect on the particle velocity vector than on the acoustic pressure. This makes it possible in principle to create methods for separately measuring the contribution to the acoustic field in an inhomogeneous medium of the density of the medium and the speed of sound in it.
In conclusion, we note that the proposed method makes it possible to analytically and numerically solve the problems of mathematical modeling of a shallow sea, remote sensing of natural media, problems of acoustics of a shallow sea, modeling acoustic and optical metamaterials, etc. Note that for applied problems of acoustics, both fields of the particle velocity vector and the intensity vector in any inhomogeneous medium have a vortex character. Therefore, the algorithms for solving applied problems of ocean and especially shallow sea acoustics, problems of modeling the propagation of acoustic energy in composite media and metamaterials should take into account the vortex component of the vector acoustic field intensity and curvature of the streamlines of the acoustic field.
Acknowledgments
The research is supported by the grant from the Russian Science Foundation (project # 19-12-00323).
\n',keywords:"inhomogeneous media, Green’s function, electromagnetic field, acoustic field, analytical method",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74282.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74282.xml",downloadPdfUrl:"/chapter/pdf-download/74282",previewPdfUrl:"/chapter/pdf-preview/74282",totalDownloads:315,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:47,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"July 22nd 2020",dateReviewed:"October 30th 2020",datePrePublished:"December 4th 2020",datePublished:"April 14th 2021",dateFinished:"December 2nd 2020",readingETA:"0",abstract:"An analytical method based on the Green’s function for describing the electromagnetic field, scalar-vector and phase characteristics of the acoustic field in a stationary isotropic and arbitrarily inhomogeneous medium is proposed. The method uses, in the case of an electromagnetic field, the wave equation proposed by the author for the electric vector of the electromagnetic field, which is valid for dielectric and magnetic inhomogeneous media with conductivity. In the case of an acoustic field, the author uses the wave equation proposed by the author for the particle velocity vector and the well-known equation for acoustic pressure in an inhomogeneous stationary medium. The approach used allows one to reduce the problem of solving differential wave equations in an arbitrarily inhomogeneous medium to the problem of taking an integral.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74282",risUrl:"/chapter/ris/74282",book:{id:"10413",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications"},signatures:"Vladimir P. Dzyuba and Roman Romashko",authors:[{id:"17033",title:"Prof.",name:"Vladimir P.",middleName:"Pimenovich",surname:"Dzyuba",fullName:"Vladimir P. Dzyuba",slug:"vladimir-p.-dzyuba",email:"vdzyuba@iacp.dvo.ru",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Electromagnetic field",level:"1"},{id:"sec_3",title:"3. Acoustic field",level:"1"},{id:"sec_4",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Caloz Ch., Itoh T. Electromagnetic metamaterials: transmission line theory and microwave applications (the engineering approach). A John Wiley & Sons, Inc., 2006. 352 p'},{id:"B2",body:'Prather, D. W., S.Shi. Formulation and application of the finite-difference time-domain method for the analysis of axially symmetric diffractive. J. Opt. Soc. Am. A.1999. Vol.16, Iss. 5. P. 1131-1142. Doi:10.1364/JOSAA.16.001131'},{id:"B3",body:'Taflove A. and Hagness S. C. Computational Electrodynamics: The Finite-Difference Time-Domain Method. 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On Acoustic Tomography Scheme for Reconstruction of Hydrophysical Parameters for Marine Environment. Theoretical and Computational Acoustics. Ed. Er- Chang Shang and Qihi Li. Published by World Scientific; 2002.P.107 -114'},{id:"B11",body:'Baster K.J. , Lanchle L.C., Mc. ConnelJ.A. Development of a Velocity Gradient Underwater Acoustic Intensity Sensor. JASA .1999.Vol. 106. P. 3178-3188. doi:10.1121/1.428172'},{id:"B12",body:'Mann J.A., Tichy J., Romano A.J. Instantaneous and time-average energy transfer in acoustic fields. JASA. 1987.Vol. 82. №1. P. 17-30. DOI:10.1121/1.395562'},{id:"B13",body:'K. J. Taylor Absolute measurement of acoustic particle velocity. The Journal of the Acoustical Society of America. 1976 Vol. 59, 691 DOI:10.1121/1.380896'},{id:"B14",body:'Nelson, P.A. and Elliott, S.J. (1991) Active control of sound: Academic Press; 1993. 250pp. ISBN: 0125154259'},{id:"B15",body:'Medwin H.. Sounds in the sea: from ocean acoustics to acoustical oceanography. Cambridge, UK: Cambridge Univ. Press. 2005. 643 pp'},{id:"B16",body:'David R. Dall’Ostoa and Peter H. Dahl Properties of the acoustic intensity vector field in a shallow water waveguide. The Journal of the Acoustical Society of America 2012. 131, 2023; DOI: 10.1121/1.3682063'},{id:"B17",body:'Woon Siong Gan New Acoustics Based on Metamaterials . Springer Nature Singapore Pte Ltd. 2018. P. 314. DOI:10.1007/978-981-10-6376-3'},{id:"B18",body:'Morse, P.N., Ingard, K.U. Theoretical Acoustics. New York: McGraw-Hill; 1987. 949P'},{id:"B19",body:'Jan-Niklas Hau1, and Björn Müller Acoustic wave propagation in a temporal evolving shear-layer for low-Mach number perturbations. Physics of Fluids 2018; 30, 016105. DOI:10.1063/1.4999044'},{id:"B20",body:'L. Friedland, G. Marcus, J. S. Wurtele, and P. Michel3, Excitation and control of large amplitude standing ion acoustic waves. Phys. Plasmas 2019; 26, 092109 DOI: 10.1063/1.5122300'},{id:"B21",body:'Zhu, X., Li, K., Zhang, P. et al. Implementation of dispersion-free slow acoustic wave propagation and phase engineering with helical-structured metamaterials. Nat Commun. 2016; 11731. DOI:10.1038/ncomms11731'},{id:"B22",body:'N. Anders Petersson & Björn Sjögreen High Order Accurate Finite Difference Modeling of Seismo-Acoustic Wave Propagation in a Moving Atmosphere and a Heterogeneous Earth Model Coupled Across a Realistic Topography.Journal of Scientific Computing 2018; volume 74, pages 290–323. DOI:10.1016/j.jcp.2020.109386'},{id:"B23",body:'S.MishrabCh.SchwabaJ.ŠukyscMulti- level Monte Carlo finite volume methods for uncertainty quantification of acoustic wave propagation in random heterogeneous layered medium. Journal of Computational Physics. Volume 312, 1 May 2016, Pages 192-217. DOI:10.1016/j.jcp.2016.02.014'},{id:"B24",body:'Elias Perras1, and Chuanzeng Zhang1 Analysis of acoustic wave propagation in composite laminates via aspectral element method// PAMM • Proc. Appl. Math. Mech. 2019;19:e201900282. DOI:10.1002/pamm.201900282'},{id:"B25",body:'Yijun Mao, Jiancheng Cai, Yuanyuan Gu and Datong Qi Direct Evaluation of Acoustic-Intensity Vector Field Around an Impedance Scattering Body AIAA JOURNA. 2015; Vol. 53, No. 5, May. DOI:10.2514/1.J053431'},{id:"B26",body:'Granino Arthur Korn, Theresa M. Korn Mathematical handbook for scientists and engineers, McGraw-Hill, 1968. P. 1130'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Vladimir P. Dzyuba",address:"vdzyuba@iacp.dvo.ru",affiliation:'
Institute of Automation and Control Processes of FEB Russian Academy of Sciences, Vladivostok, Russia
Institute of Automation and Control Processes of FEB Russian Academy of Sciences, Vladivostok, Russia
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1. Introduction
Because of the high rate of infectivity of the COVID-19 virus, the global burden associated with the disease, and its impact on the economies of different countries, efforts are being made to find a possible cure for the disease as soon as possible [1]. As with most viral infections, limited options are available for the treatment of COVID-19. Since there is no efficient therapy available for the same, given the public emergency, efforts are ongoing to find drugs helpful in COVID-19 infection. Drugs used in the past against Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS), which also belong to the group of Beta coronaviruses, included ribavirin, interferon, lopinavir-ritonavir, and corticosteroids [2]. Most randomized controlled trials (RCTs) performed to test the effectiveness of these drugs have not shown any satisfying results, apart from corticosteroids. Many RCTs are still undergoing, the results of which are awaited. Studies about the virus-induced host immune response and viral processing within target cells have led to several potential therapeutic targets. We hereby discuss the potential therapeutic drugs under investigation for the COVID-19 treatment, their modes of action (Figure 1), degree of effectiveness, and recommendations (Table 1) by different centers regarding their usage in the current settings.
Figure 1.
Site of action of different possible pharmacotherapeutics used in COVID-19 treatment.
Drug
Mode of action
Effectiveness
Recommendation
Corticosteroids
Immunosuppressant
Decreased death rate in ARDS, no effect in non-ARDS
WHO, CDC, and IDSA recommendations
Remdesivir
RdRp inhibitor
Decreases recovery time
FDA approval in October, WHO issued a conditional recommendation against use in November, IDSA suggests the use
Convalescent plasma
Anti-COVID 19 antibodies
No benefit
FDA EUA issued
Monoclonal antibodies
Directed against COVID spike proteins
Benefit in Mild cases, no benefit in hospitalized cases
Single-dose in addition to dexamethasone in critical patients with rapid progression of respiratory failure may be given: NIH
Favipiravir
Inhibits RNA polymerase
Faster viral clearance, improved imaging findings
No recommendation yet
Ribavirin
Inhibits RNA polymerase
No concrete evidence
No recommendations yet
Chloroquine/ Hydroxy-chloroquine
Increases endosomal pH, interfere with glycosylation of receptor, immunomodulator
Benefit in clinical parameter & virological clearance
Removed from Solidarity trial, no other recommendation
Lopinavir/ Ritonavir
Protease inhibitor: SARS- Cov-2 3CL pro
Not significant
Removed from Solidarity trial, no other recommendation
Interferon
Immunomodulation
No concrete evidence
Removed from Solidarity trial, no other recommendation
Tyrosine Kinase inhibitors
Inhibit STAT phosphorylation, decrease hyperimmune state
No concrete evidence
Use with remdesivir if corticosteroids are contraindicated: NIH/IDSA
Table 1.
Summary of various pharmacotherapeutics being considered for COVID-19 treatment.
RdRp: RNA dependent RNA polymerase; ARDS: Acute respiratory distress syndrome; WHO: World Health Organization; CDC: Centers for Disease Control and Prevention; FDA: Food and Drug Administration; IDSA: Infectious Disease Society of America; EUA: Emergency Use Authorization; NIH: National Institute of Health; Il-6 R: Interleukin-6 receptor; STAT: Signal transducer and activator of transcription.
2. Review of pharmacotherapy
2.1 Chloroquine/hydroxychloroquine
The first studied drugs for COVID-19 were chloroquine and hydroxychloroquine (HCQ). Chloroquine was found to be effective against Avian influenza A H5N1 virus in animal models [3, 4] and also had demonstrable activity resulting in in-vitro inhibition of SARS-CoV [5]. COVID-19 infection showed high pandemicity in countries where malaria is the least prevalent and least pandemicity where malaria is highly prevalent. This observation led to the concept that chloroquine may be beneficial in COVID-19 since it is used as an anti-malarial. The mechanism of chloroquine action depends on the pathogen involved. Chloroquine increases the endosomal pH and interferes with the glycosylation of cellular receptor [Angiotensin Converting Enzyme (ACE) II] of SARS-CoV [6]. It also inhibits quinone reductase-2, which is involved in sialic acid biosynthesis. There is inhibition of MAO-kinase, virion assembly, and processing of M protein [7]. Besides its antiviral activity, it also has immunomodulatory effects that may be synergistic. HCQ was found to be equally effective as chloroquine, although a study concluded that HCQ was more effective and less toxic than chloroquine [8]. Chloroquine inhibitory actions against SARS-CoV were equal whether the primate cells were treated before or after exposure. This suggested that chloroquine could have both prophylactic and therapeutic applications [9]. One of the first studies performed to study the effect of chloroquine was done in the Chinese population. In this trial, patients in the study group who received chloroquine had reduced symptom duration, radiological improvement, and earlier seroconversion to the virus-negative state compared to controls [10]. Following this study, the National Health Commission of the People’s Republic of China included chloroquine in its guideline for the management of pneumonia due to Covid-19. In a study conducted by Gautret et al. in France, chloroquine treatment group had significant clearing of the nasopharyngeal swab viral load compared to the control [11]. The virological clearance day-6 post inclusion (primary outcome) with HCQ vs. controls was 70% vs. 12.5% (p < 0.001). The virological clearance at day 6 in HCQ plus azithromycin, HCQ and control arms were 100%, 57.1%, and 12.5% respectively (p = 0.001) thus suggesting synergistic action of azithromycin to HCQ . Gradually the side effect profile of HCQ , that is QTc prolongation with concomitant use of Azithromycin, lead the American Heart Association (AHA) to recommend withdrawal/withholding these drugs in patients with QTc ≥ 500 millisecond (either baseline or developing during treatment). On 28 March 2020, Food and Drug Administration (FDA) had issued Emergency Use Authorization (EUA) for Chloroquine/HCQ . However, the Centers for Disease Control and Prevention (CDC) on April 7 issued a statement stating no drugs or other therapeutic measures were approved by the US FDA to prevent or treat COVID-19. In April, the FDA issued a Drug Safety Communication cautioning against the use of HCQ or chloroquine for COVID-19 outside the hospital setting or a clinical trial due to the risk of heart rhythm problems. In June 2020, it was announced by World Health Organization (WHO) that the HCQ arm of the Solidarity Trial (Multi-national trial including remdesivir, HCQ , lopinavir/ritonavir, and lopinavir/ritonavir with interferon beta-1a) would be stopped [12]. This was keeping in view the lack of any mortality benefit of HCQ . Hence in June itself, FDA revoked the EUA of HCQ and chloroquine [13]. The pre-exposure prophylaxis benefit of HCQ needs further research.
2.2 Lopinavir/ritonavir
The combination of lopinavir/ritonavir was considered as an option for the treatment of Covid-19 during initial pandemic days. Lopinavir is an HIV-1 protease inhibitor, which is combined with ritonavir to increase its half-life through cytochrome p-450 inhibition. Both anti-HIV drugs interact with residues at the active site of SARS-CoV 3C-like protease, suggesting the mechanism of action in COVID-19 [14]. Its role was first evaluated in the treatment of SARS where patients treated with lopinavir/ritonavir for 14 days combined with ribavirin for 21 days. They had a milder disease in form of less diarrhea, fever, lymphadenopathy, the incidence of nosocomial infections, viral loads, demonstration of virus in the fecal sample by reverse transcription-polymerase chain reaction (RT-PCR), and 21 days adverse outcomes [15]. The combination was tested for MERS-CoV. It was postulated that the lopinavir/ritonavir combination may inhibit the 3C-like protease of MERS-CoV and may affect apoptosis in human cells. Results revealed that treatment with lopinavir/ritonavir led to clinical, radiological, and pathological improvement. Those animals treated with this combination had the lowest mean viral load detected by RT-PCR in lung and other extrapulmonary tissue [16]. There was only a single case report of a man being treated and recovered with a combination of lopinavir/ritonavir, ribavirin, and interferon-α for the MERS [17]. Based on this data, an urgent RCT was done to study the efficacy of lopinavir/ritonavir in the Wuhan province of China [18]. The analysis revealed no significant difference in terms of time for clinical improvement and mortality at 28 days. The median time for clinical improvement was just one day shorter in the lopinavir-ritonavir group compared to the standard care group. In July 2020, WHO discontinued the lopinavir/ritonavir arm of the solidarity trial due to a lack of any mortality benefit [19]. It causes QTc prolongation, just like HCQ [20].
2.3 Azithromycin
Azithromycin is a broad-spectrum antibiotic belonging to the macrolide group, having anti-inflammatory properties also. It is commonly used for treating atypical respiratory pathogens. Azithromycin’s anti-viral efficacy against some RNA viruses has also been described. Its efficacy has been demonstrated in-vitro against Zika virus and rhinovirus, as well as SARS-CoV-2 [21, 22]. As described, azithromycin also has immunomodulatory effects and can decrease acute exacerbations of chronic airway disease. Owing to its wide availability, excellent safety profile, and easy availability, azithromycin is one of the commonest drugs being used in the COVID-19 pandemic also. The Lancet reported the result of the COALITION II trial, [23] which was an open-label randomized trial evaluating azithromycin in addition to the standard of care (including HCQ), against the standard of care alone in severe COVID-19 patients. Azithromycin demonstrated no benefit in clinical outcome including clinical status or mortality, as compared to the standard of care alone (OR 1·36 [95% CI 0·94–1·97], p = 0·11). There was no increase in adverse events with azithromycin. In a study published in NEJM, HCQ alone or in combination with azithromycin had no demonstrable improvement in clinical status at 15 days compared with standard care in mild to moderate COVID-19 admissions [24].
2.4 Ivermectin
Ivermectin is a commonly used drug for various parasitic infestations including head lice, scabies, strongyloidiasis, ascariasis, and lymphatic filariasis. It is a macrocyclic lactone, which is derived from streptomyces avermitilis [25]. Its mechanism of activity against SARS-CoV-2 is believed to be via viral IMPα/β1 (Importin) mediated nuclear import inhibition. This leads to a decrease in the multiplication of the virus and hence the viral load [26, 27]. Ivermectin and doxycycline combination also inhibit viral entry and increases viral load clearance by the targeting of multiple viral proteins [28]. A recent study from India demonstrated that 2-dose ivermectin prophylaxis (300 micrograms/kg) within a gap of 3 days led to a 73% reduction in the number of COVID-19 infections among healthcare workers [29]. In studies conducted in Bangladesh also, the ivermectin-doxycycline combination was demonstrated to be highly effective in virological clearance in mild to moderate COVID-19 patients [30, 31]. National Institute of Health (NIH) stated in January 2021 that there was insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19 [32].
2.5 Melatonin
Melatonin is a hormone, which is synthesized from tryptophan in the pineal gland of the body and also by mostly all the organs of the body, as its production is associated with mitochondria. Higher levels of melatonin have positive roles in health and aging. Melatonin promises to be a great adjunctive drug for viral infections owing to its anti-inflammatory, anti-apoptotic, immunomodulatory, and antioxidant activities [33]. Sirtuin-1 (SIRT1) is the proposed mediator of melatonin’s anti-inflammatory action. This is via inhibition of high mobility group boxechromosomal protein-1 (HMGB-1), leading to down-regulation of the polarization of macrophages towards pro-inflammatory type [34]. It inhibits the over-activity of the innate immune system. Hence, theoretically, the cytokine storm induced by COVID-19 can be suppressed by melatonin. But the use of melatonin in COVID-19 is still very sparse, with only a few studies evaluating the same, hence further research is warranted [35]. Owing to melatonin’s anti-inflammatory, anti-oxidant, and anti-viral actions, its role in critical illness caused due to COVID has been studied. Melatonin has easy availability, is not expensive, and has an excellent safety profile [36]. A trial (EudraCT: 2020–001808-42) is ongoing for the identification of the doses of melatonin that may prove effective in this disease. It is a phase II, single-center, double-blind, RCT to address the efficacy and safety of intravenous melatonin in COVID-19 ICU patients [37].
2.6 Remdesivir
Remdesivir is a 1′-cyano-substituted adenosine nucleotide analog prodrug, which was found to be effective against several RNA viruses. It was initially developed in 2017 by Gilead science for the treatment of the Ebola virus [38]. It has demonstrated extensive antiviral activity & effective treatment of lethal Ebola and Nipah virus infections in nonhuman primates [39]. Subsequently, it was investigated for SARS-CoV and MERS-CoV. Studies have shown that Remdesivir inhibits viral replication in human airway epithelial cell culture by affecting the early stages of viral replication through viral RNA synthesis inhibition, as an RNA-dependent RNA polymerase (RdRp) inhibitor [39]. This may be due to the absence of Exon-mediated proofreading in viruses sensitive to Remdesivir [40]. One of the first trials of Remdesivir was performed by the Gilead sciences center in hospitalized patients with confirmed SARS-CoV-2 having oxygen saturation < 94% or a need for oxygen support. Till 28 days of follow-up, the cumulative incidence of clinical improvement was 84% (95% CI 70–99) by Kaplan–Meier analysis and it was less among patients receiving invasive ventilation compared to non-invasive ventilation [41]. In another randomized, double-blind, placebo-controlled, multicentre trial at 10 hospitals in Hubei, China, Remdesivir use was not associated with any difference in time to clinical improvement [42]. In February 2020, WHO cast a vote of confidence for remdesivir, indicating that it has great potential. In April 2020, the US National Institute of Allergy and Infectious Diseases (NIAID), announced that a clinical trial in >1,000 people showed that those taking remdesivir recovered in 11 days on average, compared with 15 days for those on a placebo, even adding that remdesivir may become a standard for COVID treatment [43]. US FDA had issued a EUA for remdesivir for severe COVID-19 disease. On 22nd October 2020, the FDA approved remdesivir for use in adult and pediatric patients (≥12 years, ≥40 kg) requiring hospitalization [44]. In October 2020 itself, an interim analysis of the WHO-led, open-label, randomized SOLIDARITY trial demonstrated that 301 (11·0%) of 2743 patients who received remdesivir and 303 (11·2%) of 2708 patients who received standard care died by day 28 (Kaplan–Meier rate ratio 0·95, 95% CI 0·81–1·11; p = 0·50) [45]. The ACTT-1 study had also reported a 29-day mortality of 11·4% in patients receiving remdesivir as compared to 15·2% in placebo (hazard ratio 0·73, 95% CI 0·52–1·03) [43]. Hence in November 2020, WHO issued a conditional recommendation against remdesivir utilization in hospitalized patients, regardless of their disease severity. This was because they could not find evidence of remdesivir improving survival and other outcomes in the patients [46]. Infectious Disease Society of America (IDSA) still suggests the use of remdesivir in severe and critical patients, as does NIH [47, 48].
2.7 Tocilizumab
Tocilizumab is an Interleukin-6 (IL-6) Receptor inhibiting monoclonal antibody. Studies have shown that infection with the SARS virus leads to a cytokine storm with the release of inflammatory cytokines like IL-6, Tumor Necrosis Factor- α (TNF –α), and IL-12 [49]. Further research done on MERS-CoV showed IL-6, IL-1β, and IL-8 were elevated in these patients. In patients with confirmed COVID-19 infection who were admitted to ICU, levels of IL-2, IL-6, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon-γ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage inflammatory protein 1 alpha (MIP1A), and TNF-α levels were found to be high, suggesting possible cytokine storm [50]. The first trial involving tocilizumab was performed in China in February 2020. The National Institute for Infectious disease had recommended tocilizumab in moderate to severe infections and IL-6 levels >40 pg/mL (or D-dimer levels >1000 ng/mL). However, it is not recommended by the CDC. In an RCT published in JAMA, in moderate-to-severe pneumonia, tocilizumab did not reduce the WHO Clinical Progression Scale scores. The proportion of patients with non-invasive or invasive ventilation or death at day 14 was 36% with usual care and 24% with tocilizumab. There were no differences in 28 days mortality. This meant tocilizumab could decrease the requirement for mechanical and non-invasive ventilation or death by day 14 but not mortality by day 28 [51, 52]. An RCT published by NEJM in October 2020, which included patients fulfilling at least two of the following: fever, pulmonary infiltrates, or the need for oxygen therapy to maintain oxygen saturation more than 92%, concluded that tocilizumab was not effective in preventing intubation or death in moderately ill hospitalized patients with Covid-19 [53]. Sarilumab, another IL-6 receptor antagonist was being tested in a multicentre trial for hospitalized patients with severe COVID-19 [54]. It was concluded that at 28 days, clinical improvement and mortality in severe COVID-19 were not significantly different between sarilumab and standard of care [55]. Preliminary results from the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) were released in a non-peer-reviewed report. REMAP-CAP is the largest trial to date investigating the use of IL-6 inhibitors in COVID-19. In February 2021, after reviewing the evidence from REMAP-CAP and other trials, the NIH Panel revised the recommendations on the use of tocilizumab and sarilumab, stating there was insufficient data to recommend either for or against the use of these drugs. But given the REMAP-CAP trial, some members suggested administering a single dose of tocilizumab (8 mg/kg of actual body weight, max 800 mg) in addition to dexamethasone in the ICU patients having high oxygen requirements/invasive and non-invasive mechanical ventilation and exhibiting rapid progression of respiratory failure [56]. The number of patients receiving sarilumab in the REMAP-CAP trial was too low to assess the efficacy.
2.8 Convalescent plasma
There was a hypothesis that plasma collected from the persons who have recovered from Covid-19 may contain antibodies against SARS-CoV-2, which may be used as a treatment tool. A case series was done in China where 5 critically ill patients with confirmed Covid-19 and Acute respiratory distress syndrome (ARDS) were selected [57]. They received two consecutive transfusions of 200 mL to 250 mL of convalescent plasma (total dose: 400 mL) with a SARS-CoV-2-specific antibody (IgG) titer more than 1:1,000. After receiving the plasma, the SOFA score of the patients decreased and ventilator parameters of the patients (pO2/FiO2 ratio) of the patient improved, and viral load decreased by day 12. ARDS resolved in four patients by Day 12 and 3 were weaned off the ventilators by 2 weeks. Further trials are needed the study the effectiveness of convalescent plasma. FDA is encouraging people who have fully recovered from COVID-19 for at least two weeks to donate plasma. FDA had issued guidance providing recommendations to health care providers & investigators on administration and study of COVID-19 convalescent plasma during the public health emergency. FDA issued a EUA for convalescent plasma on August 23, 2020, although convalescent plasma did not show any stoppage of progression to severe COVID-19 or all-cause mortality in the PLACID trial [58, 59]. In a trial published in NEJM in November 2020, in 228 patients receiving convalescent plasma and 105 receiving placebo at 30 days, there was not any significant difference among the clinical outcome distribution (odds ratio [OR], 0.83 (95% CI, 0.52–1.35; P = 0.46). Mortality in the plasma group was 10.96% as compared to 11.43% in the placebo group [risk difference 0.46% points (95% CI, −7.8 to 6.8) [60].
2.9 Favipiravir
Favipiravir (FPV) is a purine nucleotide that inhibits viral RNA polymerase. It was initially used against Ebola but later found to have in-vitro activity against other RNA viruses. The EC50 (concentration of a drug that gives half-maximal response) of FPV against SARS-CoV-2 in vitro in Vero E6 cells was found to be 61.88 μM/L [6, 61]. A study investigated the effect of FPV vs. lopinavir/ritonavir on the treatment of COVID-19. FPV was independently associated with faster viral clearance and a higher improvement rate in chest imaging. These findings suggest that FPV has significantly better treatment effects on COVID-19 in terms of disease progression and viral clearance as compared with lopinavir/ritonavir [62]. In an RCT on moderate to severe COVID patients, FPV was compared with umifenovir (Arbidol) by measuring the clinical recovery at 7 days [63]. Results showed no significant differences between the 2 groups. At present, there are no recommendations for the use of FPV in Covid-19 patients. Just like HCQ & lopinavir/ritonavir combination, it also causes QT prolongation [20].
2.10 Ribavirin
Ribavirin, a guanine analog, inhibits viral RNA dependent RNA polymerase (RdRp). It has demonstrable activity against many coronaviruses, but when used against SARS-CoV it was found to have less effectiveness in vitro requiring higher doses with combination therapy. When used with interferon in the treatment of MERS-CoV, no benefits were observed in terms of clinical outcomes or the rate of virus clearance [64]. Ribavirin also causes dose-dependent hematological toxicity & transaminase elevation when used in SARS patients and being a teratogen, is contraindicated in pregnancy [65, 66]. A recent trial showed ribavirin not being associated with better negative conversion times for the SARS-CoV-2 test and not being associated with improved mortality rates [67]. Due to its lack of demonstrable efficacy against other coronaviruses and high toxicity profile, it has got a limited role in the treatment of Covid-19. However, its combination with other antivirals is being tried in the SEV trial, the result of which is yet to be published [68].
2.11 Interferons
Studies with interferon-β had shown its activity against MERS. Most studies involved combination therapy with lopinavir/ritonavir or ribavirin. However, there was no concrete evidence showing its effect on SARS- CoV-2 in-vitro and the lack of clinical trials precluded the justification for its use in Covid-19 patients and hence there are no recommendations regarding its use [69]. In a study, it was shown that early triple antiviral therapy with lopinavir/ritonavir, ribavirin, and interferon beta-1b was safe and superior to lopinavir-ritonavir combinations alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 [70]. In a trial utilizing interferon β-1a, clinical response time was not significantly different between interferon and the control groups (9.7 ± 5.8 versus 8.3 ± 4.9 days, respectively, P = 0.95). On day 14, 66.7% versus 43.6% of patients in the interferon group and the control group respectively was discharged (OR, 2.5; 95% CI, 1.05–6.37). The 28-day overall mortality was significantly less in the interferon than the control group (19% versus 43.6%, respectively, P = 0.015). Early administration significantly decreased mortality (OR, 13.5; 95% CI, 1.5–1.18) [71]. Another trial testing interferon β-1b showed its effectiveness in reducing the clinical improvement time without any serious adverse events in severe COVID-19 patients. ICU admission and invasive ventilation need also decreased following administration of interferon β-1b [72]. The Lancet Respiratory Medicine showed the results of an RCT of nebulized interferon beta-1a in 101 adults admitted to the hospital with COVID-19. It demonstrated better odds of clinical improvement than placebo (OR 2·32 [95% CI 1·07–5·04]; p = 0·03). No significant difference was there in the hospital discharge odds by day 28 [73]. Recently, the SOLIDARITY trial also showed no benefit of interferon therapy [74].
2.12 Corticosteroids
ARDS is a leading cause of mortality in Covid-19 pneumonia. Cytokine storm plays a key role in the pathogenesis of ARDS in Covid-19 patients and thus immunosuppression may have a role in the treatment of such patients [75]. Glucocorticoids modify the inflammation-mediated lung injury and hence can alter progression to respiratory failure and death. Studies on SARS and MERS showed that corticosteroids did not show any improvement in overall survival but showed delayed viral clearance from the respiratory tract and other steroid-related complications like Hyperglycaemia & Psychosis [76]. A retrospective study was carried out in Covid-19 patients in China who had developed ARDS. Those who received steroids had decreased death rates compared to those who did not [77]. In another study in non-ARDS patients, corticosteroid treatment did not influence virus clearance time, hospital length of stay, or duration of symptoms in mild COVID-19. Another study reported that early application of low-dose corticosteroid improves the treatment effect, presenting as improvement of hypoxia and fever, shortening disease course, and accelerating focus absorption [78]. Steroids are now the only therapy showing mortality benefit in COVID-19 severe disease. RECOVERY trial has concluded that dexamethasone 6 mg given once daily for up to 10 days decreased 28-day mortality in patients with COVID-19 on respiratory support. But a careful decision has to be made regarding severity as patients not requiring oxygen showed no benefit but had a possibility of harm with corticosteroid therapy. In the dexamethasone group, the incidence of death was less than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51–0.81) and those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72–0.94). No benefit was demonstrated among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%, rate ratio, 1.19; 95% CI, 0.91–1.55) [79]. Subsequent RCTs also confirmed the same. Hence, all guidelines advocated steroids as first-line therapy in severe COVID-19. In due course, specific dose, route, and duration of therapy will be answered.
2.13 Monoclonal antibodies
Various novel monoclonal antibodies are under investigation for COVID-19. In a study published in NEJM, it has been described that LY-CoV555 (bamlanivimab) (also known as LY3819253), is a potent anti-spike neutralizing monoclonal antibody [80]. It binds to the receptor-binding domain of SARS-CoV-2. It was extracted from the convalescent plasma obtained from a COVID-19 patient. The protection of bamlanivimab against SARS-CoV-2 in primates has been reported [81]. In the interim analysis of data, patients receiving LY-CoV555 reported fewer hospitalizations and a lesser symptom burden than placebo receivers. In November 2020, it got the FDA EUA [82]. According to FDA, bamlanivimab reduced COVID-19 related hospital admissions in patients who are at high risk for disease progression [83]. This authorization came even after the company making the drug, Lilly, had announced in October 2020 that it was holding the trial in the hospital admitted patients as it not showing any benefits in them (ACTIV-3 trial). Remaining studies of bamlanivimab remain ongoing, including ACTIV-2 trial which includes the newly diagnosed mild to moderate COVID-19 patients; BLAZE-1, including recently diagnosed COVID-19 patients in the ambulatory (non-hospitalized) setting, studying bamlanivimab as monotherapy and in combination with etesevimab; and BLAZE-2, a phase 3 study for COVID-19 prophylaxis. Based on BLAZE-1 data, Lilly had submitted a request for EUA for bamlanivimab for the treatment of recently diagnosed mild to moderate COVID-19 patients to the FDA [84]. FDA reported 3% hospitalizations and emergency room visits in bamlanivimab treated patients compared to 10% in placebo. The FDA has approved bamlanivimab for patients age ≥ 12, and at high risk for progressing to severe covid-19 or hospital admission. However, it is emphasized that bamlanivimab should not be given to in-hospital COVID-19 patients or those requiring oxygen therapy; as such monoclonal antibodies may worsen outcomes in these patients. Another potential antibody treatment for COVID-19, REGN-COV2, a combination of two monoclonal antibodies casirivimab and imdevimab (REGN10933 and REGN10987), also faced some issues among inpatients with high oxygen requirements. In November 2020, the FDA issued EUA to monoclonal antibodies casirivimab and imdevimab (REGN10933 and REGN10987- against spike proteins of SARS-CoV-2) to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥12 years of age) [85]. Although, in this case also, Regeneron Pharma had to halt its antibody cocktail trial in the admitted patients due to safety concerns, hence it was approved for non-admitted patients only [86]. Interestingly, US President Donald Trump had also received this regime when he tested positive for COVID-19 [87]. Astra Zeneca’s COVID-19 Long-Acting AntiBody (LAAB) combination AZD7442 trial has also advanced into Phase III [88]. On February 9, 2021, the FDA has issued a EUA for bamlanivimab plus etesevimab for the management of mild to moderate COVID-19 in outpatients at high risk for disease progression. The data come from a randomized, double-blind, placebo-controlled clinical trial in 1,035 non-hospitalized adults with mild to moderate COVID-19, at high risk for progression to severe disease. Hospitalization or death occurred in 36 (7%) of placebo recipients compared to 11 (2%) patients treated with bamlanivimab 2,800 milligrams and etesevimab 2,800 milligrams administered together, demonstrating a 70% reduction [89].
2.14 Janus kinase (JAK) inhibitors
The kinase inhibitors are being proposed as a novel modality of COVID-19 treatment. The rationale behind this being the prevention of phosphorylation of key proteins that are involved in the signal transduction that in turn leads to immunological activation and inflammation. This includes the cellular responses to the pro-inflammatory cytokines like IL-6 [90]. JAK inhibitors interfere with the phosphorylation of signal transducer and activator of transcription (STAT) proteins [91, 92]. These proteins are in turn involved in cell signaling, growth, and survival. The immunosuppression may reduce the hyperactive immune state induced by COVID-19. Moreover, JAK inhibitors like baricitinib have a theoretical direct antiviral activity via interference with viral endocytosis. This can prevent viral entry in the cells [93]. NIH has recommended that in the rare circumstances where corticosteroids cannot be used, baricitinib in combination with remdesivir may be used for the treatment of hospitalized, non-intubated patients requiring oxygen supplementation. IDSA guidelines also suggest the use of this combination in hospitalized severe COVID-19 patients [47]. Use of baricitinib without remdesivir is not recommended, except in a clinical trial [94]. As for the use of baricitinib in combination with corticosteroids, there is still insufficient data. Both baricitinib and corticosteroids cause immuno-suppression; hence, there is an additive risk of infection.
2.15 Other miscellaneous drugs with a possible therapeutic effect
In the pathogenesis of Covid-19, ACE 2 receptors play an important role by facilitating the entry of the virus into the cell [1, 95]. Thus it could be a possible therapeutic target with the use of ACE-inhibitors and ARB [1, 96]. However, there is a concern that the use of these drugs to stop virus replication may increase the expression of ACE-2 receptors and paradoxically worsen the infection. However, no in-vitro studies are available which show either definite detrimental or protective effect of these agents. As a result, the current guidelines state to continue these drugs in patients who are already taking them [97].
Umifenovir (also known as Arbidol) is an antiviral agent with a unique mechanism of action targeting the S protein/ACE2 interaction and inhibiting membrane fusion of the viral envelope [98]. It is approved in Russia for prophylaxis and treatment of influenza. Of particular interest is its demonstrable in-vitro activity against Covid-19 [99]. In an observational study in China, patients treated with umifenovir for a median duration of 9 days had a higher discharge rate and lesser mortality [100]. But as with other agents, the lack of RCT limits the justification for its use in Covid-19. However, ACE targeting therapy is a promising one [1].
Camostat mesylate is an agent used in the treatment of pancreatitis. It inhibits host serine protease, TMPRSS2.3, and has been shown to prevent viral cell entry in-vitro and thus could be a target for future studies [101].
Nitazoxanide, an anti-helminthic with a relatively favorable safety profile has shown in-vitro activity against SARS-CoV and MERS [102]. Besides it also has additional immunomodulatory action & thus can be used in trials in Covid-19 patients as a therapeutic option.
Many non-allopathic pharmaceuticals are also in pipeline as promising COVID-19 therapy. In June 2020, yoga guru Baba Ramdev announced that his company Patanjali Ayurved had launched a drug called ‘Coronil’ that could cure COVID-19 [103]. However, no scientific basis for this claim is produced until now.
3. Conclusion
The Global pandemic with COVID-19 is on. Drug therapy holds the key to the treatment and containment of the disease. Hence, large-scale multicentric trials are ongoing involving multiple drugs. Until now, no therapy is absolutely effective in the treatment of the patient as infection and death rates continue to mount all over the world. Corticosteroids have shown a significant effect on reducing the mortality in severe COVID-19 patients. It is hoped that the results of the ongoing trials will open further opportunities towards understanding the disease process and designing safe and effective treatments.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"antiviral, monoclonal antibody, coronavirus disease 2019, dexamethasone, immunomodulator, ivermectin, remdesivir",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75843.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75843.xml",downloadPdfUrl:"/chapter/pdf-download/75843",previewPdfUrl:"/chapter/pdf-preview/75843",totalDownloads:213,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 23rd 2021",dateReviewed:"March 4th 2021",datePrePublished:"May 17th 2021",datePublished:"December 8th 2021",dateFinished:"March 20th 2021",readingETA:"0",abstract:"Most viral infections have limited treatment options available and the same holds for COVID-19, its causative agent being the SARS-CoV-2 virus. Drugs used in the past against Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS) viruses, which belong to the same family of viruses as the novel Coronavirus included ribavirin, interferon (alfa and beta), lopinavir-ritonavir combination, and corticosteroids. There remains controversy regarding their efficacy to date, except for the last one. Hence, large-scale multicentric trials are being conducted involving multiple drugs. Chloroquine and hydroxy-chloroquine were initially taking the race ahead but have now been rejected. Remdesivir was a promising candidate, for which the FDA had issued an emergency use authorization, but now is not recommended by the WHO. Convalescent plasma therapy had promising results in the early severe viremia phase, but the PLACID trial made an obscure end. Only corticosteroids have shown demonstrable benefits in improving mortality rates among severe COVID-19 cases. Many new modalities like monoclonal antibodies and tyrosine kinase inhibitors are discussed. In this chapter, we review the therapeutic drugs under investigation for the COVID-19 treatment, their mode of action, degree of effectiveness, and recommendations by different centers regarding their use in current settings.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75843",risUrl:"/chapter/ris/75843",signatures:"Mayank Kapoor, Prasan Kumar Panda and Vivek Mohanty",book:{id:"10706",type:"book",title:"Fighting the COVID-19 Pandemic",subtitle:null,fullTitle:"Fighting the COVID-19 Pandemic",slug:"fighting-the-covid-19-pandemic",publishedDate:"December 8th 2021",bookSignature:"Manal Mohammad Baddour",coverURL:"https://cdn.intechopen.com/books/images_new/10706.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-217-9",printIsbn:"978-1-83968-216-2",pdfIsbn:"978-1-83968-246-9",isAvailableForWebshopOrdering:!0,editors:[{id:"174598",title:"Dr.",name:"Manal Mohammad",middleName:null,surname:"Baddour",slug:"manal-mohammad-baddour",fullName:"Manal Mohammad Baddour"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"269294",title:"Dr.",name:"Prasan Kumar",middleName:null,surname:"Panda",fullName:"Prasan Kumar Panda",slug:"prasan-kumar-panda",email:"motherprasanna@rediffmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"348097",title:"Dr.",name:"Mayank",middleName:null,surname:"Kapoor",fullName:"Mayank Kapoor",slug:"mayank-kapoor",email:"mkapoorsonu@yahoo.co.in",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"348098",title:"Dr.",name:"Vivek",middleName:null,surname:"Mohanty",fullName:"Vivek Mohanty",slug:"vivek-mohanty",email:"vivekmohanty.92@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Review of pharmacotherapy",level:"1"},{id:"sec_2_2",title:"2.1 Chloroquine/hydroxychloroquine",level:"2"},{id:"sec_3_2",title:"2.2 Lopinavir/ritonavir",level:"2"},{id:"sec_4_2",title:"2.3 Azithromycin",level:"2"},{id:"sec_5_2",title:"2.4 Ivermectin",level:"2"},{id:"sec_6_2",title:"2.5 Melatonin",level:"2"},{id:"sec_7_2",title:"2.6 Remdesivir",level:"2"},{id:"sec_8_2",title:"2.7 Tocilizumab",level:"2"},{id:"sec_9_2",title:"2.8 Convalescent plasma",level:"2"},{id:"sec_10_2",title:"2.9 Favipiravir",level:"2"},{id:"sec_11_2",title:"2.10 Ribavirin",level:"2"},{id:"sec_12_2",title:"2.11 Interferons",level:"2"},{id:"sec_13_2",title:"2.12 Corticosteroids",level:"2"},{id:"sec_14_2",title:"2.13 Monoclonal antibodies",level:"2"},{id:"sec_15_2",title:"2.14 Janus kinase (JAK) inhibitors",level:"2"},{id:"sec_16_2",title:"2.15 Other miscellaneous drugs with a possible therapeutic effect",level:"2"},{id:"sec_18",title:"3. 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From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). 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Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. 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He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. 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He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. He is a member of seven international specialized scientific societies, besides his local one, and\nhe has won seven prizes.",institutionString:"Cairo University",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{paginationCount:617,paginationItems:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"38",type:"subseries",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,series:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713"},editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",slug:"meng-chuan-ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",slug:"olga-anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},onlineFirstChapters:{},publishedBooks:{},testimonialsList:[{id:"18",text:"It was great publishing with IntechOpen, the process was straightforward and I had support all along.",author:{id:"71579",name:"Berend",surname:"Olivier",institutionString:"Utrecht University",profilePictureURL:"https://mts.intechopen.com/storage/users/71579/images/system/71579.png",slug:"berend-olivier",institution:{id:"253",name:"Utrecht University",country:{id:null,name:"Netherlands"}}}},{id:"8",text:"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality.",author:{id:"202192",name:"Catrin",surname:"Rutland",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",slug:"catrin-rutland",institution:{id:"134",name:"University of Nottingham",country:{id:null,name:"United Kingdom"}}}},{id:"27",text:"The opportunity to work with a prestigious publisher allows for the possibility to collaborate with more research groups interested in animal nutrition, leading to the development of new feeding strategies and food valuation while being more sustainable with the environment, allowing more readers to learn about the subject.",author:{id:"175967",name:"Manuel",surname:"Gonzalez Ronquillo",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",slug:"manuel-gonzalez-ronquillo",institution:{id:"6221",name:"Universidad Autónoma del Estado de México",country:{id:null,name:"Mexico"}}}}]},submityourwork:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],subseriesList:[],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/94481",hash:"",query:{},params:{id:"94481"},fullPath:"/profiles/94481",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var m;(m=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(m)}()