Details relevant for the independent variables used in this study.
\r\n\tIC offer services both at the macro-scale (country) and at the micro-scale (cities). The stability and the protection of these networks on both scales are a significant task, entrusted to the Operators who operate CI in a concession mandate. Due to the high level of interdependency of CI, which exchange services to each other for their functioning, their management and protection cannot be carried out by a "linearized" strategy (each infrastructure managed and protected independently on the others) due to the presence of tight links which connect each other. CI protection through provision of "smart" properties such as resilience, has become a complex task which must be tackled not only by deploying advanced technological means but also by triggering new management strategies, enabling holistic and global management policies.
\r\n\r\n\tThe book aims at providing an overview of the understanding of complex phenomena taking place on interdependent networks and of the advanced technical solutions related to management, risk analysis and resilience enhancement of networks, either from a theoretical and operational (i.e. with solution related to real or realistic cases) points of view. A large emphasis is provided to the capability opened by the use of field and remote sensing tools for monitoring and assessing risks on CI. The use of comprehensive data set, the access to big data is going to open the way to the realization of new tools for supporting the decision making process needed for both daily and emergency management.
",isbn:"978-1-83962-621-0",printIsbn:"978-1-83962-620-3",pdfIsbn:"978-1-83962-628-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"7cfcd62bae8c99be207e18bb73e2a7b1",bookSignature:"Dr. Vittorio Rosato and Dr. Antonio Di Pietro",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10256.jpg",keywords:"Complex systems, Interdependence, Resilience, Cascading effects, Event prediction, Emergency management, Decision support, AI, Field sensors, Remote sensing, IoT, GIS",numberOfDownloads:525,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 15th 2020",dateEndSecondStepPublish:"July 6th 2020",dateEndThirdStepPublish:"September 4th 2020",dateEndFourthStepPublish:"November 23rd 2020",dateEndFifthStepPublish:"January 22nd 2021",remainingDaysToSecondStep:"8 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Supervisor and Project Evaluator for EU, for the Italian Ministry of University and Research, and that of Economic Development; Consultant for several Italian Regions and the Italian Ministry of Defense; Coordinator of several National Projects; Co-founder of two SMEs active in software engineering and biotechnology; Author of more than 140 scientific papers in peer reviewed journals and conference proceedings.",coeditorOneBiosketch:"A full researcher at ENEA (Italian Energy, New Technology and Environment Agency) since 2007 and a joined member to the Laboratory for the Analysis and Protection of Critical Infrastructures (APIC) from 2015. Dr. Di Pietro took part in several European and Italian national research projects and acted as an advisor for certain Evaluation Studies commissioned by the EU.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"27002",title:"Dr.",name:"Vittorio",middleName:null,surname:"Rosato",slug:"vittorio-rosato",fullName:"Vittorio Rosato",profilePictureURL:"https://mts.intechopen.com/storage/users/27002/images/system/27002.jpg",biography:"Vittorio Rosato received the Laurea degree (M.Sc.) in Physics from the University of Pisa (Italy) and a Ph.D. in Condensed Matter Physics from the University of Nancy (France). He has extensively been working in Computational Physics, particularly in Condensed Matter and Material Science in his positions as Research Assistant at the University College of Wales in Aberystwyth (UK) and at the Centre d'Etudes Nucleaires in Saclay (France). Staff Scientist at ENEA (Italian National Agency for New Technologies, Energy and Sustainable Economic Development) since 1990, he is currently Head of the Laboratory of Analysis and Protection of Critical Infrastructures and Manager of the Italian Node of the European Infrastructure Simulation and Analysis Centre (EISAC.it).\nHis current research activities span from risk analysis to the design of Decision Support Systems for the management of complex technological networks. He acts as Supervisor and Project Evaluator for EU, for the Italian Ministry of University and Research, and that of Economic Development; he is also consultant for several Italian Regions and the Italian Ministry of Defense. He is and has been Coordinator of several National Projects. He is co-founder of two SMEs active in software engineering and biotechnology. 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He is also an Unmanned Aerial Vehicles (UAV) ENAC-certifed pilot to perform critical operations involving aerial photogrammetry tasks for biological and Infrastructure monitoring applications. He took part in several European and Italian national research projects and acted as an advisor in some Evaluation Studies commissioned by the EU. He has also been advisor of several M.Sc. students and also a teacher in several professional courses on Software Engineering and Databases.",institutionString:"ENEA (Italian National Agency for New Technologies, Energy and Sustainable Economic Development)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:[{id:"74122",title:"Risk Analysis in Early Phase of Complex Infrastructure Projects",slug:"risk-analysis-in-early-phase-of-complex-infrastructure-projects",totalDownloads:87,totalCrossrefCites:0,authors:[null]},{id:"74493",title:"Flood Risk Analysis for Critical Infrastructure Protection: Issues and Opportunities in Less Developed Societies",slug:"flood-risk-analysis-for-critical-infrastructure-protection-issues-and-opportunities-in-less-develope",totalDownloads:50,totalCrossrefCites:0,authors:[null]},{id:"74123",title:"Resilience in Critical Infrastructures: The Role of Modelling and Simulation",slug:"resilience-in-critical-infrastructures-the-role-of-modelling-and-simulation",totalDownloads:78,totalCrossrefCites:0,authors:[null]},{id:"73984",title:"Validation Strategy as a Part of the European Gas Network Protection",slug:"validation-strategy-as-a-part-of-the-european-gas-network-protection",totalDownloads:35,totalCrossrefCites:0,authors:[null]},{id:"74174",title:"Defects Assessment in Subsea Pipelines by Risk Criteria",slug:"defects-assessment-in-subsea-pipelines-by-risk-criteria",totalDownloads:44,totalCrossrefCites:0,authors:[null]},{id:"74240",title:"Analyzing the Cyber Risk in Critical Infrastructures",slug:"analyzing-the-cyber-risk-in-critical-infrastructures",totalDownloads:85,totalCrossrefCites:0,authors:[null]},{id:"74141",title:"Italian Crisis Management in 2020",slug:"italian-crisis-management-in-2020",totalDownloads:49,totalCrossrefCites:0,authors:[null]},{id:"74668",title:"A Strategy to Improve Infrastructure Survivability via Prioritizing Critical Nodes Protection",slug:"a-strategy-to-improve-infrastructure-survivability-via-prioritizing-critical-nodes-protection",totalDownloads:34,totalCrossrefCites:0,authors:[null]},{id:"74143",title:"Resilience of Critical Infrastructures: A Risk Assessment Methodology for Energy Corridors",slug:"resilience-of-critical-infrastructures-a-risk-assessment-methodology-for-energy-corridors",totalDownloads:66,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"205697",firstName:"Kristina",lastName:"Kardum Cvitan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/205697/images/5186_n.jpg",email:"kristina.k@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"60309",title:"The Relationship between Environmental Reporting and Corporate Governance: Empirical Evidence from Pakistan",doi:"10.5772/intechopen.75228",slug:"the-relationship-between-environmental-reporting-and-corporate-governance-empirical-evidence-from-pa",body:'\nThere is an increasing tendency for organizations worldwide to disseminate information regarding their social and environmental measures [1]. The concept of corporate environmental responsibility has gained considerable attention as a result of growing concern of public over the sustainability of natural environment. This concern has become particularly noticeable over the past four decades [2]. In addition the concept of Triple Bottom Line Reporting (i.e. reporting regarding economic, environmental and social activities) introduced by Elkington [3] during the mid-1990s and global reporting initiative in 2002 gained substantial attention and has recommended certain guidelines on three dimensions of corporate accountability and responsibility, i.e. economic responsibility, social responsibility and environmental responsibility.
\nParallel to this, corporate governance has enormously engrossed attention in recent years. It is generally emphasized that sound corporate governance is associated with enhanced transparency, accountability and plausible disclosure [4, 5, 6, 7]. Agency theory and other corporate governance guidelines recommend a sound corporate governance structure for an effective and transparent disclosure mechanism about the corporations.
\nMoreover, the notion of sustainable development stipulates firms to be accountable not only financially or economically but to be sound and reliable socially and environmentally [8]. The strong connection between corporate governance mechanisms and the level of voluntary disclosure has been reported by the authors in [9, 10, 11, 12, 13, 14, 15, 16, 17]. Likewise, the authors in [18, 19, 20, 21, 22] documented a significant connection between corporate social responsibility disclosure and determinants of corporate governance. Whereas the authors in [2, 23, 24, 25, 26] have acknowledged that sound corporate governance is associated with enhanced environmental disclosure practices.
\nThe literature suggests diverging views regarding association between corporate governance and information disclosure. Studies conducted by the authors in [21, 22, 25, 27] suggested that larger board leads to more efficient reporting system. On the contrary, the authors in [19, 23] found a lack of association between board size and environmental reporting. In addition, the authors in [10, 17] suggested a need for a separate leadership structure for enhanced transparency and disclosure whereas, Ho and Wong [9] found a lack of relationship between the nondual leadership structure and the level of corporate reporting.
\nThe authors in [14, 20, 25] found a positive association between board independence and environmental reporting. Likewise, the authors in [22, 25] endorsed that female directors exhibit socially responsible behavior and firms with more female directors tend to disclose more information.
\nAudit committee independence is also documented to be positively associated with corporate disclosure practices by Oscar and Juliet [26]. On the other hand, Alhazaimeh et al. [16] found no link between audit committee independence and voluntary disclosure. For institutional ownership, the authors in [12, 25] reported a positive relationship between institutional ownership and environmental reporting. On the contrary, Alhazaimeh et al. [16] argued that effectiveness of board is reduced due to the presence of institutional investors.
\nCSR has been well examined in Pakistan. The prior studies support the notion that sound CSR practices improve the financial performance of firm [28, 29, 30, 31, 32] and corporate image [33, 34, 35]. Likewise, studies conducted by the authors in [20, 21, 22] documented a substantial association between CG and level of corporate disclosure, but so far limited empirical work has been carried out to analyze whether this also relates to environmental reporting. The key motivation of the current study is to fill up the gap by investigating the impact of corporate governance elements on the environmental information disclosure of the companies listed on Pakistan Stock Exchange (PSX). The present study is expected to make noteworthy contribution to the existing accounting literature by imparting updated information on the extent of environmental reporting practices in Pakistan and by presenting empirical evidence on the relationship between corporate governance characteristics and environmental reporting in the annual reports of 50 companies listed on PSX.
\nThe findings suggest a positive association between board size and environmental reporting as larger board characterized by more qualified individuals acquires an efficient reporting system including ER. It is also found that independent directors effectively monitor board activities, stimulate autonomy within board and are positively associated with environmental disclosure practices. Likewise, separate leadership structure enhances the efficiency of board in monitoring management activities and ensures high level of transparency. Finally the study proves that institutional investors actively voice their concern over the firm’s strategies and board governance and compel management to reveal more information regarding environmental activities.
\nAfter the introduction, the rest of this chapter is arranged as follows. Section 2 discusses the corporate governance and environmental reporting nexus. Section 3 presents the literature review and explains the hypotheses development. Section 4 shows in detail the research methodology followed by the results of the empirical analysis to test the stated hypotheses in Section 5. Finally, Section 6 presents the conclusion, implications, limitations and areas for future research.
\n“Environment Reporting” offers an opportunity for firms to apprise stakeholders that their corporate operations and efforts are environmental friendly. Environmental reporting should be embraced by corporation as an opportunity rather than an impediment to the growth of business. However, it is a real challenge in a country like Pakistan, where pervasive control and command systems invade the governance of country. Regulatory framework often tends to target the disciplinary behavior of corporations, instead of providing them with a facilitating environment for better compliance on ecological and social standards. Sustainability reporting also known as triple bottom-line reporting, corporate social responsibility reporting or non-financial reporting addresses the ability of organizations to formally reveal information about their economic, social and environmental operations [36]. In this perspective, sustainable approach, i.e. to fulfill the requirements of current generation without compromising the capacity of upcoming generations to fulfill their requirements is an emerging concern among the global community. In Pakistan, sustainability reporting of which environment reporting is a significant category is in its infancy but gradually growing.
\nGlobalization is the process of economic integration of multinational and national companies. These include listing of companies at international and national stock exchanges. This cross listing provides investors with opportunities to invest and earn economic gains originating from versatile interactions because of higher level of brain storming skills [37].
\n“Environmental reporting” has been described broadly as reporting by corporations regarding the environmental implications of their activities [38]. Environmental disclosure expands the responsibility of the firms beyond the conventional role of imparting financial information assuming the broad environmental responsibilities of the firms [39]. Manifesting effective corporate governance practices and maintaining sound environmental performance are among the key challenges faced by the organization to ensure its sustainability. In this context, environmental reporting can be reckoned as means of ascertaining effective corporate governance practices that incorporate transparency in its environmental practices. This rigorous operationalization of information disclosure in the environmental sphere is also attributed as “governance-by-disclosure” [40]. Companies in Pakistan and globally are under more public scrutiny than ever before and are obliged to disclose information regarding their environmental operations. Disclosure on environmental performance helps firms to gain stakeholder’s confidence, to evaluate potential risks involved in performing such activities and to moderate the impact of these activities on the environment. It considers impact of their operations on the surrounding environment and to reveal the results to multiple stakeholders such as employees, consumers, community, regulators, the media and shareholders which become critical for the long-lasting sustainability of the organizations [41].
\nDespite the variations in theoretical frameworks being endorsed, pertinent former literature from a broader spectrum has recognized that sound corporate governance is affiliated with enhanced level of transparency and plausible reporting [4]. Therefore, sound corporate governance practices are considered as accountability catalysts, reducing information asymmetry by ascertaining the disclosure needed for meeting the informational requirements of diverse stakeholders. The existing literature on disclosure of information provides evidence of number of theories supporting the disclosure of information by corporations. However, agency theory [42] and stakeholder theory [43] have dominated the explanation of corporate governance. Jensen and Meckling [42] described agency relationship as an agreement where one person (the agent) renders some services on behalf of the other party (the principal) and safeguards their interest. Certain decision making power may be delegated to agent as a reward of these services.
\nStakeholder theory has a comprehensive dimension as compared to agency theory as it broadens the notion of principal to all concerned parties rather than just shareholders. This theory basically deals with the identification and appreciation of the association between the firm’s actions and its influence on various stakeholders [44]. With respect to stakeholder theory, the authors in [19, 45] argued that good corporate governance practices enhanced firm–stakeholder relationship by fostering corporate sustainability. Consistent with the stakeholder concept, environmental disclosure serves as a part of the discourse between the company and its stakeholders concerning various environmental dimensions [8, 44]. On the basis of above discussion and in the context of agency and stakeholder theory, the study asserts that level of satisfaction of stakeholders regarding environmental information is associated with greater accountability and transparency of the top management.
\nThe previous studies investigating the extent of corporate voluntary reporting practices are of the view that environmental reporting is a significant phenomenon employed by corporations and is influenced by many corporate governance and firm specific attributes. The present review is an endeavor to encircle the multiple determinants of environmental reporting and its relationship with corporate governance characteristics. Corporate governance characteristics are manifested and categorized into: (1) board characteristics namely the size of board, board composition, role duality and proportion of female directors; (2) board committee’s characteristics computed by audit committee independence and (3) ownership structure computed by the percentage of institutional investors. Control variables employed in the present study are size of the firm, leverage and profitability. In the sub-sections below, we develop hypotheses relevant for CG characteristics.
\nBoard size plays a significant role in monitoring firm performance and is taken into consideration mainly from the perspective of agency theory. Agency theory advocates for the smaller board size and it is anticipated that smaller board enhances efficiency, results in better coordination and effectively monitors the management decisions concerning the information disclosure [46]. Prado-Lorenzo and Garcia-Sanchez [47]asserted that larger board is detrimental to governance efficiency. The literature also shows contrary school of thought regarding association between board size and information disclosure. According to Xie et al. [48] larger board is characterized by more qualified and knowledgeable individuals and acquires a more effective reporting procedure and enhanced level of voluntary disclosure including the environmental disclosure.
\nThe authors in [49, 50] argued that larger boards are expected to be dominated by the CEO, result in poor communication, ineffective coordination and less decision-making. They suggested that boards having more than seven or eight representatives are likely to be ineffective. Yoshikawa and Phan [51] also emphasized that numerous hidden interactions and divergence of interest among board members made the larger boards less cohesive resulting in weak coordination. In addition, they elaborated that sometimes larger boards are purposely formed by CEOs to disperse the power in the boardroom by making the CEO a dominant figure and thus reduces the likelihood of integrated actions by board members. Parallel to the theoretical expectations the study conducted by Byard et al. [52] using a sample of 1279 firms over the years 2000–2002 found a negative association between board size and environmental reporting. Hence, from the perspective of agency theory it is hypothesized that the relationship between board size and environmental disclosure would be negative:
\nH1: The level of environmental reporting is negatively related to the board size.
\nAccording to the agency theory [53] the presence of independent non-executive directors on the board effectively monitors the activities of company, stimulating objectivity and autonomy within the board. Furthermore, the board independence reduces the conflicts of interests among the multiple shareholders and the management thus leading to the minimization of agency costs [19]. From the perspective of stakeholder theory, independent directors are seen as accountability mechanism [18], as they have responsibility for a wider variety of stakeholders [45, 47]. The 2013 Corporate Governance Code issued by Securities & Exchange Commission of Pakistan (SECP) requires all listed companies to have majority of independent non-executive directors on their board, thus facilitating the board to discharge its duties and responsibilities appropriately. Regarding the association between independence of board and CSR reporting [13, 14, 15, 21, 22, 54] empirically found a significant impact of the existence of non-executive independent managers on CSR disclosure.
\nAccording to Refs. [24, 25, 55] boards having more independent non-executive directors compel managers to take favorable decisions regarding the firm’s environmental performance. Moreover, the firms demonstrating active environmental concern proved to have more independent directors on their boards. Therefore, we hypothesize a significant positive relationship between the proportion of independent non-executive directors on the board and the extent of environmental reporting:
\nH2: The level of environmental reporting is positively associated with the proportion of independent non-executive directors on the board.
\nRole of CEO has been incorporated as one of the significant factor influencing the corporate environmental and social reporting by Adams [56]. It is believed that the “CEO duality” or “dominant personality phenomenon”, i.e. the positions of CEO and the chairman held by the same person can lessen the efficiency of the board in screening the management activities [10, 57]. The 2013 Corporate Governance Code released by the SECP also recommends the separate role between the CEO and chairman of the board. The authors in [42, 58, 59] proposed discrete leadership structure on the basis of agency theory. Hence, it could be assumed that the board independence attained by separate leadership framework will direct to a better and effective environmental and social reporting about the companies, thus protecting interest of the shareholders.
\nThe literature shows contrary results with regard to the practice of separation between the executive manager and the chairman of the board and the level of reporting. Furthermore, the authors in [9, 19, 60] found no substantial association between the separate leadership structure and the level of reporting. Florackis and Ozkan [50] argued that the dual role endorses CEO entrenchment by decreasing monitoring efficacy of board. Haniffa and Cooke [10] found that role duality is linked with lesser voluntary disclosure. Consistent with the arguments, the authors in [17, 45, 52, 61] found a positive association between disclosure and separate leadership framework. Finally, it is anticipated that separate leadership structure will enhance the extent of environmental reporting by the firm:
\nH3: The level of environmental reporting is positively related to the practice of separation between the Chief Executive Officer (CEO) and chairman of the board.
\nBoard diversity in terms of proportion of women on the board has been documented as having a substantial effect on firm performance and disclosure of both financial and nonfinancial matters [62]. Female directors are more diligent, committed, philanthropically driven and make effective contribution to the firm performance [25]. Ballesteros et al. [63] also documented a positive relationship between the proportion of female directors and level of CSR disclosure. Female directors exhibit more philanthropic concern as compared to men [22, 64] enhancing information transparency and accountability [65].
\nIn line with stakeholder theory, the authors in [66, 67] endorsed the view that women are socially oriented than men, develop effective stakeholder management and increase the board independence and thus social responsible behavior [45]. Furthermore, higher percentage of female directors on the board leads to the board independence and thus increases the probability of providing enhanced corporate environmental reporting [25]. On the basis of the above arguments about the monitoring potential of female directors and rationale offered by stakeholder theory, it can be asserted that female director’s commitment, independence, thoughtfulness and other attributes enable them to actively participate in corporate decision making concerning disclosure practices. Therefore, we hypothesized a significant positive relationship between the proportion of female directors on the board and the level of environmental reporting:
\nH4: The level of environmental reporting is positively related to the proportion of female directors on the board.
\nThe main purpose of board committees is to monitor the audit process, the auditor’s independence, the internal control and accounting system, the nomination and remuneration of the board directors, thus ensuring a continuous communication between the external auditor and the company’s board [68]. Agency theory advocates the audit committee as an instrument of mitigating agency costs.
\nAccording to Ref. [69], the existence of an audit committee offers an ancillary internal control mechanism, likely to enhance the performance of a firm. More appreciably, audit committee with independent members empowers the committee to discharge its responsibilities impartially and thus substantially contribute to the committee’s effectiveness [9]. According to the 2013 Corporate Governance Code issued by the SECP, all listed companies in Pakistan are required to have an independent director as the chairman of board audit committee. There is dearth of empirical support regarding the relationship between environmental reporting practices of firms and independence of audit committee.
\nAburaya [70] found a positive relationship association between audit committee independence and the reporting quality of certain environmental specific categories such as policies concerning environment, adherence with environmental legislations and other environmental information. Nevertheless, in the context of voluntary disclosure [9, 12, 55, 71, 72, 73] documented the presence of a positive link between audit committee and the incurring independence and the extent of voluntary reporting exhibited by the companies. They argued that board committees determine good corporate disclosure of information. In conclusion, the existence and independence of audit committee improves the transparency of corporate boards and is expected to guarantee that a company fulfills its social commitment including the environmental commitment. Hence, it is hypothesized that the relationship between the presence and independence of audit committee and environmental disclosure will be positive:
\nH5: The level of environmental reporting is positively related to the existence and independence of audit committee.
\nOwnership structure whether it is dispersed or concentrated is considered to be an important attribute of corporate governance [74]. Institutional ownership is the form of ownership concentration computed as the percentage of shares held by institutional shareholders comprising banks, pension funds, endowment funds, mutual funds and insurance companies, etc. [75]. It is generally argued that the efficacy and effectiveness of board is reduced due to the presence of institutional investors. Jensen and Meckling [42] argued that separation of ownership and control result in increasing demand of information disclosure by firms. Hence, it could be assumed that institutional shareholding decreases the probability of providing enhanced corporate environmental reporting.
\nInvestors having larger stake in the firm confine the decision making power of the board, which reduces the board autonomy and activism [42, 75] whereas, the authors in [14, 54, 61, 73] found no substantial association between the institutional ownership and the level of reporting. Some studies have found a negative association between institutional ownership and corporate disclosures [74, 16]. According to the agency theory, institutional investors have strong incentives to monitor corporate disclosure practices and influence corporate values [12]. Consistent with the stakeholder theory, institutional investors demand more accountability and transparency and are positively associated with corporate voluntary disclosure practices including environmental disclosure [76]. In line with the theoretical expectations, Rao et al. [25] documented a positive association between institutional ownership and environmental reporting. They suggested that institutional investors are active owners and influence management and corporate value due to their large ownership stake in the firms. Based on the above discussion and rationale provided by agency and stakeholder theory, it could be anticipated that institutional shareholdings increase the likelihood of providing enhanced corporate environmental disclosure.
\nH6: The level of environmental reporting is positively related to the ownership concentration.
\nThe conceptual framework for the study shows the role of internal, external and control variables in affecting environmental reporting practices in the firm (Figure 1).
\nConceptual framework.
The sample consists of 50 nonfinancial firms listed at Pakistan Stock Exchange that may affect the environment; forestry; the extractive and manufacture industry; food industry; construction industry; automobile industry; chemical industry; production and distribution of electricity, oil, gas and water; engineering and transport and storage. Fifty companies are selected, using proportionate stratified random sampling technique from 19 sectors.
\nThe annual report is the main source of data being utilized in the recent study to analyze the environmental reporting practices of firms listed on Pakistan Stock Exchange covering a period of 2014–2015. The selected time span is not an independent period compared to systematic factors in the economy (for details see Appendix 2 showing the major macro-economic factors) and no major economic event took place during this period. The reports have been used as the fundamental medium of reporting social and environmental activities of firms as evident from prior studies performed by the authors in [54, 61, 73].
\nThe dependent variable, environmental reporting is computed by employing content analysis of the annual reports of the firms listed at PSX. Content analysis of environmental disclosure requires the development of categorization pattern and then deciding a set of rules for coding process, estimating and documenting the information being analyzed. First, a preliminary checklist containing anticipated environmental information items is organized. The checklist is then attuned to fit with the operational measures as documented by the guiding principles on environmental performance indicators and implication of the Global Reporting Initiative (GRI) that assist ascertaining environmental reporting in the annual reports.
\nConsequently, the final checklist is reckoned viable and rigorous in portraying environmental reporting practices in the annual and sustainability reports of Pakistani firms. The final checklist comprises of 60 environmental information items classified into seven broadly identified categories, namely: (1) Environmental philosophy and strategy (7 items); (2) Environmental summary (6 items); (3) Initiatives concerning environmental reporting (6 items); (4) Governance structure and management system (6 item); (5) Credibility (9 items); (6) Environmental performance Indicators (16 items) and (7) Environmental spending (10 items). Then, a coding method is used to allocate environmental information items in the annual reports to that of the scoring sheet/checklist employing premeditated decision rules.
\nUnweighted disclosure index technique is employed to compute the level of environmental reporting where the reporting of an item in the annual reports is coded (1) and non-disclosure is coded as (0). The disclosure model (unweighted environmental disclosure) thus computes the total disclosure (TD) score for a company as additive as follows:
\nwhere di is 1 if item is disclosed and 0 if item is not disclosed and nj is the maximum number of items for firms (nj ≤ 60). To compute specific firm score, total score awarded to a firm is divided by the highest possible score and then multiplied by 100 to get the percentage scores. The maximum possible score that a firm could get is 60 because the numbers of reporting items incorporating all the seven broad categories form a total score of 60. The average score is calculated as the percentage of the number of firms reporting a specific item to the total number of items.
\nTable 1 represents the details about the independent and control variables employed in the current study and techniques used for their operationalization.
\nVariables | \nOperational definitions | \nSymbol | \nExpected sign | \n
---|---|---|---|
Independent variables | \n|||
Board size | \nTotal number of directors on the board | \nBS | \n−ive | \n
Board independence | \nPercentage of independent non-executive directors to the total directors | \nBI | \n+ive | \n
CEO duality | \nDummy variable equal to 1 if CEO is also the chairman, 0 if not | \nDUAL | \n−ive | \n
Audit committee independence | \nProportion of independent non-executive directors on the audit committee | \nACI | \n+ive | \n
Female directors | \nProportion of female directors on the board | \nFEMDIR | \n+ive | \n
Institutional ownership | \nPercentage of total shares held by institutional investors | \nINSINV | \n+ive | \n
Control variables | \n|||
Firm size | \nNatural logarithm of total assets | \nSIZE | \n+ive | \n
Leverage | \nRatio of total debt to total equity | \nLEV | \n+ive | \n
Profitability | \nReturn on asset | \nROA | \n+ive | \n
Details relevant for the independent variables used in this study.
To test the nature of the relationships proposed in this study, following sets of analyses are performed. These include descriptive statistics, correlation analyses, multiple regression analyses, robustness tests including multicollinearity test and incremental regression analysis. The details of these tests are presented as follows.
\nTable 2 depicts the descriptive statistics of different corporate governance attributes along with control variables investigated to analyze their impact on corporate environmental reporting system. The mean value for board independence which is computed by the percentage of independent non-executive directors to total number of directors on the board is 40%, demonstrating that 40% of the total board members are independent non-executive, aligned with the SECP Corporate Governance Code (2013). The mean value for board size is 8.58 reflecting that larger board has been a conventional practice among Pakistani firms. Moreover, the mean value for independence is 91.2% for the audit committee, imparting the relatively high degree of independence in audit committee. Meanwhile, the mean value for women representation on the board is only 6% with the maximum representation of around 33%. This shows that the firm’s board does not comprise of many female members. Concerning the structure of ownership, it can be observed that the mean value for institutional ownership is 58% exhibiting the fact that institutional ownership represents the major form of block holdings. On the other hand, mean value for leverage and profitability ratio is 2.16 and 4.58% respectively.
\nVariables | \nMean | \nMinimum | \nMaximum | \nStandard deviation | \n
---|---|---|---|---|
ERI | \n43.4 | \n0.00 | \n95.0 | \n27.2 | \n
BS | \n8.58 | \n6.00 | \n15.0 | \n1.93 | \n
BI | \n40.0 | \n25.0 | \n85.1 | \n8.63 | \n
DUAL | \n0.08 | \n0.00 | \n1.00 | \n0.27 | \n
ACI | \n91.2 | \n33.3 | \n100 | \n15.1 | \n
FEMDIR | \n6.22 | \n0.00 | \n33.3 | \n9.05 | \n
INSINV | \n58.1 | \n0.02 | \n100 | \n32.8 | \n
LEV | \n2.16 | \n0.05 | \n7.79 | \n1.94 | \n
ROA | \n4.58 | \n−20.2 | \n24.9 | \n9.70 | \n
Descriptive statistics.
Some exploratory details about the components of the ERI and relevant score by each company are presented in Appendix 1.
\nPairwise correlation coefficients exhibit relationship of corporate environmental reporting to all corporate governance attributes and firm specific variables used in the study and are presented in Table 3. Results indicate a positive association between the extent of environmental reporting and each of board size, independence of board, leverage, profitability and percentage of institutional investors whereas the CEO duality is negatively associated with the level of environmental reporting.
\n\nThe results by using multiple regression analysis presented in Table 4 are explained as follows.
\nThe first hypothesis (H1) proposed that board size is negatively related to the environmental reporting. Contrary to H1, the findings revealed a positive relationship between environmental reporting and the size of a board (p = 0.070). Hence H1 is not sustained. The finding is coherent with various studies [21, 22, 25, 27, 61] who deduced a direct connection between the size of a board and the level of environmental reporting, advocating that larger board acquires the needed skills and incurs more efficient reporting system to ensure sound environmental disclosure.
\nThe result implies that management of the firms needs to have an optimal board size having variety of members from national and multinational organization so that environmental reporting in these firms is sustained. The greater number of board members leads to have rigorous brainstorming and interchange of more ideas which results in economic integration of companies leading to higher globalization.
\nThe second hypothesis (H2) implies that the proportion of independent non-executive directors is positively and significantly linked with the extent of environmental reporting. The results revealed a positive and substantial linkage between environmental reporting and board independence (p = 0.010). Therefore, H2 is supported.
\nThe results are in line with the stakeholder and agency theory argument that voluntary disclosure practices of the firms are more likely to improve with an increase in the percentage of independent non-executive directors. The outcome is in harmony with the inferences of many prior studies [20, 45, 63].
\nThe result implies that the board independence (higher number of independent directors) from national and international organizations lead to independent thinking and incorporation of environmental friendly provisions in the firms. The management of the firms needs to have a higher number of independent directors resulting in higher financial integration and cross investment in the company leading to higher globalization and value for shareholders.
\nThe third hypothesis (H3) suggests a negative relationship between the level of environmental reporting and role duality. Outcome of the H3 is in harmony with the agency theory (p = 0.078), endorsing that separate headship will bring about an improved social and environmental reporting related to the firms. The results of the study are in consonance with the stakeholder-agency theory stating that the separate leadership structure is liable to offer requisite checks and balances and can enhance the efficacy of the board in controlling the management’s actions [58]. This reduces the probability of restraining information outflow and deterring unfavorable information/news from spreading to stakeholders. The result is coherent with [17, 45, 61].
\nThe result implies that a single person holding both the positions is detrimental to the environmental friendly practices and its reporting in the firm. The management of the firms needs to use nondual leadership structure to improve on the environmental reporting as the single dominant person does not let the board members think properly leading to less economic integration and globalization.
\nThe fourth hypothesis (H4) suggests a positive association between the proportion of female directors on the board and the level of environmental reporting. Contrary to the expectation, the results of the model revealed the lack of any significant association among these variables (p = 0.7063).
\nThe fifth hypothesis (H5) recommends a positive and a significant association between independence of audit committee and the level of environmental reporting. The audit committee independence appeared to have no significant association with environmental reporting (p = 0.8245) leading to the rejection of H5. The result is in line with previous evidence provided by the authors in [16, 24].
\nThe final result depicts that institutional investors have a positive and significant impact on environmental reporting (p = 0.0001) leading to the acceptance of H6. The finding is consistent with various studies [12, 25] who deduced a direct connection among institutional ownership and that of environmental reporting, advocating that institutional investors are active owners and influence management and corporate value due to their large ownership stake in the firms. The result shows a positive and constructive role by the blockholders leading to higher level of environmental reporting and economic freedom and globalization. The management of the firm needs to have a healthy relationship with the institutional shareholding so the level of environmental reporting in the firm is improved. The summary of the results for the hypotheses testing are presented in Table 5.
\nVariables | \nPredicted sign | \nCoefficients | \nt-statistics | \nProbability | \nVIF | \n
---|---|---|---|---|---|
C | \n\n | −0.7616 | \n−1.9955 | \n0.0528 | \n\n |
BS | \n— | \n0.0324 | \n1.8593 | \n0.0703 | \n1.34 | \n
BI | \n+ | \n0.8537 | \n2.6796 | \n0.0106 | \n1.13 | \n
DUAL | \n— | \n−0.1811 | \n−1.8038 | \n0.0788 | \n1.13 | \n
ACI | \n+ | \n−0.0401 | \n−0.2231 | \n0.8245 | \n1.11 | \n
FEMDIR | \n+ | \n0.1144 | \n0.3795 | \n0.7063 | \n1.11 | \n
INSINV | \n— | \n0.3612 | \n4.3243 | \n0.0001 | \n1.12 | \n
SIZE | \n+ | \n0.0414 | \n0.9315 | \n0.3572 | \n1.29 | \n
LEV | \n+ | \n0.0334 | \n2.2527 | \n0.0298 | \n1.25 | \n
ROA | \n+ | \n0.0078 | \n2.7889 | \n0.0081 | \n1.12 | \n
R2 | \n0.6369 | \n||||
Adjusted R2 | \n0.5552 | \n||||
D-W statistics | \n2.0229 | \n||||
F-statistics | \n7.7963 & p = 0.000002 | \n
Multiple regression results using (ERI) as the dependent variable.
Hypotheses | \nStatus | \n
---|---|
H1: Board size negatively impacts the level of ER. | \nRejected | \n
H2: Board independence positively impacts the level of ER. | \nAccepted | \n
H3: CEO duality negatively impacts the level of ER. | \nAccepted | \n
H4: Higher percentage of women on the board positively impacts the level of ER. | \nRejected | \n
H5: Audit committee independence positively impacts the level of ER. | \nRejected | \n
H6: Institutional ownership positively impacts the level of ER. | \nAccepted | \n
Results for the hypotheses testing.
The results for the control variables suggest a considerable positive connection among environmental reporting and each of leverage and profitability. The positive connection between leverage and environmental reporting is reported by the authors in [12, 55]. The profitability is significant at 1% level of significance advocating that highly profitable firms disclose additional information regarding environmental activities in their annual reports. Results are consistent with the studies of [4, 10, 18] who deduced a significant positive connection between environmental reporting and profitability.
\nAs discussed before, the robustness tests for the study include multicollinearity and incremental regression analysis. The values of VIF vary from 1.11 to 1.34 showing a lack of substantial multicollinearity problem in our analysis [77]. The results for the incremental regression suggest that removal of the institutional investors’ fraction leads to substantial fall in the value for the R-Squared (from 63 to 46%). The outcome shows that percentage of institutional investors is the most significant independent variable in affecting the level of environmental disclosure. The other diagnostics of the model show that the value for the R-Squared is 0.636 which reveals that 63.6% of the variations in the dependent variable are explained by the independent variables included in the model.
\nThe study primarily intends to scrutinize the association among the certain attributes of corporate governance and the environmental reporting practices of companies in Pakistan for a period of 2014–2015. The findings depicted a substantial connection among environmental reporting practices and attributes of corporate governance. The results highlighted that larger board size, higher proportion of nonexecutive independent directors, partition of the twin positions of the CEO & chairman and institutional ownership (ownership concentration) is related with enhanced environmental disclosure in Pakistan. The overall results supported the corresponding theoretical contention of agency theory and stakeholder theory that sound corporate governance practices serve as monitoring and accountability catalyst and eventually result in more environmental disclosure.
\nThe results of the study suggest that the firms should use the highlighted instruments as powerful tools and be encouraged to produce climate change policy and environmental reports on regular basis to manifest their commitment to sustainable development. The limitations of the study suggest that a longitudinal research with large sample size and a relative analysis of Pakistan with developed market would offer more insights regarding the role of corporate governance practices in affecting environmental reporting.
\nOverall extent of environmental reporting of firms.
\nS# | \n\n | Number of firms reported | \nPercentage | \n
---|---|---|---|
\n | A. Vision and strategy | \n\n | \n |
1 | \nA declaration of firm environmental performance in CEO’s message | \n31 | \n62 | \n
2 | \nA description of environmental philosophy, values, policies and environmental ethics | \n38 | \n76 | \n
3 | \nA narration of a proper managerial systems for environmental operations and risk | \n19 | \n38 | \n
4 | \nA declaration of the regular reviews and assessment of firm’s environmental performance | \n17 | \n34 | \n
5 | \nEnvironmental standards or targets | \n37 | \n74 | \n
6 | \nAn announcement of the measurable objectives regarding future environmental performance | \n25 | \n50 | \n
7 | \nAn indication of specific innovations or latest technologies regarding environment | \n19 | \n38 | \n
\n | B. Environmental profile | \n\n | \n |
8 | \nA comment regarding the firm’s adherence with particular environmental principles or targets | \n26 | \n52 | \n
9 | \nPerformance against environmental targets | \n25 | \n50 | \n
10 | \nMeasures taken to monitor compliance with policy statement | \n21 | \n42 | \n
11 | \nA brief summary of the impact of firm’s activities on environment | \n31 | \n62 | \n
12 | \nA review of how the firm’s activities or products effect the surrounding environment | \n20 | \n40 | \n
13 | \nA comparative analysis of the environmental performance to the other industries | \n13 | \n26 | \n
\n | C. Environmental initiatives | \n\n | \n |
14 | \nA proper statement of employees training sessions to create awareness on environmental issues | \n29 | \n58 | \n
15 | \nA response plan in emergency actions | \n39 | \n78 | \n
16 | \nInternal awards as recognition of environmental performance | \n8 | \n16 | \n
17 | \nInternal audits of firm’s environmental actions | \n18 | \n36 | \n
18 | \nEnvironmental certification by internal body | \n18 | \n36 | \n
19 | \nCommunity participation or environmental donations | \n42 | \n84 | \n
\n | D. Governance structure & management systems | \n\n | \n |
20 | \nDepartment or managerial position for environmental management or controlling pollution | \n21 | \n42 | \n
21 | \nPresence of CSR or environmental committee on the board | \n14 | \n28 | \n
22 | \nA set of principles for suppliers or customers concerning environmental practices | \n13 | \n26 | \n
23 | \nStakeholder participation in deciding environmental strategies | \n25 | \n50 | \n
24 | \nExecutive reward is allied with environmental conduct | \n0 | \n0 | \n
25 | \nTraining sessions for raising environmental awareness | \n34 | \n68 | \n
\n | E. Credibility | \n\n | \n |
26 | \nA declaration of an environmental/ sustainability report | \n16 | \n32 | \n
27 | \nAdherence GRI guiding principles | \n23 | \n46 | \n
28 | \nIndependent and regular audits on environmental operations or environmental certification by third party | \n18 | \n36 | \n
29 | \nCertification of products in connection with environmental influence | \n27 | \n54 | \n
30 | \nEnvironmental recognition awards by external body or nomination in a sustainability catalog | \n19 | \n38 | \n
31 | \nStakeholders participation in environmental reporting process | \n20 | \n40 | \n
32 | \nInvolvement in voluntary activities regarding environment | \n43 | \n86 | \n
33 | \nInvolvement in the operations of specific industry to enhance environmental performance | \n22 | \n44 | \n
34 | \nInvolvement in other organizations to enhance environmental performance | \n31 | \n62 | \n
\n | F. Environmental performance indicators | \n\n | \n |
35 | \nEPl regarding energy consumption or efficiency | \n34 | \n68 | \n
36 | \nEPl regarding water consumption or efficiency | \n24 | \n48 | \n
37 | \nEPl regarding greenhouse discharge | \n22 | \n44 | \n
38 | \nEPl regarding air discharge other than green house | \n23 | \n46 | \n
39 | \nEPl regarding toxic release inventory | \n19 | \n38 | \n
40 | \nEPl regarding additional discharges or emissions | \n15 | \n30 | \n
41 | \nEPl regarding waste management | \n34 | \n68 | \n
42 | \nEPl regarding biodiversity and resource conservation | \n30 | \n60 | \n
43 | \nEPl regarding impacts of industrial products on environment | \n20 | \n40 | \n
44 | \nEPl regarding compliance with environmental targets | \n13 | \n26 | \n
45 | \nEquipment for waste water treatment | \n25 | \n50 | \n
46 | \nRecycling of waste material | \n28 | \n56 | \n
47 | \nLand renovation and forestation plans | \n19 | \n38 | \n
48 | \nPollution management of industrial operations | \n36 | \n72 | \n
49 | \nPreservation Anti-litter operations | \n20 | \n40 | \n
50 | \nIntroduction of new production techniques to lessen pollution | \n24 | \n48 | \n
\n | G. Environmental spending | \n\n | \n |
51 | \nA review of monetary savings from environment programs | \n0 | \n0 | \n
52 | \nEnvironmental Policy | \n7 | \n14 | \n
53 | \nPrevious and current spending on effluence control facilities and apparatus | \n16 | \n32 | \n
54 | \nPrevious and current operating expenses on effluence control apparatus and facilities | \n8 | \n16 | \n
55 | \nFuture assessment of expense for effluence control apparatus and facilities | \n5 | \n10 | \n
56 | \nFunding for effluence control apparatus or facilities | \n34 | \n68 | \n
57 | \nEstimated pattern of potential environmental spending | \n7 | \n14 | \n
58 | \nEstimation of contingent obligations | \n0 | \n0 | \n
59 | \nExpenditure on R& D, technologies or innovations to improve environmental efficiency | \n24 | \n48 | \n
60 | \nPenalties regarding environmental concerns | \n0 | \n0 | \n
Environmental reporting items not reported by any sample company.
\nSI no. | \nEnvironmental reporting items | \n
---|---|
24 | \nExecutive reward is allied with environmental conduct | \n
51 | \nA review of monetary savings from environment program | \n
58 | \nEstimation of contingent obligations | \n
60 | \nPenalties regarding environmental affairs | \n
Ranking of companies on the basis of environmental disclosure scores.
\nS# | \nCompany name | \nNo. of items disclosed | \n% | \nRanking | \n
---|---|---|---|---|
1 | \nK-Electric Limited | \n57 | \n95.00 | \n1 | \n
2 | \nI.C.I. Pakistan Limited | \n53 | \n88.33 | \n2 | \n
3 | \nMurree Brewery Company Limited | \n51 | \n85.00 | \n3 | \n
4 | \nAtlas Honda Limited | \n50 | \n83.33 | \n4 | \n
5 | \nFauji Fertilizer Company Limited | \n49 | \n81.67 | \n5 | \n
6 | \nEngro Fertilizers Limited | \n48 | \n80.00 | \n6 | \n
7 | \nSiemens Pakistan Engineering Co. Limited | \n47 | \n78.33 | \n7 | \n
8 | \nGlaxoSmithKline (Pakistan) Limited | \n46 | \n76.67 | \n8 | \n
9 | \nPakistan Refinery Limited | \n45 | \n75.00 | \n9 | \n
10 | \nPakistan International Airlines Corporation | \n45 | \n75.00 | \n9 | \n
11 | \nUnilever Pakistan Foods Limited | \n44 | \n73.33 | \n11 | \n
12 | \nPakistan Tobacco Company Limited | \n43 | \n71.67 | \n12 | \n
13 | \nNestle Pakistan Limited | \n42 | \n70.00 | \n13 | \n
14 | \nSui Northern Gas Pipelines Limited | \n40 | \n66.67 | \n14 | \n
15 | \nEngro Foods Limited | \n40 | \n66.67 | \n14 | \n
16 | \nHub Power Company Limited | \n36 | \n60.00 | \n16 | \n
17 | \nPakistan National Shipping Corporation Limited | \n34 | \n56.67 | \n17 | \n
18 | \nMaple Leaf Cement Factory Limited | \n32 | \n53.33 | \n18 | \n
19 | \nFecto Cement Limited | \n31 | \n51.67 | \n19 | \n
20 | \nService Industries Limited | \n30 | \n50.00 | \n20 | \n
21 | \nTreet Corporation Limited | \n29 | \n48.33 | \n21 | \n
22 | \nKohinoor Industries Limited | \n28 | \n46.67 | \n22 | \n
23 | \nGul Ahmed Textile Mills Limited | \n27 | \n45.00 | \n23 | \n
24 | \nNishat Mills Limited | \n26 | \n43.33 | \n24 | \n
25 | \nPakistan Cables Limited | \n25 | \n41.67 | \n25 | \n
26 | \nBata Pakistan Limited | \n24 | \n40.00 | \n26 | \n
27 | \nBannu Woolen Mills Limited | \n23 | \n38.33 | \n27 | \n
28 | \nMillat Tractors Limited | \n23 | \n38.33 | \n27 | \n
29 | \nOil and Gas Development Company Limited | \n42 | \n70.00 | \n29 | \n
30 | \nDawood Hercules Corporation Limited | \n21 | \n35.00 | \n30 | \n
31 | \nPakistan Services Limited | \n20 | \n33.33 | \n31 | \n
32 | \nNational Foods Limited | \n19 | \n31.67 | \n32 | \n
33 | \nCherat Packaging Limited | \n18 | \n30.00 | \n33 | \n
34 | \nAisha Steel Mills Limited | \n17 | \n28.33 | \n34 | \n
35 | \nBerger Paints Pakistan Limited | \n16 | \n26.67 | \n35 | \n
36 | \nPakistan Paper Products Limited | \n13 | \n21.67 | \n36 | \n
37 | \nRupali Polyester Limited | \n12 | \n20.00 | \n37 | \n
38 | \nShabbir Tiles and Ceramics Limited | \n11 | \n18.33 | \n38 | \n
39 | \nMitchells Fruit Farms Limited | \n10 | \n16.67 | \n39 | \n
40 | \nDewan Farooque Motors Limited | \n9 | \n15.00 | \n40 | \n
41 | \nPakistan Telecommunication Company Limited | \n8 | \n13.33 | \n41 | \n
42 | \nAdam Sugar Mills Limited | \n8 | \n13.33 | \n41 | \n
43 | \nJubilee Spinning and Weaving Mills Limited | \n7 | \n11.67 | \n43 | \n
44 | \nGadoon Textile Mills Limited | \n6 | \n10.00 | \n44 | \n
45 | \nDewan Cement Limited | \n5 | \n8.33 | \n45 | \n
46 | \nShield Corporation Limited | \n5 | \n8.33 | \n45 | \n
47 | \nDawood Lawrancepur Limited | \n4 | \n6.67 | \n47 | \n
48 | \nDewan Textile Mills Limited | \n3 | \n5.00 | \n48 | \n
49 | \nBilal Fibers Limited | \n2 | \n3.33 | \n49 | \n
50 | \nOlympia Textile Mills Limited | \n0 | \n0.00 | \n50 | \n
Years | \nInflation rate% | \nGDP (annual growth rate)% | \nInterest rate % | \n
---|---|---|---|
2012 | \n9.73 | \n3.8 | \n7.98 | \n
2013 | \n7.68 | \n3.71 | \n7.17 | \n
2014 | \n7.23 | \n4.1 | \n7.26 | \n
2015 | \n2.53 | \n4.1 | \n5.97 | \n
2016 | \n3.76 | \n4.5 | \n4.83 | \n
Source: Economic Survey and other web sources.
Neurotic disorders (NDs) are among the most common mental diseases leading to a decrease in the quality of life, lack of socialization, and increased mortality [1]. Around 20–40% of primary care outpatients are diagnosed with NDs according to International Disease Classification (ICD)-10 or Diagnostic and Statistical Manual of Mental Disorders (DSM) V criteria [2].
ICD-10 classification of the NDs F40–F48 includes phobic anxiety disorders (F40), other anxiety disorders (AD, F41), obsessive-compulsive disorder (OCD, F42), reaction to severe stress, adjustment disorders (F43), dissociative and conversion disorders (F44), somatoform disorders (SD, F45), and other nonpsychotic mental disorders (F48). In the DSM V, the same disorders are classified as Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related Disorders, Dissociative Disorders, and Somatic Symptom Disorder [3, 4].
Phobias are present in 1.3–5.7% of all NDs [5]. Anxiety symptoms are thought to occur in every 14th person during the lifetime [6]. The prevalence of SD is 20–25%, but at least one medically unexplained symptom is found in 40–49% of patients [7, 8]. Around 10% of all psychiatric patients have dissociative disorder [9, 10]. A lifetime prevalence of OCD is 2.3%, and the rate of adjustment disorder is 1–2% [5].
The overlaps between AD, phobias, and SD were shown and considered a result of similarity of pathogenesis, which involves disturbances in hypothalamic-pituitary-adrenal axis (HPAA), cytokine levels, and changes in the state of receptors in the nervous system [11, 12, 13, 14, 15]. Continued and prolonged stress may disturb the HPAA to such an extent that the negative feedback mechanisms (glucocorticoid negative feedback, in particular) are disrupted, and the adaptive responses of the HPAA may then become maladaptive. Enhanced proinflammatory cytokine production and overactivation of the sympathetic nervous system contribute to a state of chronic low-grade inflammation.
NDs have a great social impact. A British survey (1993) reported that 8.3% of 10,000 responders had ND limiting their daily activities and 3.4% experienced severe “disabling” NDs, associated with a higher chance of being unemployed [16]. The cost of AD treatment in the European Union was approximately 41 billion € in 2004 and 66 billion € in 2010 [17, 18]. Taking into consideration the prediction of the growing influence of mental health problems on the economic output by 2030 [19], we expect the increasing burden of NDs.
The diagnosis and treatment of all types of NDs are challenging. More than 20% of AD patients are undertreated and continue to suffer from symptoms [11]. A study by Wang revealed a 2–3-year delay in the diagnosis of NDs [20]. Around 40–66% of SD cases are underdiagnosed in primary care [21]. The first line of treatment for most of NDs is selective serotonin reuptake inhibitors (SSRIs). Nevertheless, their efficacy and safety are still under consideration. The high placebo effect was shown in randomized controlled studies of SSRI in the treatment of phobic disorder, OCD, and generalized anxiety disorder (GAD) [22]. There are only 40–60% of responders to first-line therapy among OCD patients [23]. In the Cochrane review by Kleinstaeuber et al., low-quality evidence for the efficacy of new generation antidepressants in SD was obtained [24]. Adverse events such as insomnia, nausea, sexual dysfunction, and withdrawal are common for SSRI. Negative drug interactions are also limiting their use in patients receiving therapy for somatic diseases. Other antidepressant drugs such as tricyclic antidepressants (TCA) have been shown to be effective for the treatment of some NDs in several trials, although the Cochrane review did not reveal any significant differences in the comparison of tricyclic antidepressants (TCA) and other medications in SD [24]. The safety profile of TCA is more unfavorable than SSRI. The use of benzodiazepines in ADs is limited due to the sedation, myorelaxant effect, and negative impact on cognition they provoke in long-term use. Among nonpharmacological treatments, only cognitive behavioral therapy was shown to be effective with greater results in combination with medication [22].
In the light of the ongoing search for an effective and safe therapeutic strategy influencing certain aspects of ND pathogenesis, technologically processed highly diluted antibodies to the brain specific S100 protein (TP Abs to S100) seem to be a perspective substance for treatment.
In the central nervous system (CNS), the brain-specific S100 protein is synthesized mainly by astrocytes and then transported to neurons where it is involved in numerous processes. In particular, it was shown that S100 affects the differentiation and survival of neurons, the growth of dendrites, the integrity of cytoskeleton, and energy metabolism [25].
Increased level of S100 is considered a marker of blood brain barrier failure. S100 serum levels are elevated after stroke, subarachnoid hemorrhage, and brain trauma and correlate positively with patient outcome. However, the brain-specific S100 protein may be secreted peripherally, and its elevated serum levels are also found in heart diseases and infections. High serum levels of the brain-specific S100 protein are also found in patients with schizophrenia, depressive/bipolar disorders, and obesity, but which cells are the sources of S-100 protein in these conditions is unknown [25, 26].
A number of nonclinical studies of TP Abs to S100 efficacy, safety, and mechanisms of action using the commonly applied experimental in vivo and in vitro models preceded clinical investigation. While studying the drug’s primary and secondary pharmacodynamics, it was shown that TP Abs to S100 exert stress-protective [27], anxiolytic [28, 29, 30, 31, 32, 33], antidepressant [30, 31, 34], antiamnestic [35, 36, 37], and neuroprotective [38, 39] activities.
Target identification and mechanism-of-action studies revealed that the drug recruits serotonin-, dopamine-, GABA-, noradrenaline-, and glutamatergic systems [29, 30, 40, 41, 42] and thereby might be considered a player in various neurotransmitter-mediated processes. Moreover, TP Abs to S100 influence sigma1 receptor [41] that in turn modulates the activity of almost all neurotransmitter systems and thereby possesses a spectrum of psychotropic activities [43, 44].
Data on the TP Abs to 100 mechanisms of action and identified pharmacodynamics of the drug are consistent with the literature data on the relationship between influencing certain neurotransmitter systems (their receptors) and observing subsequent psychotropic effects. For example, it is known that benzodiazepines mediate their anxiolytic activity and sedation via GABAA receptors [45, 46]. GABAB receptor agonists are known to attenuate the behavioral deficit-restoring effect of antidepressants [47, 48]. Ligands of 5-HT1A, 5-HT1B, 5-HT1F, 5-HT2а, 5-HT2B, 5-HT2C, and 5-HT3 receptors were shown to regulate aggression, anxiety, learning, addiction, locomotion, memory, mood, and so on [49]. Ligands of the glycine site of the NMDA receptor exhibit anxiolytic and antidepressant properties and impact memory-related processes [50, 51, 52, 53, 80]. D3 receptor deficiency can result in chronic depression and anxiety [54]. Sigma1 receptor ligands have a whole spectrum of psychotropic effects due to their modulating effect on all major neurotransmitter systems [43, 44], which also are in line with TP Abs to S100 mechanism of action.
More than 2000 patients with GAD (F41.1), SD (F45), adjustment disorders (AjDs) (F43.2), neurasthenia (F48.0), and anxiety accompanying somatic diseases (cardiovascular and gastrointestinal disorders) took part in phase III, IV, and post-marketing clinical trials (CTs) of TP Abs to S100, including two double-blind placebo-controlled randomized CTs and nine open-label comparative randomized CTs [55, 56, 57]. TP Abs to S100 were shown to be as effective as clonazepam 0.5–1 mg/day, bromdihydrochlorphenylbenzodiazepine 1.5 mg/day (for 7 days), and tofisopam 100 mg/day but causing less adverse events (AEs) [58, 59, 60].
The evidence on the safety of TP Abs to S100 was obtained in clinical and nonclinical trials. In CTs, TP Abs to S100 exerted less AEs typical for other antianxiety medications such as daytime sleepiness and muscle relaxation. No cases of withdrawal symptoms, addiction to TP Abs to S100, or negative drug interactions have been registered up-to-date. In nonclinical trials, no myorelaxant and toxic effects were observed.
In the current review, we describe the mechanisms of action and pharmacological effects of TP Abs to S100 demonstrated in nonclinical (preclinical) and clinical studies. Based on the data, we attempt to evaluate the future perspectives of the TP Abs to S100 as the drug of choice for ND treatment.
Antistress activity of TP Abs to S100 was studied using three approaches.
Negative emotions arising from stress caused by the anticipation of pain or other negative expectations (in particular, on the eve of surgical operations, educational tests, important meetings, etc.) are accompanied by anxiety and fear. Concurrently, a cascade of somato-vegetative manifestations of stress is initiated [61].
Modeling of a conditioned emotional reflex to unescapable electric pain stimulation was performed on outbred white male rats weighing 220–280 g [27]. This was followed by monitoring of animal behavior in a stressful situation (repeated placement in an experimental ‘dangerous’ camera) as well as emotional responses when stress was intensified by an additional negative provocation (approaching an unfamiliar object to the animal’s head). Antistress activities of TP Abs to S100 and diazepam (‘classical’ benzodiazepine tranquilizer, positive control) were estimated by administering drugs one day after development of the conditioned reflex.
Rats in the control group (hereinafter, animals that received distilled water as a placebo) when they were subsequently placed in a “dangerous” chamber responded by freezing (45%) or actively trying to escape the chamber (35%) (Table 1A). Only 20% of rats showed calm behavior. At the same time, somato-vegetative manifestations of stress were observed in animals (especially with a passive reaction): increased frequency of breathing, urination, defecation, and squeaking. Both TP Abs to S100 and diazepam caused a decrease in the number of rats with a passive and active response to stress, as well as significantly (three times) increased the number of animals with a calm orientation-exploratory activity. Somato-vegetative manifestations of stress also dissipated in both groups.
Parameter | [A] Stress induced by anticipation of pain | [B] Stress induced by anticipation of pain with additional negative stimulation | ||||
---|---|---|---|---|---|---|
Control | Diazepam | TP Abs to S100 | Control | Diazepam | TP Abs to S100 | |
Percent of animals with: | ||||||
Passive behavior (freezing) | 45 | 35 | 25* | 55 | 45 | 15* |
Active behavior with attempts to get out of the chamber | 35 | 5* | 15* | 40 | 5* | 20* |
Calm exploratory behavior | 20 | 60* | 60* | 5 | 50* | 65* |
Freezing in response to provocation | n/a | n/a | n/a | 55 | 45 | 15* |
Aggression in response to provocation | n/a | n/a | n/a | 40 | 15 | 10* |
Hurried breathing | 55 | 35 | 25* | 75 | 40 | 35* |
Frequency (%) of: | ||||||
Squeaking | 25 | 5* | 5* | 45 | 20* | 25* |
Fecal boluses | 50 | 25* | 25* | 65 | 25* | 45 |
Urinations | 35 | 25 | 25 | 60 | 25* | 25* |
TP Abs to S100 antistress activity in a model of a conditioned emotional reflex to unescapable electric pain.
р < 0.05 versus corresponding control.Bold entries were made to emphasize the results in TP Abs to S100 group.
Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg), or diazepam (1 mg/kg) at a single dose 30 minutes prior to testing. n/a, not applicable; TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
The emotional reaction of anxiety and anxiety associated with the expectation of pain in a “dangerous” chamber was significantly enhanced when using additional provocation—bringing an unfamiliar object to the head of the animal. This was manifested as an increase in the number of rats with active (up to 40%) and passive (up to 55%) behavior and a decrease in the number of animals with calm behavior (down to 5%) (Table 1B). Respiratory symptoms, squeaking, frequency of defecation, and urination also increased. Both drugs (TP Abs to S100 and diazepam) reduced the severity of stress induced by expectation of pain. TP Abs to S100 reduced both the number of animals with a spontaneous active and passive reaction by 20%, while diazepam reduced the number of animals with active attempts to escape the chamber (by 35%) more than the number of animals with freezing (only by 10%). The same trend continued with additional negative provocation, which may be the result of the sedative activity of diazepam, which TP Abs to S100 do not have.
It is known that immediate-early response c-fos gene expression in the hypothalamic paraventricular nucleus is one of the primary biological markers of stress [62]. The effectiveness of stress-protective compounds can be assessed by their ability to suppress c-fos expression in the brain.
The study was conducted on male Wistar rats weighing 250–280 g [63], classified as active or passive (stress-resistant or predisposed to stress, respectively) in the open field (OF) test [64]. The OF test is widely used to study the behavior of rats [65]: animals are placed in the center of the OF arena and the horizontal and vertical activity, the number of entries into the center zone, as well as the number of acts of defecation and urination (emotionality) is recorded.
Rats were administered TP Abs to S100 or imipramine (antidepressant drug that modulates c-fos expression) and then subjected to 1-hour immobilization with simultaneous electrocutaneous irritation. Immunohistochemical detection of c-Fos protein in the parvocellular neurons of the paraventricular nucleus of the hypothalamus was performed in samples obtained 90 min after the procedure, at the peak of the protein expression [62].
In response to stress, c-Fos protein level significantly increased (vs. intact animals) in both active and passive animals (20–25 fold), and in the latter, this increase was more pronounced (Figure 1). TP Abs to S100 and imipramine demonstrated equally and pronounced antistress activity in passive animals: 1.2- and 1.5-fold decrease in the number of Fos-positive cells was observed, respectively.
TP Abs to S100 effect on c-Fos protein expression (stress marker) in the rat hypothalamic paraventricular nucleus after 1-hour immobilization with simultaneous electrocutaneous irritation. Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg) or imipramine (12 mg/kg) at a single dose or for 20 days preceding stress exposure. Data are expressed as M ± SD. *р < 0.05 (#р < 0.001) versus corresponding control. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
Another important biological marker of stress is development of ulcers in the gastric mucosa. For example, it is known that immobilization stress is accompanied by severe gastric ulceration [66].
The study of antistress activity of TP Abs to S100 was carried out on male Wistar rats weighing 250–280 g, classified as active or passive in the OF test [67]. Animals were administered TP Abs to S100 at a dose of 2.5 ml/kg for 5 consecutive days or placebo. On the 6th day, half of the rats from each group were immobilized by fixing their paws on a special platform for 1 h, and then the number of animals with ulcers and total number of ulcers formed in the stomach was counted.
TP Abs to S100 decreased by 33.4% the number of animals with ulcers in the group of passive (but not active) rats, which complements the previously obtained results on the higher efficacy of the drug in passive, highly sensitive to stress animals.
TP Abs to S100 also reduced the total number of ulcers in both groups by more than 50%. Again, in control passive animals, there were 1.3 times more ulcers than in control active ones. However, after TP Abs to S100 administration, there was no such difference.
The studies were carried out on outbred white male rats weighing 230–250 g [31] using the most widely validated tests (the Vogel conflict test, the elevated plus maze test, and the OF test) [65]. The activity of TP Abs to S100 was compared to diazepam.
The conflict situation in the Vogel test was created by exposing animals to opposing behavioral tendencies: motivation to drink and fear, when every attempt to drink was punished by an electric shock. This lead to a significant reduction in water consumption. Drugs with anxiolytic properties alter behavior and cause an increase in drinking.
To study the activity of TP Abs to S100, depending on the individual reaction to stress, animals were grouped into highly (stress-resistant) and low active (predisposed to stress) in the forced swim test with water wheel (Nomura test), in which stress is modeled, and asthenia and depressive behavior are evaluated. Then, animals were treated with TP Abs to S100 or diazepam, and the Vogel conflict test was performed.
Anxiolytic effect of TP Abs to S100 was not inferior to that of diazepam: the number of punished water intakes in highly active groups increased by 27.4 and 28.7%, respectively (Figure 2). Meanwhile, in low-activity animals characterized by a predisposition to asthenia and depressive behavior [64], TP Abs to S100 efficacy was superior to diazepam (2.8 and 2 times vs. control, respectively). The data obtained indicate that in addition to the anxiolytic activity TP Abs to S100 have an antiasthenia activating effect, which distinguishes them from diazepam that induces both anxiolytic and sedative effects.
TP Abs to S100 demonstrate anxiolytic activity in the Vogel conflict test. Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg) or diazepam (2 mg/kg) at a single dose 30 minutes prior to testing. Data are expressed as M ± SD. *р < 0.05 versus corresponding control. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
The elevated plus maze test is based on the fear of heights and open spaces: animals are placed on the central platform of the maze and the latent period before the first entry into the open arms, the number of full and incomplete entries and the duration of stay in them, as well as the number of head dips below the level of the open arms is recorded.
It was established that TP Abs to S100 and diazepam had a similar anxiolytic effect in this test: both drugs increased the number of entries into the open arms (1.9 and 2.3 times, respectively), the time spent in the open arms (5.4 and 7 times), as well as the number of head dips (5 and 9 times) versus control animals (Table 2).
Parameter group | Number of entries into open arms | Number of entries into enclosed arms | Time spent in open arms, sec | Number of head dips |
---|---|---|---|---|
Control | 1.1 ± 0.55 | 2.8 ± 0.65 | 12.1 ± 8.15 | 0.5 ± 0.43 |
Diazepam | 2.6 ± 0.80* | 1.5 ± 0.8 | 85.3 ± 38.5* | 4.5 ± 1.12* |
TP Abs to S100 | 2.1 ± 0.42* | 2.3 ± 0.48 | 65.4±27.5* | 2.4 ± 0.95* |
TP Abs to S100 anxiolytic activity in the elevated plus maze test.
р < 0.05 versus control.Bold entries were made to emphasize the results in TP Abs to S100 group.
Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg), or diazepam (2 mg/kg) at a single dose 30 minutes prior to testing. Data are expressed as M ± SD. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
In the OF test, the antianxiety activity of TP Abs to S100 and diazepam was demonstrated by the fact that rats began to go to the center of the field, which was not observed in the control group (Table 3). However, unlike diazepam, which reduced the horizontal activity of animals by 1.5 times, TP Abs to S100 did not change this parameter and, therefore, did not have a sedative effect.
Parameter group | Number of entries into the arena center | Horizontal activity | Vertical activity | Exploratory activity |
---|---|---|---|---|
Control | 0 ± 0 | 18.2 ± 2.4 | 8.2 ± 3.3 | 11.1 ± 3.1 |
Diazepam | 1.8 ± 0.9* | 12.5 ± 1.8* | 6.2 ± 1.4 | 8.7 ± 1.5 |
TP Abs to S100 | 2.4 ± 0.7* | 15.8 ± 2.1 | 5.8 ± 2.6 | 8.9 ± 1.6 |
TP Abs to S100 anxiolytic activity in the open field test.
р < 0.05 versus control.Bold entries were made to emphasize the results in TP Abs to S100 group.
Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg), or diazepam (2 mg/kg) at a single dose 30 minutes prior to testing. Data are expressed as M ± SD. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
Anxiety disorders are often accompanied by covert or overt aggression. The antiaggressive activity of TP Abs to S100 was studied in the tests of motivated and unmotivated aggression on outbred adult white male rats weighing 200–250 g in comparison with diazepam [68].
In the test of unmotivated aggression caused by inescapable shock, the threshold of aggressive response of a pair of animals placed on a grid floor was determined by increasing the stimulating current. Animals manifested shock-elicited aggression when they assumed upright “boxing” posture and tried to bite and strike each other with front and hind paws.
TP Abs to S100 and diazepam after a single dose and course administration exerted antiaggressive activity: single TP Abs to S100 administration increased the threshold of aggressive response by 23.1%, and after a 4-day administration—by 31.3% compared with the control, while diazepam increased this threshold by 26.3 and 34.9%, respectively (Figure 3).
TP Abs to S100 and diazepam effects on rat’s aggressive reaction parameters in the tests of motivated and unmotivated aggression. Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg) or diazepam (2 mg/kg) at a single dose or for 5 days (2 times per day) prior to testing. Data are expressed as M ± SD. *р < 0.05 versus corresponding control. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
The test of motivated aggression is based on the study of the intensity of the aggressive reaction elicited in a pair of rats trying to escape electric shock. Rats were individually taught to avoid pain caused by electric irritation of the paws on a safe bench installed in the center of the chamber. Then, they were placed in pairs in the chamber, and their behavior was observed for 2 min. Control animals began to fight for a safety on the bench, which had a capacity to tightly fit both animals. The criterion for the effectiveness of substances with antiaggressive action in this test was the duration of joint avoidance of pain exposure.
TP Abs to S100 and diazepam had a pronounced antiaggressive effect, increasing the duration of joint avoidance: with a single dose, respectively, 3.4 and 3.1 times, and with a course—3.8 and 3.3 times (Figure 3).
Along with the above-described activities (stress-protective and anxiolytic), TP Abs to S100 were shown to exert:
antidepressant effect in Porsolt’s and Nomura’s forced swimming tests [30, 31, 34];
antiamnestic and neuroprotective effects in the models of ischemic and hemorrhagic stroke [35, 36, 37, 38, 39], multiple sclerosis [69], Alzheimer\'s disease [36], attention deficit hyperactivity disorder [37], and in vitro glucose and oxygen deprivation [70].
TP Abs to S100 belong to a novel class of drugs that are produced from various antibodies (drug substances) using a single technological platform. This technology allows to obtain active pharmaceutical ingredients that, while retaining antibody specificity (targeting), exert a modulating effect on the target and its biological activity [71, 72, 73]. As the endogenous target of TP Abs to S100 is the brain-specific protein S100 that can influence functional activity of GABA-, serotonin-, dopamine-, noradrenaline-, and glutamatergic systems and sigma1 receptors [74, 75, 76, 77, 78], these CNS elements had been studied while screening TP Abs to S100 mechanisms of action (Figure 7). For this purpose, various in vivo and in vitro approaches have been used (including the in vitro assessment of receptor’s functional activity providing the validated protocols existed).
To assess the role of this system in the implementation of TP Abs to S100 anxiolytic effect, GABA-A receptors were selectively blocked, and the behavior of animals was evaluated in the Vogel conflict test [29].
The study was performed on outbred white male rats weighing 230–250 g. Before testing, animals were administered TP Abs to S100 or diazepam. For blockade of the GABA-A receptors and the chloride channel of the GABA-benzodiazepine receptor complex, bicuculline and picrotoxin, respectively, were administered simultaneously with the tested drugs.
With blockade of the GABA-A receptor, a 1.8-fold decrease in the anticonflict effect of TP Abs to S100 was observed, and a 2-fold decrease with diazepam; with blockade of the chlorine channel—1.6 and 2.4-fold decrease, respectively (Figure 4). The data obtained indicate the involvement of the abovementioned subunits of the GABA-benzodiazepine-chloride ionophore receptor complex in the implementation of the anxiolytic effect of TP Abs to S100.
Influence of GABA-A-ergic agents on anxiolytic activity of TP Abs to S100 and diazepam in the Vogel conflict test. Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg) or diazepam (2 mg/kg) at a single dose alone or simultaneously with GABA-A receptor antagonist bicuculline (1 mg/kg) or GABA-benzodiazepine receptor complex chloride channel blocker picrotoxin (1 mg/kg) 30 minutes prior to testing. Data are expressed as M ± SD. * р < 0.05 versus control, # р < 0.05 versus TP Abs to S100 or diazepam. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
In this experiment, GABA-B receptors were selectively stimulated or blocked and anxiolytic or antidepressant effects of TP Abs to S100, diazepam and amitriptyline were evaluated in the Vogel conflict test and the Nomura test [40].
Outbred white male rats weighing 200–250 g were pretreated with baclofen, a selective agonist of GABA-B receptors, or phaclofen, an antagonist of GABA-B receptors. Then, the animals were administered test drugs, and their effect was evaluated.
In the Vogel conflict test, baclofen reduced the anxiolytic effect of TP Abs to S100 by 2.2-fold and did not affect the effect of diazepam. Phaclofen increased the anxiolytic effect of TP Abs to S100 by 1.4-fold (Figure 5). Moreover, as expected, none of the ligands influenced the effect of diazepam.
Influence of GABA-В-ergic agents on anxiolytic and antidepressant activity of TP Abs to S100, diazepam, and amitriptyline in the Vogel conflict test and the Nomura test. Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg), diazepam (2 mg/kg), or amitriptyline (10 mg/kg) at a single dose. GABA-B receptors agonist baclofen (1 mg/kg) or antagonist phaclofen (10 mg/kg) were intraperitoneally administered 40 min prior to testing and 10 min prior to the administration of the drugs. Data are expressed as M ± SD. * р < 0.05 versus control, # р < 0.05 versus TP Abs to S100. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
In the forced swim test, baclofen and phaclofen reduced the antidepressant effect of TP Abs to S100 by 1.5 and 2-fold, respectively, whereas these ligands did not affect the effectiveness of amitriptyline.
Thus, it was shown that the GABA-B-ergic system is involved in the realization of both the anxiolytic and antidepressant effects of TP Abs to S100.
In an in vitro study, the ability of TP Abs to S100 to influence binding of the standard radioligands to the corresponding GABA receptors and to change the effect of the standard GABA-B1А/B2 receptor agonist (using functional analysis—measuring [35S]GTPγS incorporation into G-proteins) was investigated [41]. The study was performed on the cell membranes of Chinese hamster cells (CHO) and human embryonic kidney cells (HEK293) that expressed human recombinant GABA-B1А/B2 receptors.
In the presence of TP Abs to S100, a 25.8% decrease in standard ligand binding to GABA-B1А/B2 receptor was observed, as well as 30.2% inhibition of the GABA-B1A/B2 receptor\'s agonist-induced response was observed.
Similarly, this hypothesis was studied in experiments in vivo and in vitro.
For the in vivo experiments, ketanserin, a blocker of 5-НТ2/5-НТ1С receptors involved in the development of both anxiety and depression, and the 5HT precursor, 5-hydroxytryptophan (5HTP), were used [79].
The anxiolytic effect of TP Abs to S100 was studied using the Vogel conflict test [30]. The antidepressant effect of the drugs was determined using the Nomura test [30]. Outbred white male rats weighing 200–250 g were pretreated with ketanserin or 5HTP, and before testing, they received a single dose of TP Abs to S100 or diazepam.
Ketanserin and 5HTP reduced both anxiolytic (2 and 1.3-fold, respectively) and antidepressant effects of TP Abs to S100 (2- and 1.6-fold, respectively) (Figure 6).
Influence of serotoninergic agents on anxiolytic and antidepressant activity of TP Abs to S100, diazepam, and amitriptyline in the Vogel conflict test and the Nomura test. Note: animals were intragastrically administered distilled water (2.5 ml/kg, control), TP Abs to S100 (2.5 ml/kg), diazepam (2 mg/kg), or amitriptyline (15 mg/kg) at a single dose. 5-НТ2 receptors antagonist ketanserin (1 mg/kg) or the serotonin precursor 5-hydroxytryptophan (5-HTP, 50 mg/kg) were intraperitoneally administered 40 min prior to testing and 10 min prior to administration of the drugs. Data are expressed as M ± SD. * р < 0.05 versus control, # р < 0.05 versus TP Abs to S100. TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
Thus, it was demonstrated that the 5HT system is involved in the realization of both the anxiolytic and antidepressant effects of TP Abs to S100.
In an in vitro study, the ability of TP Abs to S100 to influence binding of standard radiolabeled ligands to the corresponding 5HT receptors and the ability to change the magnitude of the effect on binding of standard ligands to their receptors were tested. The latter was investigated using a functional analysis of the binding of [35S]GTPγS, calcium mobilization assay, and dielectric spectroscopy or by measuring the intracellular concentration of cAMP using HTRF (Homogenous Time Resolved Fluorescence) technology. The experiments were performed on CHO cells stably expressing human 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F, 5HT2A, 5HT2B, 5HT2Cedited, 5HT3, 5HT4, 5HT6, or 5HT7 receptors [41].
TP Abs to S100 increased binding of the corresponding standard ligands to 5HT1A (19.0%), 5HT1F (42.0%), 5HT2B (31.9%), 5HT2Cedited (49.3%), and 5HT3 (20.7%) receptors. Moreover, the drug enhanced the effect of 5HT1A receptor agonist by 27.8% and reduced the effect of 5HT1B receptor agonist by 27.5%.
The in vitro experiment was carried out similar to the study of the effect of TP Abs to S100 on dopamine receptors [41].
The study was performed on CHO, HEK293, and pituitary rat tumor cells (GH4) stably expressing human D1, D2L, D2S, D3, D4.4 or D5 receptors.
TP Abs to S100 increased binding of the standard ligand to the human D3 receptor by 26.3% and reduced the effect of an agonist of this type of receptor by 32.8%.
In this study that was performed in vitro using rat cerebral cortex cells, TP Abs to S100 significantly reduced binding of the standard radiolabeled ligand to the glycine site of NMDA receptors [80].
The study was carried out in vitro using MCF-7 or Jurkat cells [41].
TP Abs to S100 significantly (by 24.7–56.7%) reduced binding of the standard radiolabeled ligand to human sigma1 receptors (Figure 7).
Schematic representation of TP Abs to S100 mechanisms of action. Note: TP Abs to S100 (technologically processed highly diluted antibodies to S100 protein) molecular target—brain-specific S100 protein. This protein is secreted mainly by astrocytes in the CNS and considered to be an important regulator of many intracellular and extracellular processes (e.g., protein phosphorylation, activity of various enzymes, the dynamics of cytoskeleton components, binding of transcription factors, calcium homeostasis, cell proliferation and differentiation, generation and transmission of nerve impulses, and synaptic transmission [81]). Moreover, S100 proteins interact with almost every neurotransmitter system (serotonin-, dopamine-, GABA-, glutamatergic, etc.) and sigma1 receptors [74, 75, 76, 77, 78]. TP Abs to S100 possess their pharmacological effects via modulating activity of brain-specific S100 protein and influencing functions of the major neurotransmitter systems as well as sigma1 receptors. In vivo studies [29, 40] revealed 5-HT2a, GABAA, and GABAB receptor involvement in the drug psychotropic effects. Also, the drug was shown to normalize noradrenaline level [82]. In vitro studies [41, 42] have shown that TP Abs to S100 increase standard radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, NMDA, and D3 receptors. In addition, the drug inhibits binding of specific radioligands to GABAB1A/B2 and sigma1 receptors and exerts antagonism at GABAB1A/B2, 5-HT1B, and D3 receptors and agonism at 5-HT1A receptor. The above listed TP Abs to S100 activities at the molecular level are involved in maintaining both emotional and physiological homeostasis, and thereby, the drug exerts its stress-protective, anxiolytic, antiamnestic, antidepressant, neuroprotective, and other activities.
The study was performed on outbred white male rats weighing 230–250 g. Prior to testing (in OF test), animals were administered TP Abs to S100 or diazepam. The sedative effect was evaluated by a decrease in the horizontal activity of rats [7].
TP Abs to S100 did not decrease the motor activity of animals, while diazepam decreased this parameter by 1.5 times.
This activity was investigated in the rotarod test on outbred white male rats weighing 230–250 g [33]. Before testing, animals were administered TP Abs to S100 or diazepam. Then, the time before falling off the rotating rod and the number of rats that fell off were recorded.
TP Abs to S100 did not affect the coordination of movements and did not have a muscle relaxant effect. In contrast, only 30% of rats from diazepam group were able to keep balance.
The drug safety investigation was performed in accordance with principles of Good Laboratory Practice. It included studies of the single and repeat dose toxicities, genotoxicity, reproductive and developmental toxicity, immunotoxicity, and local tolerance.
TP Abs to S100 exerted no toxic effects even at a dose significantly exceeding the human recommended daily dose. The drug was shown to be well tolerated and thereby considered to be a low-hazard substance.
To date, 453 patients with AD, AjD, and neurasthenia took part in double-blind randomized controlled CTs (n = 2), and open-label comparative randomized CTs (n = 4) conducted in the Russian Federation and Kazakhstan according to International Conference on Harmonisation Good Clinical Practice and Declaration of Helsinki [55, 57, 58, 59, 60, 83]. Two studies were registered and approved by the regulatory agency (Ministry of Health of the Russian Federation) [55, 57].
A double-blind placebo-controlled CT of TP Abs to S100 in the treatment of AD in patients with neurological diseases [Parkinson’s disease (PD) (G.20) and chronic cerebrovascular diseases (CCD)—cerebral atherosclerosis (I67.2), hypertensive encephalopathy (I67.4), unspecified sequelae of cerebral infarction (I69.3)] was conducted in 2010 ([55], unpublished data). Sixty-two patients of both sexes aged 18–75 years were enrolled and randomized in two groups to receive TP Abs to S100 (n = 32) 10 tablets/day or placebo 10 tablets/day. Data from all 62 patients were included in the analysis, so that intention-to-treat and per-protocol sets were equal. The use of any antidepressants, antipsychotics, or antianxiety medications was prohibited in CT. The therapy of concurrent somatic and neurological diseases was permitted.
The study duration was 4 weeks with a 4-week follow-up period. Inclusion criteria were: manifested AD, the Hospital Anxiety and Depression Scale-Anxiety (HADS-A) score ≥ 11, signed informed consent form (ICF). The percentage of patients with a ≥50% decrease in the severity of anxiety according to the Hamilton Anxiety Rating Scale (HAM-A) after 4 weeks of treatment and 4-week follow-up was set as a primary efficacy endpoint. Other efficacy endpoints were: mean decrease in HAM-A, HADS-A, and State-Trait Anxiety Inventory (STAI) scores after 4 weeks of treatment and 4-week follow-up. Safety was assessed based on the results of laboratory tests (blood and urine analysis) and adverse events reports. Mann-Whitney U test, Wilcoxon signed-rank test, Student t-test, and Fisher\'s exact test were used for analysis.
The mean age of patients enrolled was 59.5 ± 2.0 years in the TP Abs to S100 group and 60.0 ± 1.9 years in the placebo group. The mean duration of neurological disease was 6.13 ± 1.2 years in the TP Abs to S100 group and 6.55 ± 0.89 years in the placebo group. No differences in demographic and clinical characteristics of patients were found (Table 4).
TP Abs to S100 | Placebo | |||||
---|---|---|---|---|---|---|
Total (n = 32) | Patients with PD (n = 16) | Patients with CCD (n = 16) | Total (n = 30) | Patients with PD (n = 15) | Patients with CCD (n = 15) | |
Demographic and clinical characteristics | ||||||
Age, years | 59.5 ± 2.0 | 61.4 ± 3.0 | 57.9 ± 2.5 | 60.0 ± 1.9 | 61.1 ± 2.9 | 58.9 ± 2.6 |
Duration of neurological disease, years | 6.13 ± 1.22 | 6.13 ± 1.15 | 5.94 ± 2.03 | 6.55 ± 0.89 | 8.0 ± 1.48 | 5.29 ± 2.56 |
Baseline data | ||||||
HADS-A, score | 14.75 ± 0.46 | 15 ± 0.68 | 14.24 ± 0.63 | 15.7 ± 0.41 | 16.93 ± 0.34 | 14.47 ± 0.59 |
STAI, trait anxiety, score | 62.28 ± 0.97 | 62.69 ± 1.76 | 60.82 ± 0.88 | 59.5 ± 1.25 | 61.53 ± 1.82 | 57.47 ± 1.61 |
STAI, state anxiety, score | 60.09 ± 1.05 | 59.31 ± 1.71 | 59.82 ± 1.24 | 60.8 ± 1.07 | 63 ± 1.06 | 58.6 ± 1.7 |
HAM-A, score | 27.28 ± 0.66 | 26.38 ± 0.82 | 28.19 ± 1.01 | 26.37 ± 0.6 | 27.13 ± 0.65 | 25.6 ± 0.9 |
After 4 weeks of treatment | ||||||
HADS-A, score | 7.74 ± 0.53 | 8.8 ± 0.97 | 6.75 ± 0.39 | 12.93 ± 0.8 | 16.0 ± 0.53 | 9.87 ± 1.0 |
STAI, trait anxiety, score | 50.58 ± 1.25 | 53.2 ± 2.27 | 48.13 ± 0.82 | 55.93 ± 1.55 | 61.07 ± 1.55 | 50.8 ± 1.95 |
STAI, state anxiety, score | 43.48 ± 1.06 | 46.4 ± 1.57 | 40.75 ± 1.07 | 54.0 ± 1.58 | 58.6 ± 1.59 | 49.4 ± 2.19 |
HAM-A, score | 14.74 ± 0.74 | 16.4 ± 1.21 | 13.19 ± 0.7 | 22.83 ± 1.05 | 26.07 ± 1.05 | 19.6 ± 1.41 |
After 4 weeks of follow-up | ||||||
HADS-A, score | 7.61 ± 0.49 | 8.8 ± 0.74 | 6.5 ± 0.52 | 13.1 ± 0.69 | 15.6 ± 0.36 | 10.6 ± 0.97 |
STAI, trait anxiety, score | 49.45 ± 1.04 | 51.0 ± 1.91 | 48.0 ± 0.84 | 56.47 ± 1.33 | 60.6 ± 1.43 | 52.33 ± 1.69 |
STAI, state anxiety, score | 43.65 ± 0.85 | 46.67 ± 1.13 | 40.81 ± 0.78 | 56.67 ± 1.27 | 60.47 ± 1.19 | 60.47 ± 1.19 52.87 ± 1.8 |
HAM-A, score | 14.13 ± 0.68 | 15 ± 1.01 | 13.31 ± 0.9 | 24.03 ± 0.89 | 26.78 ± 0.64 | 21.2 ± 1.31 |
Demographic and clinical characteristics, baseline, and post-treatment data on patients in double-blind placebo controlled CT of TP Abs to S100.
Note: Data are expressed as M ± SD. HAM-A, Hamilton Anxiety Rating scale; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; STAI, State-Trait Anxiety Inventory; CCD, chronic cerebrovascular disease; PD, Parkinson’s disease; TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
The percentage of patients with a ≥50% decrease in HAM-A total score was 41.3% in the TP Abs to S100 group and 6.7% in the placebo group (p < 0.05 compared to placebo) after 4 weeks of therapy (Table 4). After 4 weeks of therapy, the total HAM-A score significantly decreased in the TP Abs to S100 group [a 1.8-fold decrease (−45.63 ± 2.61%) from baseline in the TP Abs to S100 group versus a 1.1-fold (or −13.09 ± 3.3%) decrease in the placebo group; Student’s t-test р < 0.05]. The result of therapy persisted during the follow-up period in the TP Abs to S100 group. The anxiety level additionally decreased by 3% (−48.19 ± 2.1% from baseline in total) by the end of the follow-up period (p < 0.05 compared to placebo). The percentage of patients with a ≥50% decrease in HAM-A total score additionally increased by 3.3% after 4 weeks of follow-up (p < 0.05 compared to placebo) (Figure 8).
Dynamics of the severity of anxiety in TP Abs to S100 and placebo groups. *р < 0.05 versus placebo (Student’s t-test). HAM-A, Hamilton Anxiety Rating scale; TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
A significant decrease in the severity of anxiety was shown in patients receiving TP Abs to S100 according to HADS-A after 4 weeks of therapy and 4 weeks of follow-up (p < 0.05 compared to the placebo group). There was a 1.4-fold decrease (60.09 ± 1.05 vs. 43.65 ± 0.85) in state anxiety according to STAI in the TP Abs to S100 group after 4 weeks of therapy and result of therapy persisted during the follow-up period. The efficacy rate in reduction of the anxiety was higher in CCD patients than in PD patients according to STAI.
Data from 62 patients were included in the safety analysis. There were two AEs (pyrosis and burping) in one patient received TP Abs to S100 and one AE (pyrosis) in one patient in the placebo group. There was no significant difference in the frequency of AEs between groups. Neither TP Abs to S100 nor placebo influenced results of blood or urine tests in patients. All AEs were of medium severity and had no definite relationship with the study drug. No serious AEs were registered.
TP Abs to S100 were shown to be an effective drug for the treatment of AD in adult patients with concurrent neurological diseases.
An international multicenter double-blind randomized placebo-controlled study in 390 patients of both sexes aged 18–45 years with SD (mostly), AjD, or neurasthenia and ≥11 HADS-A points was conducted in 2017–2019 in the Russian Federation and Kazakhstan [57]. There were four treatment groups receiving TP Abs to S100 or placebo in two dosage regimens: 4 or 8 tablets/day. Preliminary (yet unpublished) data on primary efficacy endpoint showed the decrease in the mean HAM-A score by 11.25 points in TP Abs to S100 group (4 tablets/day) and by 11.91 points in TP Abs to S100 8 tablets/day groups observed after 12 weeks of treatment (vs. 9.71 points in merged placebo group; ANCOVA: pTP Abs to S100 4 tablets per day/placebo = 0.0055, pTP Abs to S100 8 tablets per day /placebo < 0.0001). A detailed analysis of the results is currently being prepared for a publication. Complete information on the study design is available at
To evaluate the advantages and limitations of novel medication, especially in the treatment of mental disorders, it is necessary to compare its efficacy and safety not only with placebo but also with the “golden standard” treatment [84]. Benzodiazepines are usually chosen as such a standard in CTs in patients with NDs and, in particular, ADs. Therefore, four CTs with the use of bromdihydrochlorphenylbenzodiazepine, diazepam, clonazepam, and tofisopam as the control therapy were conducted [58, 59, 60].
Outpatients aged 18–65 years (n = 59) with a diagnosis of GAD (F41.1), AjD (F43.2), or neurasthenia (F48.0) who signed ICF participated in this open-label randomized CT [58]. One group of patients (n = 32) received TP Abs to S100 4 tablets/day, and the other (n = 27) was administered bromdihydrochlorphenylbenzodiazepine 1.5 mg/day for 28 days. Exclusion criteria were other mental diseases, severe somatic diseases, pregnancy, or lactation period. Any medications that could influence the emotional state of participants were prohibited for use for 1 week prior to the initiation of CT and during the study.
Efficacy was evaluated based on the results of the HAM-A test and Clinical Global Impression-Improvement scale (CGI-I) after 7, 14, and 28 days of treatment. The frequency of AEs and any deviations from the reference ranges in blood and urine tests was used for safety assessment. The Kruskal-Wallis test, ANOVA, and Mann-Whitney U-test were used for statistical analysis.
The mean age of patients was 34.8 ± 3.6 years in TP Abs to S100 and 36.3 ± 4.6 years in bromdihydrochlorphenylbenzodiazepine group. The mean duration of disease was 0.8 ± 0.6 years and 0.9 ± 0.5 years in TP Abs to S100 and bromdihydrochlorphenylbenzodiazepine groups, respectively (Table 5). No significant differences between groups in any demographic and clinical characteristics were found.
TP Abs to S100 | Bromdihydrochlorphenylbenzodiazepine | p | |
---|---|---|---|
Demographic and clinical characteristics | |||
Age, years | 34.8 ± 3.6 | 36.3 ± 4.6 | >0.05 |
Disease duration, years | 0.8 ± 0.6 | 0.9 ± 0.5 | >0.05 |
Baseline data | |||
HAM-A, score | 18.2 ± 3.91 | 21.24 ± 3.25 | 0.41 |
After 7 days of treatment | |||
HAM-A, score | 10.73 ± 5.02 | 9.29 ± 4.24 | 0.46 |
CGI-I, score | 3.41 ± 1.1 | 3.05 ± 0.97 | 0.28 |
After 14 days of treatment | |||
HAM-A, score | 11.14 ± 5.49 | 6.62 ± 2.80 | 0.003 |
CGI-I, score | 3.14 ± 1.13 | 2.33 ± 1.39 | 0.004 |
After 28 days of treatment | |||
HAM-A, score | 9.59 ± 6.08 | 5.62 ± 2.18 | 0.000023 |
CGI-I, score | 2.86 ± 1.58 | 2.33 ± 1.06 | 0.21 |
Demographic and clinical characteristics, baseline, and post-treatment data of patients in comparative CT of TP Abs to S100 and bromdihydrochlorphenylbenzodiazepine.
Note: Data are expressed as M ± SD. HAM-A, Hamilton Anxiety Rating scale; CGI-I, Clinical Global Impression-Improvement scale; TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
After 7 days of treatment, the severity of anxiety was reduced by 41% (from 18.2 ± 3.91 to 10.73 ± 5.02) in the TP Abs to S100 group and by 56.2% (from 21.24 ± 3.25 to 9.29 ± 4.24) in the comparison group according to HAM-A scale. No significant differences between groups were found after the first week of treatment (p = 0.41), and TP Abs to S100 were shown to be as effective as bromdihydrochlorphenylbenzodiazepine in the short-term period. After 14 and 28 days the anxiolytic effect in the group, receiving benzodiazepine drug was superior to that in the TP Abs to S100 group (p < 0.05 between groups). In accordance with CGI-I results, the level of improvement was found to be similar in both groups (p = 0.004) on the 7th and 14th days, but later, bromdihydrochlorphenylbenzodiazepine led to a significant decrease in the severity of illness after 28 days of treatment (p > 0.05 between groups).
The frequency of AEs was higher in the benzodiazepine group. There were several cases of severe daytime sleepiness, disturbance of accommodation, and muscle weakness in patients that received bromdihydrochlorphenylbenzodiazepine. Some patients in the study group reported mild sleepiness. No severe AEs were registered in the TP Abs to S100 group. Neither TP Abs to S100 nor benzodiazepine administration affected results of blood or urine tests in patients.
Thus, TP Abs to S100 were as effective as the control medication only in the short-term period according to HAM-A but caused no severe AEs in patients with GAD, AjD, and neurasthenia comparing to benzodiazepine.
Diazepam is the most frequent standard drug used in CTs of anxiolytic agents [85]. This open-label randomized CT was conducted under the regulation of the Ministry of Health of the Russian Federation [unpublished data]. Outpatients aged 18–65 years with GAD (F41.1), AjD (F43.2), neurasthenia (F48.0) (total n = 272), and mixed anxiety and depressive disorder (mADD) (F41.2) signed ICF and then were randomized to receive TP Abs to S100 (n = 142) 6 tablets/day or diazepam (n = 130) 15 mg/day for 28 days. All medications influencing the emotional state were prohibited for use 1 week prior to CT initiation and during the study. Diagnosis of any other psychiatric disorder, pregnancy, lactation period, substance abuse, and severe somatic diseases were set as the exclusion criteria. Efficacy was measured using the HAM-A scale and STAI. Safety was assessed based on the AE reports and results of blood and urine tests.
The mean age of patients was 40.4 ± 1.13 in TP Abs to S100 group and 39.6 ± 1.06 in the diazepam group. The mean duration of NDs was 31.9 ± 4.1 and 29.2 ± 3.23 months in the TP Abs to S100 and diazepam groups, respectively. In the TP Abs to S100 group, 27.5% of patients had GAD, 31.3%—neurasthenia, 24.4%—AjD, and 17%—mADD. Among patients administered diazepam 31.6% had GAD, 37%—neurasthenia, 17.5%—AjD, and 14.8%—mADD. Mean HAM-A score was 27.1 ± 0.5 in the TP Abs to S100 group and 28.1 ± 0.46 in the diazepam group (p = 0.3). No differences in baseline characteristics were observed.
The total HAM-A score decreased to 22.0 ± 0.5 in TP Abs to S100 group at the end of the first week of therapy (p < 0.001 compared to baseline). There was a 57.2% decrease in total HAM-A score in the TP Abs to S100 group after 28 days of treatment (vs. 63% in the diazepam group, p = 0.02) (Figure 9).
Dynamics of the severity of anxiety in the TP Abs to S100 and diazepam groups. * р < 0.05 versus baseline. HAM-A, Hamilton Anxiety Rating Scale; TP Abs to S100, technologically processed highly diluted antibodies to S100 protein.
The percentage of patients with a ≥50% decrease in HAM-A total score was 72.6% in the TP Abs to S100 group (vs. 65.8% in the diazepam group) after 28 days of treatment. There were 12.8% of patients in TP Abs to S100 group with anxiety remission (less than 7 HAM-A scores) (vs. 22.1% in diazepam group). There were no significant differences between the TP Abs to S100 and diazepam groups on 7th and 28th days of treatment according to the HAM-A section “anxiety mood” (p = 0.2 and p = 0.1 between groups). Treatment with diazepam was more effective only at the 14th day of treatment [48.0 ± 0.62 (diazepam) vs. 50.0 ± 0.52 (TP Abs to S100), p = 0.02 comparing to the TP Abs to S100 group] according to STAI (state anxiety). The influence of TP Abs to S100 and diazepam on state anxiety was equal on the 7th and 28th days of therapy (p = 0.2 between groups). Diazepam and TP As to S100 were of equal efficacy in reducing the trait anxiety after 14 days [49.7 ± 0.60 (TP Abs to S100) vs. 51.0 ± 0.55 (diazepam); p = 0.1 between groups].
Only eight (5.6%) patients in the TP Abs to S100 group reported AEs (sleepiness, dizziness, dry mouth, pyrosis, bloating, excessive sweating, decreased libido, and tachycardia) of mild and moderate severity. In contrast, in the diazepam group, 51 (39.2%) patients had AEs (most frequent—daytime sleepiness, muscle relaxation, orthostatic hypotension) (p < 0.01).
To summarize the data, we consider TP Abs to S100 less effective than diazepam, though TP Abs to S100 were well tolerated by patients with GAD, AjD, neurasthenia, or mADD and exerted significantly less AEs in contrast to diazepam.
In this open-label CT, 60 patients with AjD (n = 35) or SD (n = 25) and cardiovascular diseases (CVDs) (coronary heart disease (CHD), arterial hypertension (AH) grades II–III, postmyocarditis cardiosclerosis, dyshormonal myocardial dystrophy with cardiac arrhythmias, ventricular and supraventricular extrasystoles, atrial fibrillation, and heart defects) were randomly prescribed to receive TP Abs to S100 6 tablets/day (n = 30) or clonazepam 0.5–1 mg/day (n = 20) as an anxiolytic treatment in addition to standard therapy of CVD for 28 days after signing an ICF [59]. The control group (n = 10) was not administered any antianxiety medication. No drugs influencing the mental status of participants were allowed 1 week prior to CT and after the onset of CT. The reduction of HAM-A score was set as an efficacy endpoint. Safety was assessed based on the number of reported AEs, changes in electrocardiogram (in TP Abs to S100 group), and results of blood and urine tests.
At the baseline mean, HAM-A score was 20.75 ± 8.3 in the TP Abs to S100 group, 22.3 ± 8.1 in the clonazepam group, and 14.7 ± 5.6 in control. After 28 days of treatment, the mean HAM-A score was reduced by 30.1% in patients that received TP Abs to S100 (to 14.5 ± 5.6; p < 0.01 vs. baseline), by 30.04% in the clonazepam group (to 15.6 ± 6.2; p < 0.01 vs. baseline) and 24.5% in the control group (to 11.1 ± 4.1; p > 0.05 vs. baseline). Patients in the TP Abs to S100 group reported no AEs and no changes were found on electrocardiogram or blood and urine tests. On the contrary, the extrasystoles in two participants with dyshormonal myocardial dystrophy that received TP Abs to S100 became less frequent (from 3122 to 2040) after 14 days of treatment. Patients in the clonazepam group (n = 5) noted a slowdown in mental and motor reactions, a feeling of tiredness, and daytime sleepiness.
Thus, TP Abs to S100 appeared to be slightly less effective than clonazepam but at the same time exerted less AEs that are important for patients with not only the AjD alone but also for those with CVD.
Patients (n = 51) with GAD or mADD and CVD (CHD or AH grades II–III) signed ICF and then were randomized into two groups. The first group (n = 31) received TP Abs to S100 4 tablets/day, the second (n = 20)—tofisopam 100 mg/day for 4 weeks in addition to standard CVD therapy [60]. After 4 weeks of treatment, patients were followed up for the next 4 weeks. Patients that previously received antianxiety or antidepressant medications, diagnosed with other mental diseases, having a history of substance abuse or lactose intolerance were not included in CT. The changes in HAM-A score after 2 and 4 weeks of treatment and after 4-week follow-up were set as efficacy endpoints. Safety was evaluated by analysis of AEs.
The mean age of patients in the TP Abs to S100 group was 49.3 ± 7.0 years, and the mean duration of CVD was 8.2 ± 4.5 years. In the tofisopam group, the mean age was 54 ± 5.2, and the duration of CVD was 7.6 ± 2.9 years. No differences in baseline characteristics were registered. During the treatment, anxiety was reduced by 63% after 1 week, by 73.1% after 2 weeks, and by 78.5% after 4 weeks in the TP Abs to S100 group according to HAM-A. There was a decrease in HAM-A scores by 62.5% after 1 week, by 75% after 2 weeks, and by 78.5% after 4 weeks in the tofisopam group. A positive effect of TP Abs to S100 on anxiety state was maintained for 4 weeks during follow-up, while there was a tendency for an increase in HAM-A score in the tofisopam group. The addition of TP Abs to S100 to standard CVD therapy helped to decrease the mean systolic blood pressure (SBP) by 25% (from 161.5 ± 18.5 mmHg to 122 ± 5.0 mmHg) after 4 weeks of treatment, whereas only 15.9% decrease in mean SBP was shown in the tofisopam group. No serious AEs were registered in both groups. In the TP Abs to S100 and tofisopam groups, 3.2 and 10% of patients, respectively, discontinued the treatment for personal reasons.
Thus, TP Abs to S100 were shown to be as effective as tofisopam. The compliance in the TP Abs to S100 group was slightly higher than that in the tofisopam group. The addition of TP Abs to S100 to standard CVD treatment led to a more prominent decrease in the mean SBP than the addition of tofisopam. TP Abs to S100 achieved more prolonged action on anxiety state than tofisopam.
The use of anxiolytic treatment in the patients with chronic somatic diseases is challenging [86]. Many side effects of benzodiazepines such as drowsiness, sleepiness, cognitive impairment, dizziness, and addiction can be crucial for these patients [87]. Polypharmacy is also an unwanted phenomenon. The negative interaction of antianxiety medications with standard therapy of somatic diseases is frequently observed [88]. For instance, the use of SSRI in combination with nonsteroidal anti-inflammatory drugs increases the risk of gastrointestinal tract bleeding [89]. Some authors described the association between high risk of myocardial infarction and the use of benzodiazepines and antidepressants [90]. So, the search for a possible role of TP Abs to S100 in treatment of patients with the somatic disease is relevant.
Around 40% of patients with CVD experience anxiety that can have a negative impact on the risk of adverse cardiovascular events [91, 92]. Thus, it is important to reduce anxiety symptoms in CVD patients.
Two CTs that compared TP Abs to S100 with clonazepam and tofisopam in patients with CVD were described above [59, 60]. The results showed equal efficacy of TP Abs to S100 and tofisopam in CVD patients.
In another open-label randomized comparative CT by Nikol\'skaya et al., TP Abs to S100 were used in combination with the standard treatment of patients with AH grades II–III and anxiety (n = 60, 23 women, 37 men; mean age—61.4 ± 6.9, mean AH duration—10.6 ± 4.1 years) [93]. All patients received diuretics, β blockers, and angiotensin-converting-enzyme inhibitors (ACE inhibitors). Randomly chosen participants (n = 30) were additionally prescribed TP Abs to S100 6 tablets/day for 4 weeks. At the baseline, there were 40% of patients with severe anxiety and 60% with the anxiety of moderate severity in the TP Abs to S100 group according to the Taylor Manifest Anxiety Scale (TMAS) modified by Nemchinov. Sixty percent of patients with severe anxiety and 56.6% with the anxiety of moderate severity made up the control group were receiving no antianxiety therapy.
The 1.3-fold reduction of severity of anxiety (from 23.76 ± 2.81 to 18.83 ± 2.75 TMAS points) after 2 weeks of therapy was shown in the TP Abs to S100 group (p < 0.0001 vs. baseline and the control group). There was a 24.28% decrease in SBP from 181.7 ± 10.8 to 140.0 ± 8.3 (p < 0.0001 vs. baseline and control) after 4 weeks of therapy in the TP Abs to S100 group. There was a 17.7% decrease in diastolic blood pressure from 102.3 ± 4.3 to 85.0 ± 5.7 in the study drug group after 4 weeks of therapy (p < 0.0001 vs. baseline and the control group). No negative interactions with standard therapy were registered for TP Abs to S100.
Matyushin et al. demonstrated the efficacy and safety of TP Abs to S100 in an open-label randomized comparative CT in patients (n = 60) with anxiety measured with HAM-A and CHD, AH grades II–III, angina pectoris I–III functional classes by Canadian Cardiovascular Society Classification, heart rhythm disturbances (extrasystole, paroxysmal supraventricular tachyarrhythmias) receiving standard CVD therapy (β blockers, amiodarone, sotalol, lappaconitine hydrobromide, diethylaminopropionylethoxycarbonylaminophenothiazine, etc.) [94]. The study drug group (n = 30) received TP Abs to S100 6 tablets/day, and the control group (n = 30) was administered only CVD treatment for 8 weeks. The mean age of patients in TP Abs to S100 and control groups was 64.4 ± 8.6 and 63.1 ± 8.5, respectively.
The addition of TP Abs to S100 to the standard therapy in patients with angina pectoris I–III functional classes helped to decrease the severity of anxiety (50.4% decrease vs. 32.3% decrease in the TP Abs to S100 group vs. the control group; p < 0.05) and caused cardiac rhythm normalization [80% patients with more than 75% decrease in the frequency of daily episodes of rhythm disturbances in the study group (p < 0.05 vs. control)]. There were 60% of patients with a decrease in angina pectoris functional class in the study drug group (vs. 33.3% in control; p < 0.05 between groups). No AEs and negative drug interactions were registered.
An open-label placebo-controlled study in 85 patients with acute coronary syndrome and anxiety (diagnosed with HADS-A) showed significant improvement in the quality of life assessed with the Short Form-36 in the TP Abs to S100 group after 6 month of therapy [95]. The 1.7-fold decrease in HADS-A score (from 12.1 [9;17] to 7.1 [6;8]) was observed in patients receiving TP Abs to S100 in combination with standard therapy after 6 months (p = 0.00008 vs. baseline). No reduction of anxiety according to HADS-A was found in the placebo group after 6 months (p = 0.07 vs. baseline). No negative interaction with standard therapy (acetylsalicylic acid, clopidogrel, enoxaparin, statins, ACE inhibitors, β blockers, nitrates, calcium agonists) was registered.
Thus, TP Abs to S100 is an effective anxiolytic medication that helps to reduce the severity of anxiety as well as to avoid drug interaction, polypharmacy and increase the quality of life. According to some CTs mentioned above, TP Abs to S100 increase the efficacy of standard treatment in patients with AH, angina pectoris, and some heart rhythm disturbances due to their antianxiety action. Due to reduction in severity of anxiety, the improvement of compliance in CVD patients is possible, though this consideration requires further investigation.
Anxiety is common in 20% of patients with gastrointestinal (GI) problems [96] and in 27% of patients with gastritis in particular [97]. Some publications revealed an association between mood disorders and the risk of carcinogenesis in patients with GI diseases [98, 99]. The necessity for antianxiety therapy in these patients is justified.
An open-label comparative study by Tsukanov et al. in patients with anxiety (diagnosed with HAM-A) complicating ulcerative gastritis associated with Helicobacter pylori and duodenal ulcers was conducted [100]. One hundred and two participants received standard helicobacter eradication therapy (clarithromycin, amoxicillin, omeprazole, algeldrate—magnesium hydroxide combination drug), and 49 of them were prescribed TP Abs to S100 6 tablets/day for 20 days. Mean age of participants was 41.8 ± 2.4 in the TP Abs to S100 group (n = 49) and 42.3 ± 2.8 in the control group (n = 53). The dynamics of HAM-A scale scores was evaluated.
Anxiety was significantly reduced in the TP Abs to S100 group after 20 days of treatment. The mean HAM-A score decreased by 55.2% from 23.43 ± 1.8 to 10.5 ± 0.98 (vs. 28% in the control group; p < 0.001 vs. baseline; p < 0.001 vs. control group). No serious AEs were registered in both groups.
According to another open-label noncomparative CT by Karpin et al. in patients with chronic gastritis and duodenal ulcers, the addition of TP Abs to S100 to standard treatment leads to a prominent reduction in GI symptoms (pain, intestinal dyspepsia, appetite changes) (p = 0.003 vs. baseline for pain and dyspepsia, p = 0.045 for appetite changes) [101].
So, the treatment of patients with GI diseases with TP Abs to S100 helps to reduce anxiety and indirectly decrease the severity of somatic symptoms via its anxiolytic action.
In this review, the data obtained from experimental and clinical studies of TP Abs to S100 efficacy, safety, and mechanisms of action are summarized.
In nonclinical trials, TP Abs to S100 were shown to exert stress-protective, anxiolytic, antidepressant, antiamnestic, and neuroprotective activities. All these effects were manifested at the same level as the activity of comparator drugs. At the same time, toxicological studies have shown a high safety level of TP Abs to S100: there was no any toxic activity of drug reviled even when it was administered to laboratory animals at the maximal dose for 6 consecutive months (every day).
The mechanisms of action studies confirmed the hypothesis that TP Abs to S100 biological effects are realized via recruiting of GABA-, serotonin-, dopamine-, noradrenaline-, and glutamatergic systems, as well as via sigma1 receptors.
Clinical efficacy and safety of TP Abs to S100 were demonstrated in multicenter double-blind randomized placebo-controlled trials and in open-label randomized comparative trials. In all conducted placebo-comparative studies or studies with nonmedicated control group, the main symptom of most NDs—the anxiety—was significantly reduced in TP Abs to S100 action. It should be stressed that in these CTs, the equal efficacy of TP Abs to S100, tofisopam, and bromdihydrochlorphenylbenzodiazepine (in the short-term use) with a notably higher tolerance level was demonstrated. Meanwhile, TP Abs to S100 increased the efficacy of standard treatment of somatic diseases (due to its anxiolytic activity), and there was a lower number of AEs and lack of drug interactions observed in the TP Abs to S100 group.
Thus, the discussed drug—TP Abs to S100—has been extensively studied and demonstrated favorable efficacy and safety profile. The presented evidence justifies TP Abs to S100 to be a promising treatment option for patients with NDs.
We thank Dr. Kovalchuk A.L. for valuable comments on the paper and language editing.
All authors are the employees of OOO NPF Materia Medica Holding pharmaceutical company. The substance TP ABS to S100 is produced and marketed by OOO NPF Materia Medica Holding.
ACE | angiotensin-converting-enzyme |
AD | anxiety disorder |
AE | adverse event |
AH | arterial hypertension |
AjD | adjustment disorder |
CCD | chronic cerebrovascular disease |
CHD | coronary heart disease |
CGI-I | global impression-improvement scale |
GI | gastrointestinal |
CNS | central nervous system |
CT | clinical trial |
CVD | cardiovascular diseases |
DSM | Diagnostic and Statistical Manual of Mental Disorders |
HADS-A | Hospital Anxiety and Depression Scale-Anxiety |
HAM-A | Hamilton Anxiety Rating Scale |
HPAA | hypothalamic-pituitary-adrenal axis |
HTP | hydroxytryptophan |
GABA | γ-aminobutyric acid |
GAD | generalized anxiety disorder |
ICD | International Disease Classification |
ICF | informed consent form |
mADD | mixed anxiety and depressive disorder |
ND | neurotic disorder |
NMDA | N-methyl-d-aspartate |
OCD | obsessive-compulsive disorder |
OF | open field test |
PD | Parkinson’s disease |
SBP | systolic blood pressure |
SD | somatoform disorder |
SSRI | selective serotonin reuptake inhibitors |
STAI | State-Trait Anxiety Inventory |
TCA | tricyclic antidepressants |
TMAS | Taylor Manifest Anxiety Scale |
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