1 Introduction
With the standard of living continually increasing worldwide and the increasing awareness of personal well-being, people are putting greater effort into improving their quality of life by maintaining close surveillance of their health status and longevity. Contemporary medicine has shifted from a simple biomedical model to a complex and integrative social—psychological—biomedical model since the beginning of the 21st century. Accordingly, medical research and services are also being transformed from simple biomedical research and practice to comprehensive biological, psychological, and social research. As such, systemic measures that take into consideration multifactorial human diseases are being implemented in the population to safeguard public and individual health.
Holistic integrative medicine integrates psychological, social, and environmental factors with biological factors, the most frontal scientific discoveries in all areas of life sciences with the most effective clinical practice in all areas, and the simplex mode of thinking of natural science with the multiple modes of thinking of philosophy. The aim is to build a comprehensive, systematic, scientific medical system to promote health, facilitate disease diagnosis, and improve disease treatment and prevention. As the clinical health science that links medical science with chemistry is charged with the discovery, production, disposal, safe and effective use, and control of medications and drugs, pharmacy has the responsibility to advance the development of holistic integrative medicine with all its strengths and to establish holistic integrative pharmacy (HIP), a new sub-discipline of pharmacy adaptable to China’s national conditions. This article introduces the concept and connotations of HIP and suggests suitable development strategies for China.
2 The concept and connotations of holistic integrative pharmacy
The theoretical basis of holistic integrative medicine mainly includes holism, integration, and medication. It regards human beings as a whole and examines this wholeness in the context of a larger whole by integrating environmental, social, and psychological elements. Holistic integrative medicine is formed by the combination of medical experience formed from the transformation of medical research findings and clinical practice knowledge, as well as new biomedical technologies and the art of in-depth communication with patients [1,2]. Integrative pharmacy strives to apply the concept of integration to the innovation of traditional Chinese medicine (TCM), the research and development of new drugs, the safe and effective use and control of medications and drugs, and discipline development. Integrative pharmacy helps to integrate the methods and knowledge of various sub-disciplines and to establish a new theory and practice system to promote human health and improve the medical system.
Integrative pharmacy originates from integrative medicine as well as the holistic philosophy of TCM and other traditional medicines, based on our deepened understanding of the complex nature of human diseases. Integrative pharmacy aims to regress to the root of holism philosophy on the foundation of high, precise, and sophisticated development in pharmaceutical science. This goal can be achieved only by organically integrating knowledge with practice and the future with reality in all fields and all levels of pharmacy. Integrative pharmacy is an intersection of multiple disciplines, departments, systems, and perspectives, involving all-parties academic and professional collaborations among modern and traditional pharmacy, basic research and clinical practice, new drug development and evaluation, etc. Therefore, multidisciplinary integration is the key to the development and practice of integrative pharmacy and is also the key to improving medical quality
[3]. Integrative pharmacy is the transformation and development of modern pharmacy theory and practice. Its connotations are plentiful, including the integration of modern and traditional pharmacy, the research and development of new drugs based on integrative concepts, the clinical use of drugs, discipline development, and professional training.
3 Development strategies of integrative pharmacy
3.1 Promoting the integration of modern and traditional pharmacy
Traditional pharmacy, guided by holistic thinking, has unique perspectives on physiology, pathology, and disease prevention. It attaches great importance to judging health status and disease progression based on the wholeness of the body functions and emphasizes individualized dialectical and people-oriented treatment. Integrative pharmacy, directed by systematic thinking, reveals the interactions between drugs and the human body and pathogenic organisms. It is also a systematic, inherently interdisciplinary, nonlinear science that combines nature with humanities and believes that the whole is more than the sum of its parts. The integration of modern and traditional pharmacy integrates the concept of people-oriented and dialectical treatment in traditional medicine into modern pharmacy, which promotes the implementation of integrative pharmacy in clinical practice. In addition, the integration of modern and traditional pharmacy effectively incorporates the theory and experience of traditional medicine with modern science and technology to produce original drugs and promote the innovation of TCM
[3]. The aim is not simply to strengthen the combinational applications of modern medicine and TCM. Moreover, we must utilize rigorous scientific methodologies to explore the path for the development of integrative pharmacy and to apply the respective advantages of traditional and modern medicine to clinical practice to tackle health issues and provide better services to meet ever-increasing medical demands.
3.1.1 Establishing and improving clinical guidelines for integrative drug use
With years of dissemination of information and education, physicians and patients have become increasingly prepared to accept the therapeutic concept of “integration of modern medicine and traditional medicine.” Clinical practice has accumulated increasing evidence for traditional medicine as an important player in the treatment of some human diseases. However, such effectiveness has not been firmly supported and explicitly explained by evidence-based medicine. Another obstacle that impedes the application of traditional drugs to disease therapy is the lack of general guideline for clinical practice, which restricts the common acceptance and scientific development of traditional medicine. Therefore, it is necessary to establish and improve clinical guidelines for the use of drug-based integrative medicine to ensure high efficiency and safety. Appropriate clinical guidelines not only provide a decision-making basis for the rational use of integrative drugs in clinical practice, but also promote information exchange between two different pharmaceutical systems to promote the integration of basic theory and clinical practice of the two medical systems.
3.1.2 Innovation of TCM research based on integrative thinking
The key to innovation in TCM research lies in the stability of its curative effects and the scientific nature of the research methods. TCM is a unique resource with the advantages of originality and it being a strategic emerging industry with great potential for future development. An effective way to modernize TCM involves using contemporary science and technology to excavate the wealth of TCM-related knowledge. Specifically, the first step toward the innovative research and development of TCM is to let creative thinking lead the way. TCM is rooted in the concept and theory of “principle–method–prescription–medicine.” Principle refers to the understanding of the pathogenesis and progression of diseases. Only with a more insightful understanding of diseases can we renew the intervention strategies and treatment methods and develop new drugs and formulations. The formulations should contain multicomponent and multitarget drugs, which underline the regulation of whole-body functions. Therefore, based on TCM theory and integrative thinking, the scope of clinical applications of TCM will be greatly expanded
[4]. Second, the efficacy of TCM needs to be proved both experimentally and clinically in line with the general principles and standards of contemporary science and clinical guidelines, so that it can be more widely recognized and accepted as a source of adjunct or even mainstream treatment modality
[5]. It is necessary to establish a complete technical system based on conceptual innovation for drug screening, pharmacodynamics research, safety evaluation, formulation preparation, quality control, and clinical evaluation. In clinical practice, new hypotheses need to be generated, and prescriptions should be optimized to improve therapeutic efficacy. An innovative TCM research model of theory–clinical–new drug–experiment–evidence-based medicine needs to be established to identify the breakthrough point for innovation of the discipline and achieve the goal of TCM transformation [6,7].
3.1.3 Standardizing the clinical applications of integrative medicine
To date, there are no authoritative guidelines or standards for TCM practice in China. Therefore, the clinical application of integrative TCM and modern medicine still faces great challenges. According to the existing government policies and regulations, pharmacists in TCM and modern medicine have different scopes of professional practice, and cross-disciplinary practice is not permitted. Under such circumstances, pharmacists are unable to play a role in formulating a rational combination of drugs. In recent years, TCM pharmaceutical companies in China have begun to gain momentum in rapid development; however, official practice norms for the integrative clinical application of TCM and Western medicine remain unavailable. Therefore, there is an urgent need to establish authoritative and standardized policy guidance and determine professional decision-making grounds for integrative applications of TCM and Western medicine in clinical settings
[8].
3.2 Promoting the research and development of innovative drugs based on integrative pharmacy
Clinical efficacy is the ultimate criterion for evaluating and judging the effectiveness of a drug. The human body is composed of multiple types of cells, organs, and systems. Diseases are generally caused by a series of abnormal changes, including gene mutations and expression deregulation, protein deregulation and malfunction, and functional impairment at the cell, tissue, organ, and system levels. Human diseases are generally multietiological, polygenic, multifactorial, and multifaceted in nature with complex pathomechanisms. To date, a large number of genes or proteins that can regulate pathological processes have been identified and characterized through basic biomedical research as targets for disease treatment and drug development. However, the therapeutic efficacy of currently available medications has often been disappointing in the clinical setting. It is likely that this lack of therapeutic efficacy is due to the unattacked targets being maintained, thus proceeding with the pathological process
[9]. Indeed, the “one drug, one target, one disease” paradigm in drug discovery has recently shifted to a “multitarget drugs” strategy. Multitarget drugs offer optimal solutions for treating systemic multifactorial human diseases, thereby maintaining better coordination of physiological functions of the human body.
3.2.1 Innovating design ideas for integrative drugs
In the design of new drugs based on integrative pharmacology, we should attach importance to the fundamental change in drug design; the transition of the drug discovery paradigm from single-component to multicomponent drugs, from single target to multitarget network pharmacology and systems biology, and focusing on the chemical composition of drugs to focusing on the overall effects of the drugs.
(1) Design of multicomponent and multitarget drugs for complex diseases. In the 20th century, specific activation or inhibition of a target molecule by monomer drugs was the dominant paradigm for new drug discovery in both pharmacological research and the pharmaceutical industry. Biomedicine elucidates the etiology of diseases by discovering the key regulatory molecule for a specific disease and taking that molecule as a drug target for the pathological entity. However, accumulating evidence has clarified that majority of human diseases with high incidence, such as diabetes, cardiovascular diseases, and cancers, as exemplified by chronic diseases, are caused by multiple physiological, pathological, environmental, and lifestyle factors, as well as their complex interactions. The use of single-target drugs to treat diseases that are regulated by complex biological networks has failed to match expectations, with lower efficacies and higher toxicities than expected. Often, even if screened and validated by benchtop studies and preclinical animal experiments for its pharmacological effects, the compound may not elicit satisfactory efficacy clinically and has a high probability of failing to pass a clinical trial. Such a challenge has become a driving force pushing forward the transition towards new and more advantageous multitarget and multicomponent compounds for drug discovery
[5].
(3) Exploring new indications for existing drugs. Repositioning or repurposing existing drugs by identifying new indications and applications has emerged as an important strategy in the pharmaceutical industry. Drug repositioning offers new opportunities and advantages of risk reduction and cost cutting in the development of therapeutic drugs and shortens the time lag between drug discovery and marketing. In recent years, drug repurposing has received widespread and strong support from governments and academic institutions worldwide. In the United States, the new drugs developed via the drug repurposing strategy accounted for 20% of the 84 drugs approved for marketing by the US Food and Drug Administration in 2013. In addition, several public databases for drug repositioning have been established for public use, and various financial incentives are provided to motivate research into drug repositioning for rare diseases. There are three general strategies for the development of new drugs based on drug repositioning: (1) identification of new indications of commonly used medicines that have been on the market for many years with widely recognized safety profiles; (2) exploitation of the potential off-label effects and the underlying mechanisms of existing drugs based on the experience of first-line clinicians; and (3) redevelopment of new indications for drugs that have failed clinical trials or expert panel reviews. In general, the safety profiles of these compounds have been well-established; however, they are delayed or even abandoned mostly because of their poor efficacy, as revealed by phase II clinical trials. However, the potential effectiveness of these compounds against other diseases remains unknown. Therefore, these failed drugs can be used as resources for review and reanalysis to identify those worthy of repurposing for their therapeutic potential [12–14]. In summary, drug repositioning is an important strategy for discovering new drugs and new indications for existing drugs, and unfolds new opportunities for drug research and development [15,16].
3.2.2 Establishing a drug evaluation system for integrative pharmacy
Preclinical studies lay the foundation for clinical studies and, ultimately, the clinical applications of new drugs. However, the results obtained from
in vitro benchtop experiments at the cellular or tissue level cannot be extrapolated to the complex
in vivo physiological and biochemical systems. Therefore, preclinical studies of drugs in whole-animal models of the disease of interest is an essential and necessary step for efficacy and safety evaluations, which bridges drug discovery with clinical application. However, as much as 92% of drugs that are safe and effective in animal studies fail to pass clinical trials due to their unacceptable toxicity and/or ineffectiveness. Half of the remaining 8% of drugs that successfully pass clinical trials are eventually withdrawn from the market or restricted in their application due to serious side effects. The use of improper animal models is the main cause of the increasing failure of drugs that enter clinical trials, especially for drugs positioned to treat chronic and complex diseases
[3].
3.3 Promoting the clinical practice of integrative pharmacy
Many drugs are available for clinical use in China, but there are also some serious issues related to unregulated and nonstandard use based on experience, tentativeness, and arbitrariness. The ongoing appearance and alterations of new diseases impose ever-increasing requirements for clinicians and pharmacists in clinical practice. The clinical use of drugs must conform to the guidelines (if any) and the principles of safe and rational medication. Integrative pharmacy engenders a more rational way of thinking and a more rigorous norm of practice in drug use in the clinical setting
[21]. In clinical practice, the purpose of integrative pharmacy is to integrate medicine and pharmacology. Patients are individuals who experience constant changes. Patient gender, age, basic physical conditions, disease characteristics, progress, prognosis, and other factors must be comprehensively and systematically appraised in the course of disease treatment. At the same time, drug selection, medication, and treatment regimens must be re-adjusted accordingly. The idea behind this is to treat patients well while treating their diseases. In addition to their primary pharmacological effects and indications, drugs can affect other organs. Therefore, before selecting the drugs for treatment, the patient’s overall status should be fully assessed, and the medication should adhere to the holistic concept of patient–disease–drug, rather than the old dogma of symptom– target–drug. Only in this way can we improve the effectiveness and safety of medicines. Simply put, holistic and integrative thinking should be applied to guide every step of clinical medication selection and provide more suitable medical services for patients
[22].
3.3.1 Improving the practice guidelines of patient-centered clinical medication
The rapid development of medical science has opened up more pathways and methods for the treatment of diseases. Nonetheless, many challenges and unresolved issues remain in clinical practice in terms of the safety, rationality, and specificity of drug applications. Clinical medication should conform to patient-centered concepts and principles. However, patient-centered clinical drug application is a long-term practice involving many aspects at different levels subject to gradual development, improvement, and renewal. For example, in cancer treatment, targeted therapy based on monoclonal antibodies has become an indispensable regimen, because it minimizes the adverse responses caused by chemotherapy and helps improve patient quality of life, which has produced profound fundamental changes in the clinical practice of tumor therapy. The matching method of drug and tumor-specific inducible gene provides a new strategy for the individualized treatment of tumors. Currently, there are approximately 50 compounds available for the treatment of specific types of tumors with specific inducible genes, and 10 drugs are being evaluated in clinical trials for the targeted therapy of tumors. The main mechanism for the high effectiveness of targeted therapy is that it addresses the problem of single gene mutations in the development of tumors. However, in certain circumstances, targeted therapy can be ineffective. Therefore, patient-centered targeted therapy should consider the complexity of tumorigenesis and the heterogeneity of tumor cells in different individuals. Combination therapy strategies adopted according to individual differences can address the complexity of tumorigenic genes or oncogenes, tumor cell heterogeneity, and drug resistance. Studies support that integrative therapy can substantially improve the survival rate of cancer patients. Various therapeutic modalities, such as small-molecule drugs, monoclonal antibody drugs, immunotherapy, and bispecific antibodies, should be integrated into the treatment of cancer. More rational combinations of various modalities should be examined and employed to achieve prospective therapeutic effects in cancer patients. In addition, enhancing the targeting precision of multiple joint target molecules based on a more detailed and comprehensive characterization of tumors opens up a new opportunity for tumor treatment [23,24].
3.3.2 Selecting the most appropriate drugs to achieve individualized therapy based on the comprehensive assessment of the disease phenotype using advanced technologies
Individualized therapy not only attaches great importance to the selection of the most appropriate drugs for patients, but also to the treatment of patients with the most appropriate dosage at the most appropriate time point. Moreover, individualized therapy requires sophisticated and advanced methods for identifying pre-existing pathological symptoms in the early stages of disease development to initiate targeted preventive measures as early as possible and reverse pathological manifestations and disease progression. With the reduced cost of advanced molecular biology technologies, in-depth analysis at the single-cell level, quantitative gene analysis, and molecular docking of drug–gene spectrum–disease spectrum will provide new standards for disease treatment and efficacy appraisal. Proper integration of these data into a multi-disease model will improve the course of treatment and prognosis of patients. For example, in tumor therapy, single-cell mass spectrometry can be used to perform a deep phenotypic analysis of tumor cells to determine tumor phenotypes. In addition, comprehensive diagnosis, analysis, and monitoring of tumor invasion can provide clues for the selection of specific drugs targeting specific tumors
[25]. Furthermore, a combination of whole genome sequencing, exon sequencing, and transcriptional profiling can be used to accurately identify possible changes in patient genomes. A drug for targeted therapy, which is selected based on the genomic alterations of patients and from the clinically available drugs or those under clinical trials, is expected to yield better effects and prognosis
[26]. In addition to sequencing, metal isotope labeling technology combined with laser ablation imaging technology can provide accurate information for determining tumor phases, cell heterogeneity, and cancer inducers; predicting potential therapeutic targets; and monitoring the response of the target to therapeutic drugs, which can optimize the matching between the tumor and therapeutic drugs
[27]. In conclusion, predictive, preventive, and individualized medicine is the ultimate goal of improving the quality of medical services and the level of healthcare.
3.3.3 Enriching the clinical practice of integrative pharmacy
Clinical pharmaceutical services cover all regions of China. However, many problems remain in the practice of clinical pharmacy; for example, the work mode centered on ensuring drug supply has never changed and there is a lack of effective communication between clinical pharmacists and clinicians, a lack of guidelines for rational drug use, and a lack of clinical pharmaceutical research. Integrative clinical pharmaceutical practice requires not only the professional qualifications of pharmacists but also communication and cooperation between medical professionals from different disciplines and fields, guidance and monitoring of the patient’s status during the course of drug treatment, and guidance and follow-up of daily medication. The overall task of integrative clinical pharmaceutical practice should include the essential components in accordance with the goal of drug therapy, that is, the rational selection of drugs, close attention to drug use, and patient-centered treatment outcomes. In this process, we should ensure that the selection of drugs is patient-centered, the use of drugs is justified, and the combination of drugs is coordinated, cooperative, comprehensive, and integrative. As important participants in clinical medication, pharmacists should strengthen their communication and collaboration with doctors and nurses, assist patients in selecting appropriate drugs, monitor and guide them to use medications correctly, participate in patient medication care, and evaluate the outcomes of drug therapy
[28].
3.3.4 Promoting the rational applications of integrative drugs
Integrative clinical medication should have strict regulations for practice and convincing evidence of clinical effectiveness. (1) The clinical guidance and scientific basis for rational drug use should be established to ensure the rational use of therapeutic drugs and appropriate appraisal of the rationality of drug use. (2) The supervisory standards and mechanisms for rational drug use should be established to mandate qualified professionals to supervise rational drug use and medical staff to strictly adhere to the principle of rational drug use. (3) The theoretical system of rational drug use should be established and improved, and knowledge of rational drug use should be continuously collected, summarized, and condensed, and fragmented knowledge about rational drug use should be integrated into systematic clinical practice and norms. (4) An education and training system for rational drug use personnel should be establish to train personnel and evaluate the conduct of medical staff to better implement rational drug use. In an integrated healthcare system, such practice standards and guidelines must be established as soon as possible to serve as a benchmark for professional practice in rational drug use
[21].
3.4 Promoting discipline construction and talent cultivation in integrative pharmacy
3.4.1 Enriching theoretical and practical courses for pharmacy undergraduates with integrative pharmacy
Interdisciplinarity will promote discipline construction and talent cultivation in integrative pharmacy. The theory of combinational TCM and Western medicine should be incorporated into the theoretical course of pharmacy undergraduates to promote multidisciplinary infiltration and the integration of pharmaceutical theory and practice. Courses related to TCM should be incorporated into the curriculum for students majoring in pharmacy and in practical training in pharmacy to better promote the integration of traditional and modern medicine theories. In addition, the relevance between pharmaceutical courses and clinical medication should be intensified to avoid overemphasis on the theory of professional knowledge and to facilitate the integration of pharmaceutical theory and practice. In pharmacy training, it is necessary to cultivate the ability of pharmaceutical professionals to evaluate the rationality and safety of a drug prescription to accelerate and improve the construction of the integrative pharmacy discipline and talent cultivation system at both theoretical and clinical practice levels.
3.4.2 Strengthening the collaboration among clinicians of different medical specialties and attaching importance to education and training
Integrative pharmacies play an important role in clinical diagnosis. A system and mechanism should be set up for physicians and pharmacists to be able to maximally demonstrate their knowledge and expertise and to encourage their exchange and cooperation so that they can provide comprehensive pharmaceutical services, especially in relation to the rational and safe combination of TCM and Western medicine. It is necessary to strengthen the policy-driven development of integrative pharmacies, construction of new disciplines, and cultivation of professional talent.
The authority and related administrators governing pharmacies and the pharmaceutical industry should formulate practice standards and promote collaborations among research institutions, universities, and pharmaceutical enterprises to speed up the development of integrative pharmacy as a new discipline. It is necessary to develop specific training plans for pharmacists and residents in pharmacies, offer high quality programs for continuous training, and intensify the education and cultivation of pharmaceutical professionals. Education and training of pharmaceutical professionals should focus on pharmaceutical information, pharmaceutical therapy, and physician–patient communications. In addition, we should focus on the accumulation of clinical practice experience and follow-up of patients on medication and enhance pharmaceutical professionals’ sense of responsibility in their clinical practice.
4 Conclusion
Integrative medicine is not only a new idea, model, and medical concept for maintaining health status at all levels throughout the human lifespan, but is also a major theoretical innovation and technological support for transforming the Healthy China initiative into reality. “Medicine and pharmacy are teachers for each other.” Medicine is the basis of pharmacy, and pharmacy is the means of distributing medicine. In China, the exact definition of integrative pharmacy has not yet been perfected. Nevertheless, the concept of holistic integrative medicine and supportive policies has become a powerful driving force with momentum by which integrative pharmacies are gradually including innovation in TCM, research and development of new drugs, the clinical use of therapeutic drugs, discipline construction, and talent cultivation for pharmacy, among others. However, the practice of integrative pharmacy requires further improvement. It is necessary to incorporate the integrative concept into basic and translational pharmaceutical research and clinical pharmaceutical practice, as well as pharmaceutical education, training, and management. There is also a need to facilitate the development and application of integrative pharmacy in all related areas, including policy making, pharmaceutical education, clinical medicine, and pharmaceutical industry, to push forward the strategic transformation of pharmacy towards the integrative mode in favor of the realization of the core goal of Healthy China.
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