11The Hormetic Pharmacy The Future of Natural

The Hormetic Pharmacy: The Future of Natural Products and Man-Made Drugs in Disease Prevention and Treatment Edward J. Calabrese and Mark P. Mattson Abstract This chapter proposes a new look at the modern pharmacy of natural products and man-made drugs. It shows that local pharmacies have been dispensing drugs based on hormesis for many decades. Among drugs that act via the hormetic dose response are those that combat anxiety and depression, make bones stronger, grow hair thicker, enhance cognitive function, and lessen pain. These drugs are some of the staples of the industry, permitting millions of people to live more normal and better lives. This chapter also shows that even when commonly used drugs such as antibiotics are administered to kill bacteria, they act hormetically at low doses and may be of concern because they can cause harmful bacterial colonies to grow. This is the case for antitumor drugs as well. Thus, the modern pharmacy is really a hormetic pharmacy, but this is really just the beginning. The currently unfolding future is one in which the biomedical and pharmaceutical giants will be developing so-called hormetic mimetics—drugs that can induce the normal adaptive pathways seen in the thousands of studies demonstrating hormesis but without exposing individuals to toxic doses of chemicals, ionizing radiation, extreme heat, or hard- to-maintain caloric restriction regimens. Screening chemicals based on their ability to activate, at subtoxic doses, specific adaptive cellular stress response pathways is a promising approach for drug development. The future pharmacy will be enhanced by research strategies and clinical practices that adopt hormetic principles and applications. Keywords Antidepressants · Cardiovascular disease · Dietary supplements · Dose and frequency · Nutriceuticals · Pharmaceutical industry E.J. Calabrese (B) Department of Environmental Health Sciences Division, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA e-mail: edwardc@schoolph.umass.edu 177M.P. Mattson, E.J. Calabrese, Hormesis, DOI 10.1007/978-1-60761-495-1_10, C© Springer Science+Business Media, LLC 2010 178 E.J. Calabrese and M.P. Mattson Introducing the Pharmacist to Hormesis The concept of hormesis is a central and integrative feature of modern pharmacol- ogy and the pharmaceutical industry. This may seem odd, given that neither entity has used the term very often, if at all. Yet entire areas of drug development (e.g., anxiolytic/antianxiety drugs, antiseizure drugs, cognitive/memory-enhancing drugs, male sexual dysfunction/erectile dysfunction drugs), as well as many other drugs on the market, are based to a considerable degree on the hormetic dose response. In fact, we would contend that the history of drug development, although empirically making use of the concept of hormesis and building an industry with it, has not been guided by its underlying theory and its numerous practical applications, thereby retarding the successful development of marketable drugs. We believe that the field of pharmacology and the pharmaceutical industry would benefit greatly from the use of hormesis-based strategies in drug discovery, development, and therapeutic applications within clinical settings. Hormesis-based concepts and approaches also extend to the regulatory community, such as the U.S. Food and Drug Administration (FDA), which could take a leadership role to provide direction in this critical area. This chapter assesses how the pharmaceutical and natural product industries have been using hormesis in the development of numerous products but without appreciating that the hormesis concept has been a driving factor in drug develop- ment and therapeutic dosing. It also shows how this lack of understanding impedes seeing hormesis as a general biological concept that could be applied to other crit- ical areas of the pharmaceutical industry. It addresses how hormesis affects key pharmacological concepts such as the dose response and its quantitative features, understandings of drug potency within a dose-response context, the width of the therapeutic zone, drug interactions, and the design of preclinical and clinical studies. A general overview of the occurrence of hormesis within a broad range of pharma- ceutical target areas is presented. A final section is directed toward the development of agents that can activate hormetic pathways (see the chapters Hormesis: What It Is and Why It Matters and The Devil Is in the Dose: Complexity of Receptor Systems and Responses for examples of specific hormetic signaling pathways), resulting in protection against a plethora of human diseases and age-related conditions. In effect, this chapter introduces the reader to the emerging world of the hormetic pharmacy. Why the Pharmaceutical Industry Is Missing the Hormesis Revolution The nature of research in the biomedical/pharmacological sciences has become progressively and strikingly specialized. This is seen with the development of a bewildering array of professional societies and their subsequent splintering and eventual subdividing into further, more focused specialties. Bates (1965) provided a detailed history of scientific societies throughout a large portion of the 20th The Hormetic Pharmacy 179 century. This hyperspecialization process has been widespread and has led to profound advances in all areas of scientific and engineering research. However, such specialization is not without it limitations or concerns. In most cases, each professional society develops its own means of communication, educational and technology plans, professional meetings, terminology, concepts, priorities, and agenda. Once closely related professional societies, no longer regularly commu- nicating, have even developed different names for the same concept. This is seen in the area of the dose response, where approximately two dozen terms, most often dis- cipline specific, have been used to describe the hormetic dose-response relationship (Calabrese, 2008a, b). In general, there is a strong tendency to only follow develop- ments in one’s narrow area of research and teaching interest. This tendency has had a major impact on the recognition of the hormetic dose response and its generaliza- tion and applications to other areas. In effect, the general nature of the hormetic dose response became lost or missed within this process of hyperspecialization as various biomedical subdisciplines failed to appreciate the general nature of the hormetic biphasic dose-response relationship and its broad implications. However, the resurgence of interest in the area of hormesis has revealed striking and impor- tant commonalities with respect to dose-response relationships across the various biological and biomedical disciplines. This comparative assessment of biphasic dose-response relationships has revealed similarities with respect to temporal and quantitative features and mechanistic strategies all set within a framework of bio- logical plasticity. Such assessments have revealed that most, if not all, drugs act within a hormetic framework. This finding supports the conclusion that the strong tendency toward specialization has tended to prevent the discovery of new processes based on the biological concept that essentially all cell types, tissues, and organisms follow an evolution-based hormetic dose-response strategy (see also chapter The Fundamental Role of Hormesis in Evolution). Hormesis and Biological Plasticity Dietary Factors Several dietary factors that have been conclusively shown to affect health and mod- ify the aging process exhibit biphasic dose responses. We believe that low doses of such dietary factors may exert their beneficial effects by imposing a mild stress on cells that is analogous to that of physical exercise. Regular light to moderate exercise decreases the risk of several major diseases, including cardiovascular dis- ease, stroke, diabetes, and Alzheimer’s disease (see the chapter Exercise-Induced Hormesis). In muscle cells and apparently in other cells, including those in the ner- vous and reproductive systems (van Praag, 2008; Chigurupati et al., 2008), exercise results in metabolic and oxidative stress. As long as the intensity and duration are not too extensive, the cells respond adaptively to the exercise period by increas- ing the production of proteins that increase their resistance to more severe stress and protect against degeneration and disease (Arumugam et al., 2006; Radak et al., 180 E.J. Calabrese and M.P. Mattson 2008). However, sustained high-intensity exercise can result in tissue damage and even death (Hubbard, 1990; Drory et al., 1991). One dietary factor that appears to tap into some of the same adaptive stress response pathways is moderate dietary energy restriction. Studies of humans have shown that excessive energy intake increases the risk for a range of major diseases, including diabetes, cardiovascular and cerebrovascular diseases, and several differ- ent types of cancer (Pender and Pories, 2005). Recent findings suggest that dietary energy restriction improves cardiovascular risk profiles (Fontana, 2008; Redman et al., 2008) and can reverse oxidative and inflammatory processes underlying dis- ease processes, including asthma (Johnson et al., 2007). In rodents moderate reduc- tions in energy intake (10% to 40%) and/or intermittent fasting increase lifespan and reduce the incidence of disorders such as diabetes, cancers, and sarcopenia (Carter et al., 2007; Colman et al., 2008). We and others have provided evidence that a major component of the mechanism by which moderate dietary energy restriction coun- teracts aging and protects cells against disease is by inducing a hormetic response (see the chapter Dietary Energy Intake, Hormesis, and Health). For example, dietary energy restriction results in increased production of neuroprotective proteins in brain cells, including brain-derived neurotrophic factor (BDNF), glial cell line–derived neurotrophic factor (GDNF), heat-shock proteins, and mitochondrial uncoupling protein 4 (Yu and Mattson, 1999; Lee et al., 2002; Maswood et al., 2004; Liu et al., 2006). Conversely, excessive energy intake may impair adaptive cellular stress response pathways (see the chapter Hormesis and Aging). Plants produce a remarkable array of chemicals and also contain numerous chem- icals produced by bacteria or fungi that live within (endophytes) or on (epiphytes) them (Strobel et al., 2004). The majority of drugs currently used in the clinic were derived from plants as either the purified natural product or synthetic analogs thereof (Grotewold, 2005; de Kok et al., 2008). For example, paclitaxel (Taxol) is a chemi- cal originally isolated from the yew tree that is used for cancer therapy; it stabilizes microtubules and thereby inhibits cell division (Adams et al., 1993). Of interest, it has recently been shown that paclitaxel is not produced by cells of the yew tree but by fungi that inhabit the tree (Miller et al., 2008). We have found that although high doses of paclitaxel are toxic, low doses can have beneficial effects on neurons, effectively protecting them against degeneration in experimental models relevant to stroke and Alzheimer’s disease (Furukawa and Mattson, 1995). One reason that many phytochemicals exert beneficial effects on cells is that they activate hormetic signaling pathways. Indeed, there is good evidence that metabolic pathways that generate hormetic phytochemicals evolved as a defense mechanism in which novel toxic chemicals are produced to protect the plant against insects and other organ- isms [see chapter The Fundamental Role of Hormesis in Evolution and Mattson and Cheng (2006)]. Several phytochemicals that can be classified as “botanical pesticides” have been shown to have interesting actions on the plasticity of brain cells in mammals. For example, curcumin (from the turmeric plant) enhances neurogenesis (the production of new nerve cells from stem cells) in rodents (Kang et al., 2006; Kim et al., 2008) and can improve learning and memory in mouse models of Alzheimer’s disease (Frautschy et al., 2001). The flavanol epicatechin, which is present in high amounts The Hormetic Pharmacy 181 in cocoa, enhanced retention of spatial memory and increased angiogenesis in the brains of mice (van Praag et al., 2007). Administration of sulforaphane attenuated the degeneration of photoreceptors in a mouse model of retinal degeneration (Kong et al., 2007). Resveratrol, a phytochemical present in red grapes, attenuated memory impairment and reduced neuronal degeneration in a mouse model of Alzheimer’s disease (Kim et al., 2007). As described in the chapter The Devil Is in the Dose: Complexity of Receptor Systems and Responses, many of the hormetic effects of low doses of phytochemicals are mediated by their activation of specific adaptive stress response pathways involving transcription factors such as Nrf2, FOXO, and NF-κB. We believe that in the future, research efforts that use hormetic principles to identify, characterize, and move forward drugs to the clinic will greatly expand the pharmacopeia and so improve health throughout the lifespan. Drugs Drugs have historically been directed toward treating diseases and increasing per- formance, such as improving cognition, strengthening bones, growing hair, and accelerating healing times, among others, or in killing threatening organisms, such as harmful bacteria, fungi, yeasts, or viruses, or killing tumor cells. In the case of increasing performance, such responses are seen to occur at the lower end of the dose-response relationship. In the case of the killing activities, these are typically observed at the higher end of the dose-response relationship. Thus, the pharmaceu- tical industry is interested in the entire dose-response continuum, depending on the endpoints of concern. The hormetic dose response is unique in that it indicates that there is biological activity below pharmacological and toxicological thresholds. The key concept to understanding this low-dose stimulation within a pharmaceutical framework is that it relates to biological performance. That is, the low-dose stimulation is a manifes- tation of gain the system permits and it is this function that many pharmaceuticals are designed to exploit. However, as will be shown, the capacity of gains in per- formance is limited to the percentage range rather than the fold range, and this is a consistent feature seen across all biological systems. For example, at low doses, aspirin inhibits platelet aggregation and clot formation, at moderate doses it has anti-inflammatory actions, and at high doses it can cause severe bleeding and even death. In the case of hormetic dose responses, an assessment of many thousands of examples reveals that the maximum stimulation (i.e., biological performance) is typically modest, being only 30% to 60% greater than control values. This has been reported for a wide range of plants (Calabrese and Blain, 2009), microorganisms (Calabrese and Blain, 2005), cell lines (noncancer and cancer) (Calabrese, 2005), physiological functions, and responses of whole organisms. This prevalent obser- vation is critical because it suggests strongly that pharmaceutical agents that act hormetically will have the magnitude of the response set within a maximum range of 30% to 60%, being constrained by inherent biological limits that we regard as a quantitative description of biological plasticity. Hormesis therefore sets limits on 182 E.J. Calabrese and M.P. Mattson what drug and pharmaceutical companies can expect to achieve with drug treat- ments. This important limitation has not been widely recognized or discussed within the pharmacological and/or pharmaceutical literature. Yet it is the prime controlling feature affecting drug performance. This is a critical perspective, especially in terms of what the health care industry can expect to achieve and what patient expectations of treatment should be. The issue of whether and how it may be possible to avoid the constraints of biological plasticity within the context of improving performance is an important theoretical question and one that is likely to be explored as the biological engineer- ing of molecular systems evolves. However, it is important to recognize that these apparent biological constraints are very generalizable and long conserved within an evolutionary context. It is unknown what the biological implications would be if one were able to engineer around the constraints imposed by biological plastic- ity to achieve increases in biological performance that far exceeded the limits seen within the hormetic dose-response context. It would be expected that most systems will have redundant controls that could be activated should one be eliminated via a genetic or chemically induced manipulation. Based on this assumption, the prospect of chemically exceeding constraints imposed by biological plasticity is not likely to be easily achieved, but it nonetheless would be an intellectually compelling area of research. Implications of the Quantitative Features of the Hormetic Dose Response for the Pharmaceutical and Nutraceutical Worlds The quantitative features of the hormetic dose response can have important implica- tions for the drug and nutraceutical industries. In fact, these quantitative features of the hormetic dose response are basic to this issue of “getting the dose right” because they guide scientists and physicians on the magnitude of the response, the range over which it works, and its relationship to the onset of toxicity. Limiting the maximum increase in performance to only 30% to 60% has impor- tant implications for the selection of the biological model, study design, sample size, and statistical power, as well the number and spacing of doses within the hormetic zone. It affects how much a patient can be helped by the drug treatment that exploits the hormetic zone for a beneficial outcome. It also affects how much a patient may be damaged by a treatment within the low-dose zone that leads to undesirable effects. In the following we discuss how the concept of hormesis may affect a number of critical aspects of the process of hazard assessment. Biological Model Selection Hormesis can be very difficult to discern in experimental studies. One reason is that the magnitude of the hormetic stimulation is generally quite modest. If the biological model selected for study has high control-group variability for the endpoint of The Hormetic Pharmacy 183 interest, then it creates a serious limitation with respect to being able to distinguish a hormetic response from chance or normal variability. Biological models with high background variability place considerable pressure on the need for larger sample sizes to have adequate statistical power. Failure to take this into account could lead to missing the potential to discern a statistically significant response. This is a com- mon failure of many studies in which the investigator is unaware of the hormesis concept. In effect, the lack of a rigorous study design and/or statistical sensitivity prevents an evaluation of a potential low-dose hormetic response. Another issue with biological models and hormesis is that drug treatments that are testing whether an agent can reduce disease incidence need to employ a control group with a relatively high disease incidence to test whether the drug treatment can reduce the disease incidence in a hormetic fashion. In the drug testing domain this is typically accomplished by inducing a disease and then assessing whether the treatment reduces the occurrence of the disease condition. This is perhaps the most cost-effective approach for addressing this issue, although it has its limitations. The induced disease may not be an excellent model of the h