Opinion
Polypharmacology Shakes Hands with Complex Aetiopathology

https://doi.org/10.1016/j.tips.2015.08.010Get rights and content

Trends

Some successful ‘selective’ single target drugs were shown to act via multiple mechanisms or ‘repositioned’ for the treatment of other conditions because of their ability to interact with ‘off-targets’.

The use of polypharmacy is not uncommon in clinical practice and represents a way of addressing the multifactorial aetiology of disorders and their ensuing complications and comorbidities.

Many tools are available to accelerate discovery of single target drugs but new models to predict the efficacy/safety of multitarget drugs and their combinations are required.

A model is proposed here to describe the spatiotemporal fit between target activation/repression required in disorders and multitarget treatments.

‘Polypharmacological handprints’ are matched to ‘aetiopathological handprints’ establishing a ‘therapeutic handshake’.

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex®), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the ‘therapeutic handshake’, to predict efficacy/safety of compound combinations of either natural or synthetic origin.

Section snippets

Introduction: The Demise of ‘Magic Bullets’?

One hundred years ago the term ‘magic bullet’ was coined by Paul Ehrlich for medicines with highly specific properties. He discovered that compound ‘606’ within a library of synthesised arsenic analogues was the most effective treatment for syphilis: the world's first example of ‘lead optimisation’ [1]. Now we know that diseases are characterised by dysregulation of enzymes, receptors, and signal transduction pathways, whose pharmacological modulation is an appropriate way to treat

Existing ‘Multitarget’ Approaches and Barriers to the Development of New Ones

Nowadays, it is not uncommon for patients to have a collection of medicines for each facet of a complex diagnosis, often designed through clinical experience. A very recent review article emphasised how combination therapy is four times more likely to result in the success of obesity clinical trials than single drug therapy [25]. Likewise, diabetes is managed with medications for insulin resistance [26], hypertension [27], and dyslipidemia [28], and cancer treatments combine cytotoxic drugs

Considerations When Designing a Predictive Model for Multitarget Medicines

‘Targets’ are defined as molecular structures, or systems thereof, with which a chemical can interact. This interaction must correlate with a meaningful downstream effect, which, in the case of proteins, can usually be determined through biochemical assays or X-ray crystallography [3]. This could be followed by gene deletion studies to determine if ‘knockout’ models provide confirmation that loss of protein correlates to a loss of efficacy [40]. This concept has been the basis of modern drug

A First Step towards an Empirical Predictive Model for Multitarget Drugs: The ‘Therapeutic Handshake’

When defining the molecular basis of physiological or pathological states where targets need to be corrected (i.e., activated or repressed) for therapeutic gain, we have coined the term ‘requisite/desirable pharmacology’. This includes compensatory or adaptive/maladaptive mechanisms (i.e., endogenous systems that are being altered as a disease progresses and which either counteract the disease or contribute to the symptoms as the disease progresses). These must therefore be manipulated

The ‘Therapeutic Handshake’ Explains the Efficacy and Relative Safety of Sativex®

‘Nabiximols’, marketed in more than 20 countries as Sativex®, is a drug approved for treating spasticity due to multiple sclerosis (MS) and is in Phase III development for cancer pain. It is an oral spray that contains two principal cannabinoids (Box 2), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) [60], as well as other minor cannabinoid and non-cannabinoid plant constituents. Initial academic research in the field of plant cannabinoids focused almost exclusively on THC, reporting its

The ‘Therapeutic Handshake’ Suggests Efficacy of a Cannabidiol/5-ASA Combination in Inflammatory Bowel Disease

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease affecting the colon. It causes pain, urgent diarrhoea, severe tiredness, and loss of weight. In addition, patients with UC have an increased risk of developing colorectal cancer [88]. Medical treatment for UC has two main goals: achieving remission (the near absence of symptoms) and, once that is accomplished, maintaining it (prevention of ‘flare-ups’); hence, treatment is aimed at controlling the ongoing colonic

The ‘Therapeutic Handshake’ Suggests Efficacious and Safe Cannabinoid-Based Treatments for Epilepsy

Epilepsy is one of the most common neurological disorders in adults and children. Russ recently reported that, according to the National Survey of Children's Health conducted on over 90 000 American children in 2007, there was a point prevalence of 6.3 per 1000 children currently diagnosed with epilepsy [94]. Specialists estimate that over one-third of these cases show pharmacoresistance to current treatments [95], meaning that seizures persist, despite accurate diagnosis and carefully monitored

Concluding Remarks

We have discussed the rationale for the use of polypharmacology in the treatment of multifactorial diseases, and hence for the development of a model to eventually predict the efficacy and safety of multitarget drugs, alone or in combination with other drugs, in a given disease. We have also described a possible first step towards the development of such a model, the ‘therapeutic handshake’, which explains a posteriori the efficacy and safety of Sativex® against MS spasticity and neuropathic

Disclaimer statement

J.B. is an employee of GW Pharmaceuticals. V.D. acts as a consultant for GW Pharmaceuticals and is the recipient of research grants from GW Pharmaceuticals and Epitech Italy. G.W.G. is the chairman of GW Pharmaceuticals.

Acknowledgments

The authors are very grateful to Professor Angelo Izzo, Endocannabinoid Research Group, Department of Pharmacy, University ‘Federico II’, Naples, for sharing unpublished data on cannabidiol and 5-ASA in the dinitrobenzene sulfonic acid (DNBS) model of colitis and for his help at identifying the targets shown in Figure 3; and to Joel Boyer for his contributions to the illustrations used in all figures.

References (159)

  • V.V. Uteshev

    The therapeutic promise of positive allosteric modulation of nicotinic receptors

    Eur. J. Pharmacol.

    (2014)
  • I.G. Karniol

    Cannabidiol interferes with the effects of delta 9-tetrahydrocannabinol in man

    Eur. J. Pharmacol.

    (1974)
  • D. Baker

    The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis

    Mult. Scler. Relat. Disord.

    (2012)
  • E. de Lago

    In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake

    Eur. J. Pharmacol.

    (2004)
  • D.J. Rog

    Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial

    Clin. Ther.

    (2007)
  • R.K. Portenoy

    Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial

    J. Pain

    (2012)
  • J.R. Johnson

    Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain

    J. Pain Symptom Manage.

    (2010)
  • J.R. Johnson

    An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics

    J. Pain Symptom Manage.

    (2013)
  • J.D. Feuerstein et al.

    Ulcerative colitis: epidemiology, diagnosis, and management

    Mayo Clin. Proc.

    (2014)
  • W.A. Faubion

    The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study

    Gastroenterology

    (2001)
  • N.A. Jones

    Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures

    Seizure

    (2012)
  • B.E. Porter et al.

    Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy

    Epilepsy Behav.

    (2013)
  • F. Bosch et al.

    The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize

    Pharmacology

    (2008)
  • J.P. Hughes

    Principles of early drug discovery

    Br. J. Pharmacol.

    (2011)
  • N.A. Listed

    Recent pa-tent applications in high-throughput drug screening

    Nat. Biotechnol.

    (2010)
  • H.F. Ji

    Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia?

    EMBO Rep.

    (2009)
  • A. Fleming

    Classics in infectious diseases: on the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae by Alexander Fleming, Reprinted from the British Journal of Experimental Pathology 10:226–236, 1929

    Rev. Infect. Dis.

    (1980)
  • J. Gonzalez-Gallego

    Fruit polyphenols, immunity and inflammation

    Br. J. Nutr.

    (2010)
  • A. Cuevas

    Modulation of immune function by polyphenols: possible contribution of epigenetic factors

    Nutrients

    (2013)
  • M.E. Baker

    Xenobiotics and the evolution of multicellular animals: emergence and diversification of ligand-activated transcription factors

    Integr. Comp. Biol.

    (2005)
  • M.D. Rawlins

    Variability in response to drugs

    Br. Med. J.

    (1974)
  • Q. Ma et al.

    Pharmacogenetics, pharmacogenomics, and individualized medicine

    Pharmacol. Rev.

    (2011)
  • P. Farahani et al.

    Pharmacovigilance in a genomic era

    Pharmacogenomics J.

    (2006)
  • M.D. Rawlins

    Cutting the cost of drug development?

    Nat. Rev. Drug Discov.

    (2004)
  • H.G. Eichler

    Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma

    Nat. Rev. Drug Discov.

    (2008)
  • I. Kola

    The state of innovation in drug development

    Clin. Pharmacol. Ther.

    (2008)
  • M.J. Keiser

    Predicting new molecular targets for known drugs

    Nature

    (2009)
  • V.C. Jordan

    Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer

    Br. J. Pharmacol.

    (1993)
  • F. Armani

    Tamoxifen use for the management of mania: a review of current preclinical evidence

    Psychopharmacology

    (2014)
  • J.J. Lu

    Multi-target drugs: the trend of drug research and development

    PLoS ONE

    (2012)
  • A. Petrelli et al.

    From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage

    Curr. Med. Chem.

    (2008)
  • H. Zheng

    From single target to multitarget/network therapeutics in Alzheimer's therapy

    Pharmaceuticals (Basel)

    (2014)
  • H.T. Hussain

    Clinical trial success rates of anti-obesity agents: the importance of combination therapies

    Obes. Rev.

    (2015)
  • C. Arauz-Pacheco

    Treatment of hypertension in adults with diabetes

    Diabetes Care

    (2003)
  • K.A. Spratt

    Managing diabetic dyslipidemia: aggressive approach

    J. Am. Osteopath. Assoc.

    (2009)
  • A.M. Scott

    Antibody therapy of cancer

    Nat. Rev. Cancer

    (2012)
  • M. Vanneman et al.

    Combining immunotherapy and targeted therapies in cancer treatment

    Nat. Rev. Cancer

    (2012)
  • H.M. Shepard

    Herceptin

    Handb. Exp. Pharmacol.

    (2008)
  • C. Chen

    Editorial: Signalling pathways in anti-cancer drug resistance

    Curr. Med. Chem.

    (2014)
  • B.L. Roth

    Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia

    Nat. Rev. Drug Discov.

    (2004)
  • Cited by (31)

    • A perspective on cannabinoids for treating epilepsy: Do they really change the landscape?

      2020, Neuropharmacology
      Citation Excerpt :

      Preclinical studies further suggest that GPR55 might be a primary target of action in a well validated mouse model of Dravet syndrome (Kaplan et al., 2017). Others have also postulated there may be targeting of abnormal sodium channels, modulation of voltage-dependent anion selective channel protein (VDAC1), and of Tumour necrosis factor alpha release (Bialer et al., 2018; Brodie et al., 2015). Presynaptic CBD also has affinity for 5-Hydroxytryptamine (5HT) 1a and 2a receptors, but pre-treatment with serotonin antagonists doesn't block the antiseizure effects, so this may not be relevant (Brodie et al., 2015).

    • Multi-target therapeutics for neuropsychiatric and neurodegenerative disorders

      2016, Drug Discovery Today
      Citation Excerpt :

      A transition then occurred toward rational drug design, which resulted in molecules that lacked the multiple actions of the naturally occurring compounds. It was this approach that led to the ‘one drug for one target’ principle of drug design, which bore molecules that would never naturally exist and whose presence in the body would often induce unpredictable biological interactions [2]. Despite the presence of numerous successful marketed magic bullets there are also many existing marketed molecules that are now known to have a polypharmacological effect primarily as a result of the integration of specific targets within numerous biological networks, thus making the magic bullets victims to redundancy or adaptation [2].

    View all citing articles on Scopus
    View full text