Trends in Pharmacological Sciences
OpinionPolypharmacology Shakes Hands with Complex Aetiopathology
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.
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