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Different people respond differently to any given drug, even if they present with essentially identical disease symptoms, e.g. optimum dose requirements can vary significantly.
Furthermore, not all patients respond positively to a specific drug (e.g. interferon-b is of clinical benefit to only one in three multiple sclerosis patients; see Chapter 4). The range and severity of adverse effects induced by a drug can also vary significantly within a patient population base.
While the basis of such differential responses can sometimes be non-genetic (e.g. general state of health, etc), genetic variation amongst individuals remains the predominant factor. While all humans display almost identical genome sequences, some differences are evident. The most prominent widespread-type variations amongst individuals are known as single nucleotide polymorphisms (SNPs, sometimes pronounced ‘snips’). SNPs occur in the general population at an average incidence of one in every 1000 nucleotide bases and hence the entire human genome harbours 3 million or so. SNPs are not mutations; the latter arise more infrequently, are more diverse and are generally caused by spontaneous/mutagen-induced mistakes in DNA repair/ replication. SNPs occurring in structural genes/gene regulatory sequences can alter amino acid sequence/expression levels of a protein and hence affect its functional attributes. SNPs largely account for natural physical variations evident in the human population (e.g. height, colour of eyes, etc.).
The presence of a SNP within the regulatory or structural regions of a gene coding for a protein which interacts with a drug could obviously influence the effect of the drug on the body. In this context, the protein product could, for example, be the drug target or perhaps an enzyme involved in metabolizing the drug.
The identification and characterization of SNPs within human genomes is, therefore, of both academic and applied interest. Several research groups continue to map human SNPs and over 1.5 million have thus far been identified.
By identifying and comparing SNP patterns from a group of patients responsive to a particular drug with patterns displayed by a group of unresponsive patients, it may be possible to identify specific SNP characteristics linked to drug efficacy. In the same way, SNP patterns or characteristics associated with adverse reactions (or even a predisposition to a disease) may be uncovered. This could usher in a new era of drug therapy, where drug treatment could be tailored to the individual patient. Furthermore, different drugs could be developed with the foreknowledge that each would be efficacious when administered to specific (SNP-determined) patient sub-types. A (distant) futuristic scenario could be visualized where all individuals could carry chips encoded with SNP details relating to their specific genome, allowing medical staff to choose the most appropriate drugs to prescribe in any given circumstance.
Linking specific genetic determinants to many diseases, however, is unlikely to be as straightforward as implied thus far. The progress of most diseases, and the relative effectiveness of allied drug treatment, is dependent upon many factors, including the interplay of multiple gene products. ‘Environmental’ factors, such as patient age, sex and general health, also play a prominent role.
The term ‘pharmacogenomics’ is one which has entered the ‘genomic’ vocabulary. Although sometimes used almost interchangeably with pharmacogenetics, it more specifically refers to studying the pattern of expression of gene products involved in a drug response.
Plants as a source of drugs
Traditionally, drug discovery programmes within the pharmaceutical industry relied heavily upon screening various biological specimens for potential drugs. Prior to the 1950s, the vast bulk of drug substances discovered were initially extracted from vascular plants (see also
THE DRUG DEVELOPMENT PROCESS 53
Chapter 1). Examples include digoxin and digitoxin, originally isolated from the foxglove (a
member of the genus Digitalis), as well as aspirin, codeine and taxol.
Today, well over 100 drugs (accounting for 25% of all prescriptions issued in the USA), were initially isolated from vascular plants. While some are still extracted from their native source, most are now obtained more cheaply and easily by direct chemical synthesis or semi-synthesis.
Plants are a rich potential source of drugs as they produce a vast array of novel bioactive molecules, many of which probably serve as chemical defences against infection or predation. In addition, the variety of different plant species present on the earth is staggering. There exist well over 265 000 flowering species alone, of which less that 1% have, thus far, been screened for the presence of any bioactive molecules of potential therapeutic use.