Chapter 3 Therapeutic modalities

Introduction

Therapeutics in its broadest sense covers all types of intervention aimed at alleviating the effects of disease. The term ‘therapeutics’ generally relates to procedures based on accepted principles of medical science, that is, on ‘conventional’ rather than ‘alternative’ medical practice.

The account of drug discovery presented in this book relates exclusively to conventional medicine – and for this we make no apology – but it needs to be realized that the therapeutic landscape is actually much broader, and includes many non-pharmacological procedures in the domain of conventional medicine, as well as quasi-pharmacological practices in the ‘alternative’ domain.

As discussed in Chapter 2, the desired effect of any therapeutic intervention is to improve symptoms or prognosis or both. From a pathological point of view, therapeutic interventions may be directed at disease prevention, alleviation of the effects of existing disease, or permanent cure (i.e. restoration to a state of function and prognosis equivalent to those of a healthy individual of the same age, without the need for continuing therapeutic intervention). In practice, there are relatively few truly curative interventions, and they are mainly confined to certain surgical procedures (e.g. removal of circumscribed tumours, fixing of broken bones) and chemotherapy of some infectious and malignant disorders. Most therapeutic interventions aim to alleviate symptoms and/or improve prognosis, and there is increasing emphasis on disease prevention as an objective.

It is important to realize that many types of intervention are carried out with therapeutic intent whose efficacy has not been rigorously tested. This includes not only the myriad alternative medical practices, but also many accepted conventional therapies for which a sound scientific basis may exist but which have not been subjected to rigorous clinical trials.

Therapeutic interventions that lie within the field of conventional medicine can be divided into the following broad categories:

• Advice and counselling (e.g. genetic counselling)

• Psychological treatments (e.g. cognitive therapies for anxiety disorders, depression, etc.)

• Dietary and nutritional treatments (e.g. gluten-free diets for coeliac disease, diabetic diets, etc.)

• Physical treatments, including surgery, radiotherapy

• Pharmacological treatments – encompassing the whole of conventional drug therapy

• Biological and biopharmaceutical treatments, a broad category including vaccination, transplantation, blood transfusion, biopharmaceuticals (see Chapters 12 and 13), in vitro fertilization, etc.

On the fringe of conventional medicine are preparations that fall into the category of ‘nutriceuticals’ or ‘cosmeceuticals’. Nutriceuticals include a range of dietary preparations, such as slimming diets, and diets supplemented with vitamins, minerals, antioxidants, unsaturated fatty acids, fibre, etc. These preparations generally have some scientific rationale, although their efficacy has not, in most cases, been established by controlled trials. They are not subject to formal regulatory approval, so long as they do not contain artificial additives other than those that have been approved for use in foods. Cosmeceuticals is a fancy name for cosmetic products similarly supplemented with substances claimed to reduce skin wrinkles, promote hair growth, etc. These products achieve very large sales, and some pharmaceutical companies have expanded their business in this direction. We do not discuss these fringe ‘ceuticals’ in this book.

Within each of the medical categories listed above lies a range of procedures: at one end of the spectrum are procedures that have been fully tried and tested and are recognized by medical authorities; at the other is outright quackery of all kinds. Somewhere between lie widely used ‘complementary’ procedures, practised in some cases under the auspices of officially recognized bodies, which have no firm scientific foundation. Here we find, among psychological treatments, hypnotherapy and analytical psychotherapy; among nutritional treatments, ‘health foods’, added vitamins, and diets claimed to avoid ill-defined food allergies; among physical treatments, acupuncture and osteopathy; among chemical treatments, homeopathy, herbalism and aromatherapy. Biological procedures lying in this grey area between scientific medicine and quackery are uncommon (and we should probably be grateful for this) – unless one counts colonic irrigation and swimming with dolphins.

In this book we are concerned with the last two treatment categories on the list, summarized in Table 3.1, and in this chapter we consider the current status and future prospects of the three main fields; namely, ‘conventional’ therapeutic drugs, biopharmaceuticals and various biological therapies.

Table 3.1 The main types of chemical therapeutic agent

Conventional therapeutic drugs

Small-molecule drugs, either synthetic compounds or natural products, have for a long time been the mainstay of therapeutics and are likely to remain so, despite the rapid growth of biopharmaceuticals in recent years. For their advantages and disadvantages see Box 3.1.

Box 3.1

Advantages and disadvantages of small-molecule drugs

Advantages

• ‘Chemical space’ is so vast that synthetic chemicals, according to many experts, have the potential to bind specifically to any chosen biological target: the right molecule exists; it is just a matter of finding it.

• Doctors and patients are thoroughly familiar with conventional drugs as medicines, and the many different routes of administration that are available. Clinical pharmacology in its broadest sense has become part of the knowledge base of every practising doctor, and indeed, part of everyday culture. Although sections of the public may remain suspicious of drugs, there are few who will refuse to use them when the need arises.

• Oral administration is often possible, as well as other routes where appropriate.

• From the industry perspective, small-molecule drugs make up more than three-quarters of new products registered over the past decade. Pharmaceutical companies have long experience in developing, registering, producing, packaging and marketing such products.

• Therapeutic peptides are generally straightforward to design (as Nature has done the job), and are usually non-toxic.

Disadvantages

• As emphasized elsewhere in this book, the flow of new small-molecule drugs seems to be diminishing, despite increasing R&D expenditure.

• Side effects and toxicity remain a serious and unpredictable problem, causing failures in late development, or even after registration. One reason for this is that the selectivity of drug molecules with respect to biological targets is by no means perfect, and is in general less good than with biopharmaceuticals.

• Humans and other animals have highly developed mechanisms for eliminating foreign molecules, so drug design often has to contend with pharmacokinetic problems.

• Oral absorption is poor for many compounds. Peptides cannot be given orally.

Although the pre-eminent role of conventional small-molecule drugs may decline as biopharmaceutical products grow in importance, few doubt that they will continue to play a major role in medical treatment. New technologies described in Section 2, particularly automated chemistry, high-throughput screening and genomic approaches to target identification, have already brought about an acceleration of drug discovery, the fruits of which are only just beginning to appear. There are also high expectations that more sophisticated drug delivery systems (see Chapter 16) will allow drugs to act much more selectively where they are needed, and thus reduce the burden of side effects.

Biopharmaceuticals

For the purposes of this book, biopharmaceuticals are therapeutic protein or nucleic acid preparations made by techniques involving recombinant DNA technology (Walsh, 2003), although smaller nucleotide assemblies are now being made using a chemical approach. Although proteins such as insulin and growth hormone, extracted from human or animal tissues, have long been used therapeutically, the era of biopharmaceuticals began in 1982 with the development by Eli Lilly of recombinant human insulin (Humulin), made by genetically engineered Escherichia coli. Recombinant human growth hormone (also produced in E. coli), erythropoietin (Epogen) and tissue plasminogen activator (tPA) made by engineered mammalian cells followed during the 1980s. This was the birth of the biopharmaceutical industry, and since then new bioengineered proteins have contributed an increasing proportion of new medicines to be registered (see Table 3.1 for some examples, and Chapters 12 and 22 for more details). The scope of protein biopharmaceuticals includes copies of endogenous mediators, blood clotting factors, enzyme preparations and monoclonal antibodies, as well as vaccines. See Box 3.2 for their advantages and disadvantages. This field has now matured to the point that we are now facing the prospect of biosimilars consequent on the expiry of the first set of important patents in 2004 and notwithstanding the difficulty of defining ‘difference’ in the biologicals space (Covic and Kuhlmann 2007).

Box 3.2

Advantages and disadvantages of biopharmaceuticals

Advantages