The Pharmaceutical Journal Vol 267 No 7175 p759
24 November 2001

Manchester school of pharmacy

Medicines: from research to practice

Identifying proteins from the human genome will become simple over the next decade, Professor Graham Richards, University of Oxford, told symposium participants.

But academics need to look one step beyond this, he said. "It is not inconceivable that all protein structures will be known before long, but there are billions of small molecules [which interact with proteins] that will have the properties that are required to make a drug."

Professor Richards went on to describe work his group was doing on developing methods to screen billions of molecules. The Screensaver Lifesaver project uses computer software in screensavers to work out where a particular molecule could bind within a protein known to be involved in cancer.

Participants in the project obtain the special screensaver for their personal computer (PC) with a model of a protein built in. They are then sent a virtual batch of small molecules over the internet for the screensaver to test. The software creates three-dimensional models and looks for interactions between the molecule and protein. Professor Richards explained that the method, which is based on pattern matching, was crude because the screensavers can only support a certain amount of software. At the outset of the project, the group had hoped to screen 100 million molecules against four proteins. In fact, the project is able to screen 3.5 billion molecules against a target protein in just two days. "This is many orders of magnitude more than the pharmaceutical industry could manage," he said.

Dr DENNIS SMITH, Pfizer Ltd, described ways in which pharmacokinetics could be used to improve molecules and allow drugs to be of benefit to more patients. Drug effects varied between patients and one reason for this was that patients took drugs when they remembered, not necessarily as prescribed.

Taking certain drugs without food means that they can go from being efficacious to non-efficacious, he said. However, in drug design there are a number of things that can be done to combat this problem.

Ketoconazole, the first orally active antifungal, is effective but highly lipophilic and therefore poorly soluble, said Dr Smith. Incomplete absorption can occur resulting in a loss of specificity. Working on a follow-on drug, the pharmaceutical industry was able to reduce the lipophilicity associated with ketoconazole and develop fluconazole, which gives complete absorption and is unaffected by food.

There were other ways of improving drugs, said Dr Smith. Polymorphic metabolism means that drugs show different degrees of efficacy among patient populations. By designing drugs that do not fit the cytochrome P450 2D6 template, it was possible to decrease variation among the population.

"The pharmaceutical industry is arrogant in that it issues labelling for directions and expects patients to comply." However, only one sixth of patients take drugs as they are prescribed, he said. To help patients follow directions, drugs ideally need to be taken once daily. And in order to produce once daily drugs, they need to be designed so they have a long half-life. One way of doing this is to increase the volume of the drug molecule and so increase its interactions in the body. Dr Smith gave the examples of nifedipine and amlodipine. Amlodipine was similar to nifedipine in terms of its metabolic action but its larger volume translated to a 40 hour half-life, sufficient for once daily dosing.

Similarly, drug design has been used to improve erythromycin, he said. Azithromycin has two basic centres, which results in an increase in volume and hence a longer half-life. "This was a big step forward but only a slight change in structure."

Dr Smith went on to say that there needed to be "forgiveness" in drug design whereby the duration of action of a drug was longer than the dosage interval. This means that if a patient misses a dose, they are still getting therapy. "We have to incorporate the behaviour of the patient into drug design."

Professor DAVID ATTWOOD, University of Manchester, described some of the school's research activities in the area of drug delivery. Block co-polymers were being designed for solubilisation of poorly water-soluble drugs. "The idea is to produce areas within the core [of the block co-polymer] that the drug will prefer to reside in." It was also possible to use multilayered micelles to provide a choice for the drug of where to reside, he said.

Block co-polymers could be used in controlled drug delivery. It was possible to move from a mobile solution to a gel by increasing the temperature of the block co-polymer. This solution–gel transition was useful for forming subcutaneous implants because it was possible to inject a solution which then turned to a gel at body temperature.

One problem with this technique was that the gel is left under the skin. "We are still working on ways to make the gel biodegradeable," he said.

Dr SUE AMBLER, head of practice research, Royal Pharmaceutical Society, told the symposium that creating health for the population provided the focus for all those involved in discovering, developing and deploying medicines.

"There is growing recognition that to maximise benefits and minimise risks, we need to consider not just the medicines themselves, but also the systems and contexts in which they are prescribed, supplied, administered and taken." Practice research should inform and be informed by pharmaceutical science, she said.

The contribution that research had made to the development of the pharmacy programme could not be underestimated. The fact that the evidence base was available when policy makers wanted to make changes was fortuitous, said Dr Ambler. "For a profession that is neither large [in number], like the nurses, nor politically powerful, like the medics, robust research provides the impetus for pharmacists to be considered as key players in the modernised National Health Service," she concluded.