On a quest for colour-blind drugs

September 3, 2008

On a quest for colour-blind drugs

TAKE a ball of silly putty and stretch it slowly: it pulls out in a smooth, floppy string without lumps or breaks. For Charles Darwin and the many evolutionary theorists who followed in the next century, human development was like that: a smooth transition from monkeys to man. True, there was a �missing link� somewhere, but human populations were thought to occur along a continuum in which all races blended imperceptibly into each other.

The paradigm began to break down as scientists realised that populations on different continents had developed along varied genomic pathways from their original African roots. We are still one species, but our genes clump around certain group characteristics and this has enormous implications
for our health.

Many people of African origin don�t respond well to certain blood pressure drugs that are routinely prescribed for Europeans. As knowledge of genetic differences in drug metabolism grows, it is becoming clear that more refined drug therapies are needed to cope with genetic variations.

When a drug is taken, it is metabolised, or broken down, and removed by the body by means of specialised enzyme systems. But
drug developers have found that medications may be excreted from the body too fast, or used too slowly, or remain too long, causing side effects.

According to a study presented at the American Society for Clinical Pharmacology Therapeutics in 2000, more than a million African-Americans with a genetic variation of a certain liver enzyme may be at risk for bleeding problems when they take the anticoagulant drug, warfarin.

In the past decade, human genome studies have identified genetic associations affecting blood pressure or weight in different populations spread across the world. The new science of population genomics, as described by one its leaders, geneticist Prof LB Jorde at the University of Utah, is a bridge from evolutionary history to genetic medicine.

�Evolutionary genetic studies yield critical clues about the histories of human populations, and they provide substantial support for an African origin of modern humans,� wrote Jorde and colleagues in Human Molecular Genetics in 2001.

Jorde says the variation between the original populations within continents is much less than the variation between populations on different continents. In other words, there are disparities in drug metabolism between Africans, Asians and Europeans.

This is despite the fact that human genetic diversity is relatively low, compared with other species, due to our fairly recent evolutionary origin. The human putty of which we are all made may be all very similar, but our inherited differences are crucial for designing appropriate drug therapies.

To the credit of Africans themselves, researchers on this continent are making a huge contribution in the field. A Zimbabwean biomedical scientist based in Harare has helped scientists across the globe to understand how Africans metabolise certain drugs.

�My work probably has great implications for emerging African business executives needing treatment for heart disease and hypertension,� says Dr Collen Masimirembwa, chief scientific officer and founder of the African Institute of Biomedical Science and Technology, a private research and education establishment in Harare. �As much as their money might fly them to Europe or US, their genetic make-up will haunt them if it is not addressed with respect to the variability that
our results are indicating.�

Masimirembwa, who was a principal scientist with AstraZeneca in Sweden for eight years, says Africans are likely to respond differently to drugs discovered and optimised for use in Caucasian populations. Specifically, the enzyme variant, CYP2D6*17, which Masimirembwa discovered, would have implications when taking beta blockers such as metoprolol for high blood pressure. Metoprolol is used in treatment of angina as well as the prevention of heart attacks, but is known to carry a risk that if the treatment suddenly stops, it can worsen the heart condition.

Various tests have suggested that metoprolol has a clear advantage over some other hypertensive drugs for reducing kidney damage and preventing death, but these findings could turn out to be misleading when applied to Africans. Further research is needed. The distinctive contribution of Masimirembwa and his colleagues locally and abroad has been to show that genetic variability must be taken into account when searching for new or improved medicines. His research is likely to prompt the biotechnology industry to develop special diagnostic tools for Africa.

�This will lead to a serious revision of the position of one drug, one dose, or one diagnostic tool which, developed in Europe, fits all approaches and which drives current diagnostic and clinical medicine,� he says.

Drug discovery is a difficult enough business without this complication. Companies spend billions on exhaustive high-throughput screening of compounds that might yield treatments for common diseases, and then the developers must prove through clinical trials that a new drug does not have adverse effects.

One of the major concerns of drug regulators is adverse drug reactions and interactions between drugs, as well as between drugs and herbs. A new product is unlikely to pass with the US Food and Drug Administration if such adverse effects make their appearance.

Masimirembwa and University of Cape Town organic chemist Prof Kelly Chibale, a Zambian, have collaborated on identifying drug-drug and drug-herb interactions. The fact that more than 80% of patients in Africa at one time or another combine traditional medicine and conventional drugs
gives this work a special urgency.

The findings may lead to changes in the labelling of some products, and the education of doctors, pharmacists and patients to be cautious in the African setting. A software package is planned to help physicians make intelligent and safe choices.

Has it been difficult to accomplish all of this from Zimbabwe in its dark years? Masimirembwa says there has been a loss of skilled manpower to other countries, and most patients cannot afford diagnostic services due to the hyperinflation.

Some funders are not keen to support research in countries where bilateral relationships with their mother countries are strained. But there has been continuing support from the World Health Organisation, Special Programme for Research and Training in Tropical Diseases, International Programme in Chemical Sciences and the European Union, says Masimirembwa.

These funders �have understood and realised that biomedical
research must transcend these circumstances�, he says.

BUSINESS DAY 27th August 2008

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