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The Bioavailability of DigoxinMOST doctors in Britain will by now have received

a circular letter from Burroughs Wellcome & Co.,entitled WARNING—DIGOXIN. Apparently a changein the manufacturing process of Burroughs Wellcomedigoxin (’ Lanoxin ’) has led to the production andmarketing of lanoxin tablets, of both the 0-0625 mg.and 0-25 mg. doses, which have approximatelydouble the effective potency of earlier batches.From the letter it appears that lanoxin tabletsmanufactured before May, 1972, have about half thepotency of the tablets manufactured after that date.The batch numbers of the new higher potencytablets are listed below*-batch numbers greaterthan these will also be of the higher potency. Theletter recommends that all stock not bearing one ofthese numbers should be returned to the wholesaler,who will replace it with material from a new, and

presumably higher potency, batch.The situation which has now arisen in the United

Kingdom needs careful examination, and it hingeson the question of the bioavailability of digoxin indigoxin tablets. Bioavailability is a term coined toexpress the concept of the amount of a drug whichenters the body after administration of a preparationand is then available to exert its pharmacologicaleffect. Many factors may be involved in bioavail-ability, some undoubtedly dependent upon patientvariation in absorption of a drug, but in the presentcontext there are others attributable to the amount of

drug available for absorption from the gastrointestinaltract. The latter will depend upon the disintegration-time of the tablet in gastric and intestinal juices, andthe size and solubility of the particles of the activeingredient-all related, of course, to the site in thegastrointestinal tract where absorption mainly occurs.The data have not yet been presented, but it is

reasonable to infer that the change in the bioavail-ability of the new lanoxin tablets brought about bya change in the manufacturing process is due to analteration in the physical characteristics of the tablet.On July 8 (p. 90), Professor GRAHAME-SMITH and

his colleagues, from the new M.R.C. Unit of ClinicalPharmacology, briefly described a study comparingthe bioavailability of Sandoz digoxin, Nativelle

* Lanoxi.n P.G. tablets (0-0625 mg.).-1486-X, 1531-X, 1559-X,1571-X, 1594-X, 1740-X, 1748-X, 1749-X, 1750-X.

Lanoxin tablets (0-25 mg.).-1482-X, 1/1482-X, 1483-X,1,’1483-X, 2/1483-X, 1484-X, 1485-X, 1546-X, 1580-X,1579-X, 1538-X, 1621-X, 1620-X, 1623-X, 1666-X, 1667-X,1745-X, 1746-X, 1767-X.

These are the new higher potency batches. Lanoxin can beidentified by the word Wellcome on one side together with acode number, X3A for the 0-25 mg. product and U3A for the0-0625 mg. pasdiatric/geriatric product.

digoxin, and Burroughs Wellcome digoxin (lanoxin)and found all these to have similar bioavailability.In this week’s issue (p. 303), Dr. HAMER and hiscolleagues, from St. Bartholomew’s Hospital, de-scribe a different investigation in which the plasma-levels of digoxin in 76 patients on stabilised doses ofdifferent brands of digoxin (including lanoxin) werecompared. Again in most patients the bioavailabilityof the various brands appeared to be similar for thelower dose-ranges (0-125-0-5 mg. daily), though inthe higher dose-ranges (0-625-0-75 mg. daily)lanoxin tablets appeared perhaps to give slightlyhigher plasma-digoxin levels. 7 other patients whowere taking a brand of digoxin other than lanoxinwere noted to have a wide range of plasma-levels ofdigoxin, but when switched to lanoxin all but 2 ofthese patients showed little change in their meanplasma-digoxin levels. In these 2 patients lanoxingave a higher plasma-digoxin level, and, when

investigated further, the lanoxin tablets appeared tohave a greater bioavailability than the other brand.It is of interest, however, that when the tablet ofthe brand with lower bioavailability was crushedand given in capsule form the bioavailability of itsdigoxin content increased considerably above eventhat of lanoxin tablets. HAMER and his co-workersconclude that delayed tablet disintegration maysometimes cause low biological availability and apoor therapeutic response.

In a letter on p. 325, Dr. HAMER and ProfessorGRAHAME-SMITH explain that the batches of lanoxintablets they used were manufactured before thebatches which now have approximately double thepotency, and that their results may no longer reflectwhat will happen when the new higher potencylanoxin tablets are used. They go on to criticise theinadequacies of existing standards governing the

preparation of digoxin tablets and point to the

importance of having digoxin tablets of reliable thera-peutic potency and bioavailability-the manufac-

turing processes and formulation of digoxin tabletscontaining stated and verifiable amounts of digoxin,although conforming to official standards, may resultin preparations with widely different bioavailabilitiesand thus different therapeutic potencies.As an interim measure, the Committee on Safety

of Medicines is recommending that lanoxin shouldnot be dispensed by chemists unless this brand is

specified on the prescription. Open prescriptions fordigoxin should be dispensed with other brands. For

repeat prescription, the Committee asks pharmaciststo confirm the dosage of lanoxin with the doctor(when the prescription was clearly not written afterthe company’s warning). And doctors are advisedto indicate, in communications about patients,whether lanoxin was the brand being used. But thereseems to be only one long-term solution to the prob-lem. A properly conducted investigation is neededin which the physical properties of digoxin tablets

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and their method of pharmaceutical preparation arecorrelated with the bioavailability of their containeddigoxin in man. From the results of such an investiga-tion new official standards for the formulation and

preparation of digoxin tablets could be introduced.Doctors must be able to rely on the predictablepotency, in terms of bioavailability, of the preparationsthey use. The vagaries of patient variability aredifficult enough to cope with, without the addedproblem of different pharmaceutical potency.

It seems extraordinary that none of this mighthave come to light without the advent of methods ofmeasuring the concentration of digoxin in plasma.This experience highlights another problem. Manyinvestigations on the bioavailability of drugs and theirpharmacokinetics-particularly those carried out withradioactive isotopic derivatives-have involved oraladministration of solutions and tablets whose physicalcharacteristics were not stated. If such investiga-tions are to be relevant to everyday therapeutics,these variables will have to be taken into considera-tion more carefully.

World Health and Technical AssistanceINTERNATIONAL concern for the health of the world

is comparatively recent in origin. It really began withthe need for the Old World to protect itself from thescourges of the East and the unknown parts of

Africa; the sanitary conventions beginning in 1851were drawn up mainly for this purpose. These werefollowed by the establishment of the Paris Office, theLeague of Nations, and finally the World HealthOrganisation in 1948. Even then, the Third Worldwas an indeterminate entity, largely the responsibilityof colonial governments. As long as disease wascontained within the boundaries of Africa and Asia,the concern of the well-to-do communities was

minimal. The disappearance of most of the colonialempires has resulted in the emergence of new nations,clamouring for deliverance from ill-health and for theright to have the same living standards as the restof the world. The expansion of communication-particularly the introduction of television-confrontsthe people of the Old World with the plight of thoseless fortunate than themselves. The speed of inter-national travel has revived threats long since forgotten.How improbable to have cholera in Huddersfield.We are told that, on balance, the world is a healthier

place to live in today than it was fifty years ago, andthis must of course be true in Europe and America.One can only be sceptical about the application ofthis view to the increasing millions in tropical andsubtropical areas. Reports from the World HealthOrganisation confirm that there is less malaria, lesssmallpox, and less measles, yet there remain horrifyingoutbreaks of cholera and yellow fever. Still thecommon lot of those living in African jungles, thesavannahs, and the semi-deserts of the world, is

birth, life, and death without help from the medicaladvances which benefit the sophisticated peoples ofthe world. Indeed, the director-general of the WorldHealth Organisation doubts whether there will bemuch further improvement until certain seriousendemic hazards-trypanosomiasis, schistosomiasis,filariasis-have been the subject of further funda-mental research.

If effective vaccines or chemotherapy could beapplied to the communicable diseases, still the baneof tropical and subtropical areas, there would bemuch improvement. It must not be forgotten that theaffluent world suffers comparatively few environ-mental disadvantages, since the sanitary era of the19th and early 20th centuries removed the biggestkiller of them all-" diarrhoeal disorders ". Endemic

poverty is a thing of the past, and education universal.It is difficult to see how better knowledge of major

endemic disease can overcome, by itself, the funda-mental handicaps of relative poverty, lack of sanita-tion, and minimal education against a background ofa heavily infected increasing population. Economistsbelieve that the economic development of countriesin the Third World will result, ipso facto, in animprovement of health. This can only be true if thateconomic development includes within its componentsinvestment in the health sector.Yet many of the Third World countries are simply

incapable of realising the dream of developmentcherished by the economists. It is these " un-

developing " countries which require and demandthe most international assistance to improve theirhealth. The people of the Third World should nothave to wait for long-term economic developmentwhen intelligent use of resources now being offeredcould benefit them today. Disease knows no barriers,but efforts so far to combat disease have seldom beensuccessful on a regional basis. Most effort is made bynations striving to improve the health of the peoplewithin their own boundaries. World government is

surely a long way off and a global health service notyet contemplated.

Against this background of complexity and neardespair, countries giving medical aid must make

every effort to find out what is needed in real terms.

They must realise that the mere provision of aid isno guarantee that it will be used to advantage, orindeed at all. There are many stages between thedecision to provide aid and the effective applicationof it to the people for whom it is intended. Aid mustbe appropriate for the community and effectivelyapplied. Without real concern for all the problems-social, political, and scientific-all the aid pro-grammes, research, individual work, and teamworkwill just be so much wasted effort.With all this in mind, let us now take stock of

Britain’s own medical-aid programme to developingcountries, particularly since ten years have elapsedsince Sir ARTHUR PORRITT’S working-party reported