TIPS -July 1982

wide as commuditics. The provision to all those in need of chloroquinc. pipcrazine or Iron and folic acid for malaria, ascaris or imn deficiency anemia teaches us much about the quanlities required for immediate provision of essential drugs.

Methodology for assessment of bcnefi~s and risks of large selective pqndation based drug usage. needs to be developed. The anticipated benefits or opportunity costs require pupulation acceptance. Endemic diseases yield many examples, for instance. diethylc-ne in onctier- ciasis or sulfa-pyrimethamine combina- tions for malaria. Another example is the continued use of cliquinol or chloram phenicol for various diarrheas in many trap ical countries. How can this phenomenon be explained?

In improved safety. easier compliance and lower cost, pharmacology and the pharmaceutical sector will have much mom for innovation in assisting primary care. Treatment methods that require less fre- quent drug administration could gain con- siderable acceptance, e.g. long acting anti- malarials, preferably effective against recurrent or resistant strains. Also desrrable would be polymers releasing levonorgestnzl from vaginal rings as novel delivery forms of contraceptives. Inhibitors of entemtoxin-induced intestinal hypersecre tion for the clinical management of diarrhea, as well as vaccines against malaria and mtavirusinduced diarrhea might be feasible R&D targets.

TlteprocessofbeaRbforall How does the concept of ‘Health for

All/2COO’, become a realistic process? Within their present expenditures for health, most countries could make signifi- cant progress towards this goal by teorient- ing their health systems, and reallocating health budgets. In many developing coun- tries. considerable improvements in health status can be produced by shifting fmm other investment or consumption secton as little as 2?4 of the per capita gmss national product (Table I).

Countries will vary greatly in their interpretation of an aLxzptable level of health. Each will set national targets. depending on their baseline health status. morbidity patterns and the state of development of their health systems. By measuring the changes in health status. as well as in the provision of health services, the effectiveness of strategies can be moni- tored and evaluated. taking baselines cam- ftdly intoconsideration. Such vital statisticb as reduction of infant mortality or increase of life expectancy may serve as targets ini- tially.

But health for all in personal human

Icrms has ia limitaticm5. it dcrr not mean that in the year 2000 nobody uill be \Ick or disabled. But all will realize that healthcan bc made or broken. Spacing births can benefit mothers and childten. All children will be immunized against crippling and killing diseases. Disabling conditions. like strnke or Karl diwasc. can be signifcantly reduced. Ill-health is not incvitablc.

The call for revolutionary progress in health is timely! Global ineq@ities in health status and distribution of health resources are intolerable. Currer.t wayc of dealing with health problems are made- quate in all countries, whatever their rage3 of development. For the remaining I8 years of this mnrbled twenti& ccztuty. N cqlogists tou need to reassess theu health priori& and become socially committed.

Acknowledgement Lecture given at the Pharmaceuticals and

Public Health Course, University of Geneva. Switzerland on I I June. 19111.

tDMUNDH J DtMA\R

Green tips by Jay

Topics of interest in current litemture

Diethylstilboestrol In a retrospective investigation alth matched controls carried out in 1971. Dn He&t, Ulfelder and Poskanzer in Boston. Massachusetts. established an association between the unusual occurfence of adenocarcinomd of the vagina in young women and the treatment uith the bynthctic nonsteroidal oestrogen dicth) I~tilbocstrol (DES) which the mothers of these patients had received during the Wt trimester of their pregnancies’.

Since then, structural abnormdhtics of the upper genital tract and unusual prep nmcy outcomes in females exposed to DES years before in mw have also been studied, among others by Dr Kaufman and his colleagues in Houston. Texas’. They found that there was a greater pjtcntial for morbidity and abortion rate in the DES- exposed patients. which confirmed that their own DES-exposure in UOYU cuuld zontribute to deletetious effec% even unto :he third generation thmugh cervical and

inma-utennc ahnormalitic3 (not nccc\~mlj mahgnam) detectable b? S-m\ and c~hcr nranb.

Such long+-ml conxqucnccs of DES- exposure in human3 hare nol unndtursll! prompted a ercat deal of rc,sarch on .mi- maI,. to JIsco\cr the long-tern1 cifcc~~ ot prenatal cxpohure I~I DES in ternIs rbi gent- tal trac‘l abnormahlie\ m pregndnt nncc or rats’.

The North Can>hna group curbing ulth m~cr:’ confirmed that there \\a~ .I ranpe of mahgnant and non-nlahgnant k~lon3 inbolvmg the gcmtal tact In nucc. hu1 apparcntl) there ucrc no Ggmficant cWagcnital target organs atkcted In imcc rxposrct gest&>nall) to DES. The devclopmcntal stage at \rhich DES trcsl- mcnt is applied detcrmincd the scvcrrtq of the long-term effects awribablc to DES.

The mechanism for the transplacental toxicity of DES, u hich 1% not obscrvcd \: ith gcstationally applied l7/34cstradiol or the DES anidogue dimethyls.tilborstroL

270 W?S -Jury I982

remains nbrcure. althnugh the competitive (alion to a rather speciai party for jaded knocks out mouse stem ceils does i2nt pro-

hinding of certain metabolites of DES IO spirits, it is in fart ~4 concise and easily Corn-- duct permanent sterility in humans. different embryonic rudiments or uterine prehensible iisting of the categories Of In contrast. cc&lain courses of cc:lmbina-

int~~eliU1~ ~stro~enic receptors” pro- drttgs which can lower the sperm count, lion c~~~~y produce ~rma~nt vidcb some clues that will obviously have to The emphasis is not so much on trying to sterility in humuns, but the same cctmbina-

be foiiowcd up. devise a magic formula for a male pill. (ions of drugs. although they drastically An even more recent stud> with rats is because the au&or sets out to warn of pass. reduce testicular stem cell survival in aice.

likely to become a classic. tn this *. Drs ible side e@cts of concurs that may be do not prevent the recovery of spcm p- Miller. Heckmann and McKenzie of prescribed for quitc other pUrplsCs. duction in the treated animals. Rochester, New York intused [“C]DES Among the compounds which cause It is clear that the mouse data cannot be into near-term pregnant animals at tbe time mom than rnimw R~tUations in the sperm freely extT~~t~ either in techn~ue or in corresponding to the p&d of maximal count or semen quality is SUlphasalazine interpretation to the human condition with- reproductive tract rlevelopment in ufem. (salicylazosulphapyridine) which was out a pinch of gossypol’“. They were able to assess the placental Iran!& introduced 40 years ago for treatment of fer of DES and its met&&es in a very infl~rn~o~ bowrl disease.. Semen Vet A kr New Hprtrpshi~ Nllphisirated way by establishing compari- density, sperm motility and morphology In a minireview of the functions nf vita- sons withdistributionandcovalent binding can be adversely affected by a course of min A at a recent minisymposium”, the to foetal tissue components in parallel ex- therapy with sulphasalazine’ which involvement of vitamin A in such diverse pcriments where they administe~d nonetheless prodaes no inrversibte infer- manifestati~~ns of mammalian integrity as (‘CIDES directly into the factuses. tility. On withdrawal from long-term vision. growth promotion. reproduction,

With the maternal infusion of (“ClOES, maintenance treatment, male patientsccluid ieliuku differentiation and immune ‘T-activity was concentrated within the prove their reproductive rapabilities. responses was ~nentio~d. foetoplacental unit. When specitic foetal The time course of sulphasalazine- It is a remarkable coincidence that two organs and tissues were analysed. it became related effects and their reversibility impii- groups working independently in New clear that both the male and female foetal cate direct toxic effects on spermatozoa by Hampshire, almost as neighbours. should rejective tracts had the highest relative the drug or one or more of its calcites, concern themselves with the concentrations of radiiactivity associated rather than hormonal aberraationsor induced chcmother+eutic effects of vitamin A and with ~hc UES infusion. Moreover, conju- folate deficiency”. A grest deal of some of its derivatives on the pmgression of gated and oxidative metabolites of DES speculation’ could be resolved by simple carcinogerrinduced tumours in the rat. nominated over u~hanged DES in experiments where labelted sulp~la~i~ foetal l&r and foetai reproductive tract, would be administered to rats to see what although in the fetuses as a whole, turns up in the semen and what is bound to unchanged DES appeared to be more abun. testicular tissue, knowing that at least with dant. respect to metabolism of this drttg the rat is

Direct injection of exposed foeluses with very close to man. [“CJDES demonstrated that the concentra. The recognition that cytotoxic drugs tion of DES from mother to foetus was a cause oii~~~ia6 is dealt with in greater unidirectional phenomenon. More impor- detail by Dr Meistrich and his colleagues in tantly still, it provided evidence that the Houston, Texas”. They investigated the dif- organdiitribution and the spectrum of DES ferential long-term (up to 2 months) darn- metal&es found in the foetus was equiv- age to mouse testis cells caused by single alent to that seen after maternal infusion. i.p. injections of over a dozen cytotoxic

With regard to covalent binding to drugs used in human cancer chemotherapy. selected tiss;ue components other than oes By Varying the doses a~in~re~ and the tmgen receptors. the ‘%J originally times of exposure they were able to estab administered as DES was significantly lish a specific ranking order for cytotox. associated in higher concentration with icities to differentiated and stem cell sper. foetal reproductive tract than wirh foe&l ~togania. Prednisone (PRED) and tivet. Moreover, the foetai reproductive Gmercaptopurine (6MP) had little or no Dr Longnecker and his ream in Hanover, tract had among the highest concentrations effect on differentiated spermatogonia, New Hampshire have been working on the of onidative metabolites which could be whilst §.tluorouracil (LFU) and procar. chemoprevention of the progressive ~ntif~, namely, ~~~ne~o1, 4 bazine (PCB) could kill nearly al! of such development of pancreatic turnours in rats OH-propiophenone and tibhydroxyDES, cells depending on dosage. Several drugs initiated by multiple injections of and others as yet unknown. The types of including PRED and 6.MP had practicdly azaserine’**- with dietary supplements of metabolites formed in mothers and foetuses no effect on stem cell survival 2 months various chemically modifted derivatives of %@t that reactive inrermediates in their after treatment. 5.FU and PCB wcrz among vitamin A a&r the completion of the car- formation are critically important in evok- the drugs that had only slight cytotoxic cinogen treatment”‘. ing the bizarre carcinogenic and teratologi. effects on stem cells. Triethylenethiophos_ Essentially. azaserine-l,iduced pancrea cai events foll~in~ exposure to DES dur- ~~rn~de and ~~~yc~ (ADR) were the tic turnoUrs ~mgress ~gh various stages mg gestation. most lethal compounds to stem cells. tOWiBdSnnWeandmOreplKM#dhiSt~

The qwstion of whether or not such pathological lesions that can be quite Dmmfortbl!rwnt mouse data would necessarily have toalatm readily graded at autopsy one year after the

Although Dr Drife entitled his inviting httman Patients in search of Progeny can last ~ni~tion of the c~i~~n. review ‘hugs and Sperm”‘. which SMuHk only be answered with a certain ambiva Appropriate amounts of three of the vit- rather suggestively as if it might be an id- knee. ADR, for example, which really arnin A derivatives (N-Zhydroxyethylene-

TIPS -July I’d82

~~i~rni~, ~~~myl~~xy~flyl~ti~ amide and retinylidene dimedone) were chosen hy the Longnecker team’” as rat chow supplement in an appropriate vehicle for a whole year before autopsy and these sisnif~antly reduced the incidence of all neoplasmr in the femaIe rats. in male rats. which appeared to be mote suscepihle to turnmu initiation hy azaserine, the three retinoids suppressed the progression to the more advanced hislff~~log~al pimcres tic lesions quite dramaiically. The experi- ence with a fourth vitamin A derivative was ambiguous, hecause this was dissolved in a vehicle which produced unexpected efferzr in what should have been Ihe contmls. Obviously. the constituents of that son+= what complex cwk:ktail will have to be evaluated in further experiments.

Not far away, in Durham. Ycu Hamp shire. Dr fhompson and his team have hen Io,Bking al dimethyt benwnthraccne- (DMBA).induced mammary cancers in female rats“. In the post-initiation period the ruts were given retinyl acetate or placebo headlets in theii chow to see how effectively retinyl acetate could modulate

the ~~i~~nie process. An extra retine- menl was Ihe alteration of Ihe hormone status of the rats hy comparing Ihe rc~pnn9e of intact and ovari~xtomuxxl animals.

Although rrninyl accl;lle reduced the tar burden of the DMBA.~~ ani. mals, attempts to discover rrh&eT the eflecls depended on hormnne status uere inconclusive and were overshadowed hy wcighi-loss rmbiguilies after ovariecr~m)

h would seem altogether more likely that vilamin A-related effects on turnour induc- tion depend as much on tissue-repair far= Iors’” as on hormon.4 factor\. The car- cinogen. on the other hand. ma) ui!l induce lesions in specifx rdrget organs which are predetermined by hormone status. Supposing that Dr Thomnson and nib lLarn hd tried to induct mammary tumoun in ov~ectorni~ rats right from the start. what would have hawned?

Reading list

Current awareness series Recelrtor mediated phosphorylation reactIons Within the space of 1 monlh, two very stimulating communications have appeared, documenting receptor-directed phosphorylation of membrane con- stituents’~*. These fecent ~~r~tiom with insulin’ and with platelet-derived growth factor (PDGF)’ can be added to an exciting, growing lisr of receptor-associated membranaiocalized phosphorylation ozac- tions (Tabfe I) that u~~bt~y play a mie in cell activation. What is particularly novel about the recent observation is that. in con- trast to the adenylale cyclase-associated honnone receptors, the phosphorylation reactions de&bed in the recent work are not mediated via cyclic AMP-moduhned protein kinaws. but appear to he intimately relaled to cyclic AMP-independent protein kinase reactions involving the ~zplors themselves. This newly ~blis~ work prompted a review of some other t&lively went observations describing n*eptor- related phosphorylation reactions. in which context the recent reports can he appreci- ated.

Although 11 has been recognized for some time that hormone-modulated protein phosphorylatioit-dephosphorylation reac- tions (in particular. those comrolled by cyclic AMP~~~ent protein kinase) pla? a critical mle in rhe regulalion of cell pro- ccsseC’. it is only compiuativel~ recend) that anention has focused specifically on such processes occurring at the level of Ihe hormone receptctrs themselves. Per@ the first terliza~ion that such cyclic ASIP- independent protein kina! reactions might play a role in signal transduction was heralded by work demonstraunp the light-nlediat~ cyclic AMP.in~~n~nt phosphorylation of rhodopriti,“. What dis- linguishes the phosphorylation of rhodop sin from the mom recent observations u irh PDGP. epidermrl growth f3ClN. ur~astm~ {EGF-UR~)~,” and tumur gmwrh factor (TGF)” is &at in rhodopsin, serine and threonine residues become phosphorylated, whereas the more reczm work focuses on tymsine residues as Ihe target of the kiuase reactions.