Postgraduate Medical Journal (September 1970) 46, 562-575.

CURRENT SURVEY

Prostaglandins: a report on early clinical studies

J. W. HINMANPh.D.

Head, Natural Products Research,The Upjohn Company, Kalamazoo, Michigan

SummaryThe prostaglandins are a unique group of phar-macologically active lipids which are widely distri-buted in mammalian tissues and body fluids. Thechemistry of this family of compounds has beenestablished in elegant detail. Research quantities ofthese highly active natural compounds were obtainedby enzymatic bioconversion of essential fatty acidsand now studies devoted to the elucidation of theirphysiological roles and their clinical potential areprogressing rapidly. Fields of greatest currentinterest in clinical medicine include renal-cardio-vascular research, induction of labour and therapeuticabortion, control of the reproductive cycle (includingfertility control), bronchodilation, enhancement ofnasal patency and antisecretory activity. Resultsavailable to date are too preliminary for many con-clusions to be drawn, but are sufficiently encouragingto assure continued and expanding efforts in severalfields.

IntroductionObservations made in the early 1930s indicated

the presence of a pharmacologically active principlein human seminal fluid. Euler (1936) showed that alipid-soluble acid with the same biological charac-teristics could be extracted from sheep vesicularglands and could be differentiated from otherbiologically active substances known at tha time.He named the principle 'prostaglandin'. Bergstrom& Sj6vall (1960) succeeded in isolating two activecrystalline compounds from extracts of sheepseminal vesicles and these were designated pro-staglandins E and F. Within a very short timeBergstr6m and his co-workers, particularly Samuels-son and Sjovall isolated and characterized a wholefamily of prostaglandins (Bergstrom, 1967). Six ofthese are regarded as primary prostaglandins anddesignated as PGE1, PGE2, PGE3, PGFia, PGF2a,and PGF3a. The rest of the naturally occurringmembers of the family are derived metabolicallyfrom these six. All are related chemically to the

hypothetical parent fatty acid prostanoic acid (Fig. 1).All of the naturally occurring prostaglandins (PGs)are unsaturated hydroxy-acids containing a 5-membered ring in a 20-carbon skeleton. For thepurposes of this survey, the most important com-pounds of this series are PGE1, PGE2, PGF2a andPGA1 (Fig. 1).Once the chemical structure of the prostaglandins

was established, it became apparent that a formalrelationship existed between them and certainunsaturated fatty acids which nutritionists have longreferred to as the essential fatty acids. These com-pounds were found to serve as percursors for thebiosynthesis of prostaglandins (van Dorp et al.,1964; Bergstrom et al., 1964; Wallach, 1965). Thusthe in vitro production of prostaglandins by theenzymatic bioconversion utilizing these unsaturatedfatty acids and enzyme systems derived from animalseminal vesicles provided for the first time adequateamounts of these rare compounds to permit wide-spread biological evaluation (Hinman, 1967; Ram-well et al., 1968). A great deal of effort has beendevoted to the total chemical synthesis of pro-staglandins (Pike, 1970) and for the future this willmost likely be the preferred method of production.Occurrence and biological activities

Prostaglandins occur in the highest concentrationsin human and sheep seminal fluid, but they also arepresent at low concentrations in a wide variety oftissues and body fluids including kidney, lung,nervous tissue, menstrual fluid, thymus, spleen,uterus, amniotic fluid at term, and adipose tissue.With the exception of human seminal fluid and inrare pathological situations, e.g., human medullarycarcinoma of the thyroid (Sandler et al., 1968),prostaglandins have been found in very low con-centrations of a few nanograms to a few microgramsper gram of wet tissue. Positive identification andquantitation of a specific prostaglandin in biologicalsamples is still difficult and time-consuming, andmany results which have been reported should be

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7 5 39 8%,,v,-s^6COOH10 20 H3

13 15 17 19

Prostanoic acid

0

ccOOH^0CO G;EOH OH

8,11,14 -Eicosatrienoic acid - -COOH

OH OHPGFIa

0

..,,,, 00H

PGE2OH

5,8,11,14 -Eicosatetraenoic acid

OH OHPGF2a

011 ,^ COOH

OH

PGAI01( COOH

OH

PGBI0

'% CcOOH

OH

PGA20

)-COO COOH

POH

PGB2FIG. 1. 8,11,14-Eicosatraenoic (bishomo-y-linolenic acid and 5,8,11,14-Eicosatetraenoic (arachidonic) acidare the biological precursors of the PG1 and PG2 compounds respectively. The PG3 compounds (not illus-trated) are derived biologically from 5,8,11,14,17-eicosapentaenoic acid. The PGAs are produced by loss ofthe elements of water from the 5-membered ring of the PGEs. PGBs are produced from PGAs by isomeriza-tion of the double bond. Structures of metabolites mentioned in text can be deduced from the formulas illustra-ted and the numbering system given for the parent compound, prostanoic acid.

confirmed when improved methods become avail-able. Nevertheless there is no doubt that pros-taglandins are widely distributed in mammaliantissues and they have significant-though incom-pletely understood-physiological activities.The activities originally ascribed to the prosta-

glandins were stimulation of smooth muscle andvasodepression. Many diverse biological activitiesare known now and they vary considerably depend-ing on the structure of the individual compound.Prostaglandin E1 or PGEI, the most thoroughlystudied member in the family, exhibits potentaction as a non-vascular smooth muscle stimulant,a vasodepressor agent, a nasal vasoconstrictor, andas an inhibitor of lipolysis, gastric secretion andplatelet aggregation. PGE1 causes sedation whenadministered into brain ventricles and causespersistent miosis and a rise in intraocular pressurewhen injected into the anterior chamber of the eye.It exerts synergistic and antagonistic actions withcatecholamines in some organs. The PGAs exhibit

many of the activities of the PGEs in that they havea qualitatively similar action on blood pressure andgastric secretion but lack the potent action on non-vascular smooth muscle. The PGFs tend to bepressor rather than depressor and cause venoconstric-tion in some cases. In most of their areas of activitythe prostaglandins are among the most potentcompounds known with activities in some systemsat concentrations of 0-01 ng/ml in vitro and at 10ng/kg in vivo. Nerve activity is known to stimulateprostaglandin formation and release both centrallyand peripherally. Prostaglandins have been im-plicated in anaphylaxis, inflammation and in parturi-tion. Several excellent reviews are available on thebiological actions of the prostaglandins (Berg-str6m et al., 1968; Pickles, 1969; Horton, 1969).

MetabolismIt was apparent from the early studies with

isotopically labelled prostaglandins that thesecompounds are rapidly metabolized when introduced

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into the circulation of an intact animal. Largelythrough the work of Anggard, Samuelsson andHamberg many of the metabolites have beenthoroughly characterized and some of the enzymesystems responsible for the degradative reactionshave been studied. Relatively large amounts ofcertain metabolites occur in human seminal fluidalong with the primary prostaglandins. These arePGA1, PGA2, PGB1 and PGB2, which are producedby dehydration and isomerization (Fig. 1) from theprimary E compounds, and the four corresponding19-hydroxy compounds formed by enzymatichydroxylation of the PGAs and PGBs (Hamberg& Samuelsson, 1967).

In the lungs the PGEs are metabolized by reduc-tion of the A13 double bond and by oxidation of thesecondary hydroxyl group at carbon atom 15 to acarbonyl group (Anggfrd & Samuelsson, 1966).Reduction of the double bond did not appreciablyalter the biological activity of the PGE1, but oxida-tion of the 15-hydroxyl to a ketone caused drasticreduction of activity in two systems studied. Invitro incubation studies by Hamberg (1968) showedthat the prostaglandins are subject to 3-oxidationin rat liver mitochondria. Evidence of 3-oxidationhas also been reported in the intestine (Parkinson& Schneider, 1969). These studies revealed that theprostaglandins undergo one or two steps of 3-oxidation ofthe carboxyl side chain to yield dinor andtetranor metabolites. 3-oxidation from the methylend has been demonstrated also after an initialco-hydroxylation yielding urinary metabolities whichare dicarboxylic acids. The major urinary metabolitesof the PGEs and PGFs in man have carboxyl sidechains with 2 or 4 carbons removed, the A13 doublebond reduced and the 15-hydroxyl group oxidizedto a ketone (Hamberg & Samuelsson, 1969; Gran-strom & Samuelsson, 1969). Recent experimentshave shown that dinor and tetranor PGE1 andPGFIa are poor substrates for prostaglandin de-hydrogenase (Nakano, Anggard & Samuelsson,1969). These findings suggest that catabolism of thePGs is probably initiated by the dehydrogenase andreductase reactions. It is worthy of note that of theprostaglandins which have been studied clinicallyonly PGA1 and PGA2 escape rapid inactivation inthe pulmonary circulation (McGiff et al., 1969) andare, therefore, the only ones which might function ascirculating hormones.

Clinical studiesThe first human pharmacology studies with a

purified prostaglandin were reported by Bergstromet al. (1959). Chemically pure PGE1, isolated fromsheep vesicular glands, was infused in doses of0-2-0-7 ,ug/kg/min in two healthy male subjectsover periods of 4-10 min. 'Tachycardia, reddening

of the face, headache and an oppressive feeling inthe chest were noted.' It was noted also that bloodpressure fell moderately. During the 1950s and early1960s some attempts were made to relate theoccurrence of prostaglandins in seminal fluid tosome function or role in reproduction, but nodefinitive studies were possible until practicalresearch quantities of the pure compounds becameavailable and appropriate animal studies could becarried out. This was accomplished during the midand late 1960s. During this period the clinical,cardiovascular and metabolic responses of infusionsof PGE1 to healthy volunteers were reported(Bergstrom et al., 1965; Carlson, Ekelund & Oro,1968; 1969). These studies demonstrated clearlythe potential of PGE1 to induce profound phar-macological responses in man and they establishedthe safety of certain dosage regimes, but they didnot point directly to clear-cut clinical utility. How-ever, other studies both in animals and man revealedareas of clinical investigation which may havepractical application. The main purpose of thissurvey is to highlight these developments.

Renal-cardiovascular pharmacologyPGE1 and PGE2 are powerful vasodilators caus-

ing a fall in blood pressure, increased cardiacoutput and increased heart rate. The decrease inblood pressure appears to be a direct vasodilatoreffect on resistance vessels which is not blocked bya- and ,3-adrenergic blocking agents or prioradministration of atropine, lysergic acid diethyl-amide or the antihistamine, tripelennamine (Strong& Bohr, 1967). The cardiovascular effects of PGF2,are complicated by variations of response in dif-ferent species. Although less potent, like the PGEs,it is depressor in the cat and rabbit while in therat and dog, unlike the PGEs, it is pressor. In thedog i.v. injections of PGF2a cause a rise in bloodpressure that is associated with an increase in bothcardiac output and peripheral resistance broughtabout by venoconstriction and increased venousreturn (DuCharme et al., 1968). In common withthe PGE compounds, the PGFs possess potentsmooth muscle-stimulating activity. The cardiovas-cular effects of PGF2a in man are strikingly dif-ferent from those of PGE1 and are quantitativelydifferent from the effects of PGF2a in the dog.Continuous infusion of 0-01-2-0 ,[g/kg/min ofPGF2a for 60 min in six volunteers produced noeffect on blood pressure, heart rate, ECG or respira-tion rate and none of the volunteers complained ofany discomfort during or after the infusion (Karimet al., 1969a). One of the same subjects was infusedwith 0-2 ,ug/kg/min of PGE1 for 30 min and thisproduced the same objective and subjective responsesreported earlier by Bergstr6m et al. (1959, 1965).

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The most interesting of the prostaglandins withrespect to renal and cardiovascular activities are thePGA compounds. PGA1 was first isolated andcharacterized as one of the PGs present in themixtures obtained from the in vitro enzymaticbioconversion of bis-homo-y-linolenic acid uti-lizing the sheep seminal vesicle system (Danielset al., 1965). This compound was detected anddistinguished from the other prostaglandins becauseof its striking vasodepressor activity and lack ofnon-vascular smooth muscle-stimulating activity.Similar activity had been detected in the mixturesof lipids extracted from renal medulla (Muirheadet al., 1965). Lee et al., (1965) isolated a lipid acidwith similar properties from rabbit renal medullaand named it medullin. This was quickly identified(Lee et al., 1966) as PGA2. Subsequently PGE2was shown to be the most abundant PG in rabbitrenal medulla (Daniels et al., 1967) and PGF2aalso occurred in significant amounts (Lee et al.,1967). The facile conversion of PGE2 to PGA2 (andPGE1 to PGA1) by nonenzymatic dehydration undermildly acid conditions makes it difficult to determinehow much PGA2 occurs normally in the kidneyas compared with the amount of PGE2 which isconverted to PGA2 during the isolation. PGA1has been isolated from human seminal fluid (Ham-berg & Samuelsson, 1967) where it is considered tobe a normal component and not an artifact of theisolation procedure. Vasodepressor lipids have beenisolated from human kidneys and concentrationsof a PGE2-like lipid ranging from 40 to 234 ng-equivalent/ml were detected in the renal venousblood of hypertensive patients but none was detec-ted in samples from normotensive subjects (Edwards,Strong & Hunt, 1969). Recently, McGiff et al.(1970) have shown that angiotensin II inducedthe release of PG-like substances in dogs andsuggested that an alteration of the balance betweenpressor substances (renin, PGF2,) and depressorsubstances (PGE2, PGA2) may determine the devel-opment of renal hypertension. The neutral anti-hypertensive lipid of the renal medulla (Muirheadet al., 1967) may also be a factor in this balance.

Irrespective of their physiological occurrence andfunction, the potent vasodepressor and natriureticactivities of the PGA compounds made themattractive candidates for clinical evaluation in therenal-cardiovascular field. Also, in contrast to thePGE and PGF compounds, the PGAs are notquickly metabolized and inactivated by the lungs(McGiff et al., 1969). In early studies using purifiedPGA2 isolated from rabbit kidneys, Lee (1967)reported that in dogs and in a human patient withessential hypertension PGA2 caused a short-termhypotensive action and marked diuresis.Current clinical studies are being carried out

with PGA1 because it was more readily available asa pure crystalline entity than PGA2 and its biologicalproperties appeared to be equivalent to those ofPGA2. Carr (1970) reported that PGA1, administeredby infusion at the rate of 0-48-1-32 ,ug/kg/min tofive patients with mild essential vascular hyper-tension, resulted in increased cardiac output andrenal blood flow, reduced blood pressure anddecreased peripheral resistance. The renal fractionof the cardiac output was reported to increasedramatically. There was enhancement of freewater clearance and decreased solute free waterclearance in association with a sodium diuresis.In spite of the significant drop in mean arterialpressure, no change in plasma renin activity wasdetected. Christlieb et al. (1969) have reportedbriefly on the administration of PGA1 to sixhypertensive patients by i.v. infusion at rates varyingfrom 0-3 to 1-2 ,ig/kg/min for 30-60 min. Bloodpressure was lowered during the infusions, but themagnitude of the response varied with the individual.They reported that post-infusion rebound of theblood pressure was common and at times severe.Fichman (1969, 1970) administered PGA1 to morethan thirty-five patients (normals, hypertensives,hyponatraemics, cirrhotics, anephrics) by infusion atrates varying from 0-03 to 5 ,ug/kg/min. His studieswere concerned mainly with the natriuretic action ofPGA1 under various circumstances. Greater aug-mentation of urinary sodium excretion occurredwhen PGA1 and vasopressin (ADH) were infusedat the same time. The most pronounced natriureticresponse occurred in a cirrhotic patient withascites in whom urinary sodium increased manyfold. He interpreted his findings as suggesting thatPGA1 failed to alter the effect of ADH on waterexcretion but the natriuretic effect of PGA1 waspotentiated by ADH infusion, and the vaso-depressor effect of PGA1 was enhanced in anephricstates.Some details from the study of Westura et al.

(1970) will serve to illustrate the antihypertensiveand haemodynamic effects of PGA1 in patients withessential hypertension. The study with six patientswas divided into three 15-min periods. After thefirst 15-min which served as control, PGA1 wasadministered by i.v. infusion at the mean rate of1-0 ,ug/kg/min for 15 min (Period I). This was followedimmediately by a 15-min period (Period II) duringwhich the infusion-rate was increased to a meanrate of 2-0 ,ug/kg/min. During Period I there wasan initial rise in sodium excretion and urine flow.This was followed quickly by a progressive fall insystemic blood pressure and a drop in peripheralresistance. There was a slight rise in stroke-volumeindex and in cardiac index, but a reflex increasein heart rate of from 72 + 2 to 96 + 3 beats per

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250 - 2.0PGAiI'0

I (gAg/kg/min) 0EE 200

0

:3i)

150 Control 15 I 30 450o.0

= Ioo -

0 Control 15 I 30 Tr 45Time (min)

FIG. 2. Effect of PGA1 on blood pressure in patientswith essential hypertension. Each result is the mean± SE of 12-18 determinations in six hypertensive pa-tients. Control period (15 min), and period I andperiod II (15 min each) during PGA, infusion (1 and 2lg i.v./kg/min respectively) are subdivided into threeconsecutive 5-min intervals. (From Westura et al., 1970by permission of the American Heart Association, Inc.)

PGA, 2 C(.g/kg/min) 120 E

6 --100£^-{c 80

·o

8 60

0 Control 15 I 30 45Time (min)

FIG. 3. Effect of PGA1 on heart rate and cardiac index.See Methods and Fig. 2 for experimental details.n = 6. (From Westura et al., 1970 by permission of theAmerican Heart Association, Inc.)

minute (Figs. 2-5). During Period II with the in-fusion of 2 (Lg/kg/min a further small decrease insystolic blood pressure was recorded but no furtherlowering of diastolic pressure occurred. The heartrate continued to increase while the cardiac indexdecreased slightly. Urinary flow fell to a meanvalue which was higher than control but signi-ficantly lower than that observed during Period I.Changes in sodium excretion paralleled those ofurinary flow. Potassium excretion (Fig. 6) was

PGA 2

20 (/jg/kg/min) C

16

E - X_ .I Ic12ti// \\

4 \/-

Contol I 30 1 45Control

Time ( 3in)Time (min)

FIG. 4. Effect of PGA1 on urinary flow in patients withessential hypertension. Each point represents the resultof a 5 min collection interval from an individual patientduring the control period and during PGA1 infusion(period I and II). (From Westura et al., 1970 by per-mission of the American Heart Association, Inc.)

PGAi 22000 (gA/kg/min) 0

1600I\\

'r 1200 -/

,800_ ",---V0

400 -

0 Control 15 I 30 45Time (min)

FIG. 5. Effect of PGA1 on sodium excretion in patientswith essential hypertension. See Fig. 4 for experimentaldetails. (From Westura et al., 1970 by permission of theAmerican Heart Association, Inc.)

elevated during the 1 tig/kg/min infusion period,but decreased to control levels during the periodof higher infusion rate. According to Lee and hisassociates (Westura et al., 1970) they did not detecta direct effect of PGA1 on cardiac performance.They believe that the mechanism of anti-hyper-tensive action is 'by direct peripheral arteriolar

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200 PGAPGAi

(/Lg/kg/min) 0

160

120120/6D *\ \/1'

///',

,80///Y%%e. ///! /' -.·

40

0 Control 15 30 45Time (min)

FIG. 6. Effect ofPGA1 on potassium excretion in patientswith essential hypertension. See Fig. 4 for experimentaldetails. (From Westura et al., 1970 by permission of theAmerican Heart Association, Inc.)

dilation leading to a fall in peripheral resistance anda decline in systemic arterial blood pressure accom-panied by a compensatory increase in cardiacindex which is almost entirely the result of a reflextachycardia.'

It should be kept in mind that Lee and others haveshown that the PGA compounds are perhaps themost potent natriuretic agents known in that theyare effective at concentrations of the order of 0-1ng/ml of renal arterial blood. When administeredto man at low infusion rates of 0'1-0-3 tg/kg/min,rates which do not affect arterial blood pressure,renal blood flow, urinary sodium and potassiumexcretion, urine flow and free water clearance all risesignificantly. At higher infusion rates, as shownabove, the effects are reversed with renal plasmaflow, urine flow, and electrolyte excretion falling tocontrol values. Neither the role of these compoundsin the physiological regulation of blood pressure,nor their place in the treatment of pathologicalconditions is clear at this time. However, availableinformation indicates that they are worthy of furtherstudy and especially if long-acting, orally-activeforms can be prepared, general therapeutic use maybecome feasible.

Induction of labour and therapeutic abortionFor many years clinicians had known that during

menstruation the human uterus extruded thedisintegrated endometrium by means of powerfulcoordinated contractions, but it was not until 1963that the 'menstrual stimulants' presumably respon-sible for this action were identified as PGE2 and PGF2a(Eglinton et al., 1963). When pure prostaglan:-ins

became available, numerous investigations wereconducted on the influence of these compounds onhuman myometrium in vitro. Reports of the resultshave been somewhat conflicting, but in generalit appeared that PGEs inhibit and PGFs stimulateactivity in the non-pregnant human myometriumin vitro. However, in the human pregnant myome-trium in vitro, Embrey & Morrison (1968) found thatwhile the lower segment myometrium was relativelyunresponsive, marked responses were observed withthe upper segment and both PGFs and PGEsexhibited the stimulatory effects.Karim and his co-workers demonstrated the

presence of several PGs in human umbilical cord,human amniotic fluid and human decidua obtainedat term (Karim & Devlin, 1967). High levels werefound in amniotic fluid only from patients in spon-taneous labour. They showed also that PGF2aappeared in maternal venous blood in variableamounts during labour and that the concentrationincreased with progression of labour. A strikingcorrelation between PGF2a concentration and thecontraction was noted. Blood levels rose during theperiod immediately before a labour contraction,were highest during the contraction, fell sharplyimmediately after the contraction and were usuallyundetectable between contractions.With these findings suggesting a physiological

role of PGF2a in parturition, Karim and associatesproceeded with the clinical investigation of the useof infusions of this prostaglandin to induce labourat or near term. A recent report (Karim et al.,1969b) describes their experience in thirty-five cases.PGF2a, given by i.v. infusion at the rate of 0-05 ,.g/kg/min (1/40 of the rate found previously to be well-tolerated in men and one non-pregnant woman),stimulated uterine contractions to a pattern ofuterine activity very similar to that of normallabour with complete relaxation between con-tractions. Hypertonicity was not encountered andthe contractions were well spaced. In most casescontractions commenced 15-20 min after theinfusion was started. Infusion was continued untillabour was induced as determined by the positionof the foetal head, strong regular contractions at2-3 min intervals and by a cervical dilatation of 6-8cm. Upon stopping the infusion, the uterus conti-nued to contract regularly leading to successfuldelivery. In the twenty-nine patients in whom labourwas successfully induced with a single infusion, theinfusion time varied from 1 to 11i hr. The averageinfusion delivery interval in thirty-three successfulinductions was 9 hr 35 min. All babies deliveredalive showed immediate spontaneous respiration andno discernible abnormality was noted.

In the latest report available from Karim et al.(1970), i.v. infusions of PGE2 were used to induce

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labour in fifty women at or near term. The infuseddose was approximately 1/6 that of PGF2a or 0-5 Vg/min. Using a Palmer slow infusion pump a patient re-ceived between 0-005 and 0-01 ,lg/kg/min. The uterineactivity produced by this treatment resembled thatof normal spontaneous labour and no unphysio-logical increase in uterine tone was observed.Labour was successfully induced in all fifty cases.The average infusion time was 5-5 hr and theaverage infusion-delivery interval was 10 hr. Theinfusions produced no discernible foetal difficultiesand had no effect on maternal blood pressure. Theonly side-effects reported were headache in onepatient and vomiting in another.Embrey (1969) reported observations made in

fifteen patients in late pregnancy and five in earlypregnancy undergoing i.v. infusion of prostaglandins.Six patients at or near term received PGFs (PGF,a,one patient; PGF2a, five patients) at an infusion rateof 2-8 ug/min. (ca. 0-02 to 0-14 ,lg/kg/min).Definite stimulation of uterine contractions wasdemonstrated in two cases and less marked ordoubtful increase in contractility reported in four.The maximum infusion time was 80 min and themaximum total dose 200 ,lg. Contractions, whichbegan within 15-30 min of infusion, continuedlong after cessation of infusion and diminishedslowly. With two of the patients labour becameclinically established within a few hours and onewas already in labour at the beginning of theexperiment. Labour ensued within 48 hr in two ofthe remaining three patients and after surgicalinduction in the other. In a parallel study withnine patients in late pregnancy PGEs were adminis-tered using the same infusion dosage regime. Onepatient received PGE1 and eight received PGE2.The threshold dose was judged to be ca. 2 [lg/minand dosage in the range of 2-6pLg/min induced markedincreases in both frequency and amplitude of contrac-tions. Hypertonus was observed in only one instanceat the highest dose used (8 ,tg/min). With one excep-tion labour was established within a few hours of theinfusion and within 48 hr with the one exception. Atthese doses, even with the PGEs, no changes in bloodpressure or pulse rate and no subjective side-effectswere observed.The effects of PGs on uterine contractility were

determined in five early pregnancy cases involvingpatients recommended for termination of pregnancy.Evacuation of the uterus was performed within 24 hrof the infusion regardless of the response producedby prostaglandin treatment. Using the same in-fusion rate (2-6 ,ug/min), Embrey reported that thesensitivity of the myometrium appeared to be atleast as high as in late pregnancy. PGE2 produceda more pronounced effect than PGF2,. In contrastto the experience in late pregnancy, the response

in early pregnancy was characterized by an increasein tone: as well as stimulation of contractions.PGF2a interrupts early stages of pregnancy in

rhesus monkeys (Kirton, Pharris & Forbes, 1970a)and laboratory rodents (Gutknecht, Cornette &Pharriss, 1969). Kirton, Pharriss & Forbes (1970b)subsequently reported both PGE2 and PGF2aterminated pregnancy when administered to monkeyseither subcutaneously or intravenously between 30and 41 days after conception. Increased uterinetonus and contractions of about 60 mmHg occurredat a frequency of three per min within 10 minafter starting an infusion of PGF2a at a rate of60 ,Ag/min. PGE2 was effective by infusion at 8 [lg/min. Plasma progestin concentrations declined24-48 hr after initial administration.Bygdeman et al. (1970) studied the effects of single

i.v. injections of PGFi. and PGF2a in thirteen womenin mid-pregnancy and one at the thirty-sixth weekof pregnancy. They reported that the thresholddose of PGF,1 for production of a stimulatingeffect predominating in elevation of tone wasbetween 200 and 500 ug and ca. 100 ,tg for PGF2a.These authors also reported that i.v. infusion ofPGF2a at a constant rate of 3 txg/min (roughlyequivalent to the 0.05 ,lg/kg/min rate used byKarim) had no effect on uterine motility, but theydid not report the duration of the infusion or thestage of pregnancy of the patient. More recentlythis group (Roth-Brandel et al., 1970) reportedresults of a study in which i.v. infusion or repeatedsubcutaneous injections of PGE1 or PGF2a weregiven to eleven women admitted for therapeuticabortion in the thirteenth to to eighteenth week ofpregnancy. Both methods of administration induceduterine hypertonicity, which diminished slowlyduring treatment, and at the same time strong, some-what labour-like, contractions. The effect lasted1-2 hr and was normally sufficient to cause cervicaldilation leading to termination of pregnancy in threeof the eleven women. Side-effects of nausea (withPGE1) and diarrhoea (with PGF2.) were observedin some patients in high doses. The authors ex-pressed a preference for PGF2a for this purpose.The latest report from this group (Wiqvist &Bygdeman, 1970) described their findings using i.v.infusions of PGF2a at rates of 13-360 iag/min inseven women in the eighth week of pregnancyor earlier and in five women in the twelfth to sixteenthweek. With those in the early stages of pregnancybleeding started within a few hours after initiationof infusion followed by partial or complete expul-sion of the conceptus within 2 days. Abortion wasaccomplished in three of the five cases of womenin the twelfth to sixteenth week of pregnancy. Againthe side-effects of diarrhoea or vomiting occurredbut disappeared on reducing the infusion rate. It was

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noted that the abortive mechanism differed de-pending on the stage of pregnancy.Karim followed his studies of induction of labour

at term with an investigation of the use of PGF2afor therapeutic abortion. A recent report (Karim& Filshie, 1970) describes successful results in four-teen of fifteen cases using i.v. infusion of PGF2aat the rate of 50 ,ug/min until abortion was com-plete. Diarrhoea occurred in seven of the womenin this series, three of whom also vomited. Thesewere the only side-effects noted and they were not

severe. These authors point out that there are bothqualitative and quantitative differences in theresponse of the early pregnant uterus to PGF2acompared with those at term. In the latter situationi.v. infusion of 4 ,xg/min stimulated uterine con-tractions which were regular and rhythmicalwithout increase in resting tone. On the other hand,during the first and second trimester of pregnancyan infusion rate of the order of 50 ,zg/min wasrequired to stimulate the uterus. The initial effectwas hypertonus and this was followed by rhythmic

05 ... t tf*ani «tstertJ T5 .. 20.

FIG. 7. Effect of 0-05 jLg/kg/min. of prostaglandin F2a infusion on uterine activity'of a pregnant womanaged 22, gravida 2, at 38 weeks gestation. Membranes had ruptured prematurely 36 hr before the startof the infusion. The infusion was given for 31 hr. The cervix (Cx) at the end of this period had dilated to 6cm. A live baby weighing 2812 g was delivered 4 hr 50 min after stopping the infusion. (From Karim et al.,1969b). Reproduced by permission of the Editor, Journal of Obstetrics and Gynaecology of the BritishCommonwealth.)

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FIG. 8. Typical record of a PGF2a-induced uterine activity at 18 weeks illustrating hypertonus followedby rhythmic contractions with increase in frequency and amplitude. A = Control period or spontaneousactivity; B = Sitting up to pass urine; C = Intact sac expelled. The patient was aged 17 years, parity 1and the period from induction to abortion was 4 hr 20 min. (From Karim & Filshie, 1970.) (Repro-duced by permission of the Editor of the Lancet.)

contractions. Typical records of PGF2a-induceduterine activity in these two situations are shown inin Figs. 7 and 8.The three groups whose work is summarized

briefly here all commented favourably, but withunderstandable caution, on the possible advantagesof infusions of prostaglandins, particularly PGF2aand PGE2, over currently accepted methods forinducing labour at term and for therapeutic abor-tion. Compared with oxytocin, which acts quickly,the prostaglandins are notably slow in action, andtheir effect persists after infusion is stopped. Controlof the action is readily achieved by the rate ofinfusion. Furthermore, the uterus in early pregnancyis relatively insensitive to oxytocin. The results todate, in the words of Karim, '... reinforce the pos-sibility that prostaglandins may have a physiologicalrole in parturition, and further suggest that prosta-glandin F2a may represent a potentially valuableaddition to the armamentarium of the obstetrician.'(Karim et al. 1969b). In the light of the more recentreports, one might also expect PGE2 to be includedin this category.

Fertility controlBecause the prostaglandins were originally dis-

covered in human seminal fluid and because theirconcentration in this fluid is the highest known in

nature, it is not surprising that as early as 1947Asplund suggested a correlation between totalprostaglandin concentration in human seminalfluid and degree of fertility. Considering the com-plexity of the problem with thirteen prostaglandinsbeing present and each with different biologicalaction, it is also not surprising that 22 years wererequired to get meaningful support for Asplund'ssuggestion. The analysis and quantitative deter-mination ofthesecompounds required methods whichhave only recently been devised (Bygdeman et al.,1969). Results of a study of a total of 137 differentsemen samples obtained from men with documentednormal fertility, from men in infertile marriages ofnonexamined origin and from men in 'functionally'infertile marriages indicate with statistical signi-ficance that the concentration of PGEs in humanseminal fluid is of importance for normal fertility(Bygdeman, 1969). Semen samples from 40%/ ofthe men in functionally infertile marriages had aPGE content of less than 15 Lg/ml whereas thosefrom men of normal fertility had an average PGEcontent of 55-2 ± 20-2 pg/ml and none had acontent of less than 15 ug/ml. Bygdeman con-cluded that determination of PGE content ofseminal fluid may be of relevance in routine in-vestigation of functionally infertile marriages.The antifertility potential of the prostaglandins

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seems in the light of current knowledge to restmainly on a suggested luteolytic action of PGE2a.This is, however, a very new area of research and thefindings should be regarded as preliminary. In thenormal ovarian cycle it is known that after thefollicle develops and matures an ovum is dischargedand a corpus luteum is formed. When the ovum isimpregnated the corpus luteum continues to growand to secrete the hormone progesterone. If ferti-lization does not take place, progesterone secre-tion stops, the corpus luteum regresses and in womanand primates menstruation occurs. The events lead-ing to the development of the corpus luteum areknown to be under the control of pituitary hor-mones and are relatively well understood, but themechanism leading to regression of the corpusluteum when pregnancy does not occur remainsobscure. There is evidence suggesting that theuncharacterized factor involved is produced bythe uterus. For example, in species with a bicoruateuterus, if only one uterine horn is removed, thecorpora lutea on that side persist, but those in theopposite ovary regress.As a working hypothesis, Pharriss & Wyngarden

(1969) proposed that PGF2a be considered as themissing factor which should meet the followingrequirements: (1) be produced in the uterus, (2)permit unilateral effects on the ovary, and (3) haveproperties consistent with luteal regression. Picklesand his co-workers (Eglinton et al., 1963) hadalready demonstrated that PGF2a was formed inthe uterus and discharged in the menstrual fluid.Considering the second requirement, it was knownthat in most, if not all, species there is no directvascular connection between the uterus and theovary, but venous drainage from the ovary isshared with the uterus. Pharriss suggested thatrestriction of venous outflow from the ovary mightlead to relative ovarian ischemia, limitation ofsubstrates for hormone synthesis and/or accumula-tion of metabolites in such a fashion as to meet thethird requirement. As related earlier, DuCharmeet al. (1968) showed that in the dog some of thecardiovascular actions of PGF2G were probablysecondary to venous constriction. Therefore, itseemed possible that uterine PGF2a could impedeutero-ovarian vein flow and thereby depress lutealmetabolism.

In experiments designed to test this hypothesis0-1 or 0-2 mg PGF2a reduced venous outflowas assessed via a cannula inserted into the utero-ovarian vein of rats and rabbits (Pharriss, Corette& Gutknecht, 1970). Investigations to detect apossible luteolytic action of PGF2a were carried outin animals treated to induce a persistent corpusluteum (Pharriss & Wyngarden, 1969). PGF2. wasinfused at 1 mg/kg/day via the uterus or the right

heart into pseudopregnant rats on days 5 and 6 ofpseudopregnancy. The ovaries were removed anddetermination of the progestogen content revealedthat progesterone levels were decreased and con-centrations of its metabolite, 20a-dihydropro-gesterone, were increased. PGF2a administeredsubcutaneously to pseudopregnant rats shortenedthe pseudopregnancy to 7 days from a normal of14 days. However, addition of PGF2a to rat ovariesincubated in vitro did not decrease the rate ofprogesterone synthesis. The pituitary did not seemto be involved because when pseudopregnancy wasmaintained in hypophysectomized rats by prolactinadministration, PGF2a still decreased the ratio ofovarian progesterone to its metabolite. These andsimilar animal experiments supported the concept ofan indirect mechanism for local luteal control byuterine tissue and an indirect effect of PGF2aon the ovary.

Since progesterone from a persistent corpusluteum is necessary for maintenance of earlypregnancy, early regression of the corpus luteumwould prevent nidation of fertilized ova and estab-lishment of pregnancy. When PGF2G was given atappropriate times after mating it either prevented orreduced the incidence of pregnancy in mated rats,rabbits (Gutknecht etal., 1969), and monkeys (Kirtonet al., 1970). Exogenous progestogen in the form ofmedroxy-progesterone acetate (Provera,* Upjohn)protected rats against the antinidatory action ofPGF2a (Gutknecht et al., 1969) presumably becauseit replaced the progesterone lost when the corpusluteum regressed. Early pregnancy in the monkeyis associated with a sustained elevation of plasmaprogesterone. When 30 mg of PGF2a/day wasadministered subcutaneously for 5 days and injec-tions were initiated on day 11, 12 or 13 postovula-tion of fertile cycles, plasma-progesterone levels fellpromptly to nearly undetectable levels and men-struation occurred shortly thereafter. Several of thetreated monkeys were mated again and normalpregnancies ensued (Kirton et al., 1970a).

Studies on the effect of PGF2U on corpus luteumfunction in women are apparently in progress, butno details have been published. However, Wiqvist &Bygdeman (1970) reported that preliminary ex-periments on non-pregnant women 'show thatvigorous uterine contractions and menstrual-likebleeding may be induced also during the secretoryphase of the cycle by infusion of PGF2a. Theeighteenth to nineteenth day of the cycle, whenimplantation of the blastocyst takes place or 2-4days following the first missed menstrual periodmight even be more vulnerable periods to pros-taglandin administration than later stages of preg-nancy.' It seems likely that the evaluation of the

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antifertility potential of the prostaglandins will bevigorously pursued.

Bronchodilator activityRosenthale et al. (1968) reported that i.v. adminis-

tration of PGE2 at doses of 4-8 ,zg/kg completelyprevented bronchoconstriction induced in anaesthe-tized guinea-pigs by histamine, serotonin, acetyl-choline or bradykinin. This action of PGE2 was notinfluenced by bilateral vagotomy, adrenalectomy,double pithing or pretreatment with reserpine orpronethalol. PGE2 administered in aerosol pre-vented bronchoconstriction induced by aerosols ofhistamine in normal and in horse serum-sensitizedguinea-pigs. In this species, PGE2 was reported tobe as active a bronchodilator as isoprenaline butwith shorter duration of action. Other experimentsindicated that PGE2 caused considerably greaterbronchodilation in the monkey than in the dog.This differed from isoprenaline which was equi-active in both species. Large, Leswell & Maxwell(1969) have compared the bronchodilator activitiesof aerosols of PGE1 and isoprenaline in the anaes-thetized guinea-pig and found PGE1 to be 10-100times more active than isoprenaline. However, byi.v. administration PGE1 was slightly less potentthan isoprenaline. They found that the bronchodi-lator responses to aerosols of isoprenaline could bepartially or completely inhibited by propranolol, butthere was no inhibition of the responses to aerosolsof PGE1. Since severe cardiovascular disturbanceshave been reported in man particularly followingover-doses of sympathomimetic drugs such asisoprenaline, these authors recommended studies ofthe bronchodilator activity of PGE1 aerosol in man.

Cuthbert (1969) recently reported the results of apreliminary study on the comparison of the actionsof PGE1 and isoprenaline in healthy and asthmaticvolunteers on timed forced expiratory volume in onesecond (FEV1). In addition to measuring FEV1 by aVitalograph, blood pressure, pulse rate and ECGwere monitored. Inhalation of aerosols containingPGE1 as the free acid proved irritating to the upperrespiratory tract, but the neutral triethanolaminesalt of PGE1 was tolerated with little or no irritanteffect in both normal and asthmatic volunteers. Ablind comparison was made between metered dosesof the triethanolamine salt of PGE1 (55 ,ug), iso-prenaline sulphate (550 ,g) and placebo in fiveasthmatic subjects. The results indicated thatPGEi caused an increase in FEV1 comparable indegree and duration to that of isoprenaline. Nochange was noted in blood pressure, pulse rate orECG in any of the patients. Isoprenaline producedits maximum effect in 3 min in four of the fivesubjects in contrast to 30 min for PGE1 whichmaintained higher FEV, levels for a longer period,

but there appeared to be little difference in theoverall duration. Cuthbert concluded that theseresults suggest that aerosol administration of PGE1can cause substantial reduction in airways obstruc-tion in asthmatic patients and that the relation ofthe prostaglandins to the function of respiratorysmooth muscle merits further investigation.Nasal vasoconstrictor activityAlthough the prostaglandins are usually con-

sidered to be vasodilating substances, some in-stances of vasoconstrictor activity have beenreported. An interesting example with some possi-bility of practical application is found in the workof Stovall & Jackson (1967) who reported thatprostaglandins induced a constriction of the bloodvessels of the nasal mucosa in dogs. PGE1, PGE2,PGAI, PGF1a and epinephrine were injected into acarotid artery and the resistance offered by the nasalpassage to a constant stream of humidified air wasrecorded. The PGEs were equipotent (doses in therange of 5 jig/kg) to epinephrine, but their durationof action was more than seven times as long. PGA1and PGF1a were about 1/100 as potent as the PGEs.Individual dogs varied in their sensitivity to theprostaglandins but the consistency of the response,its correlation with a decrease in nasal mucosaltemperature and its occurrence independent of ablood pressure change were cited as evidence of anactual vasoconstriction. The prolonged durationof increased nasal patency suggested the possibilityof clinical use.Jackson & Turner (1969) reported results of a

preliminary study in human volunteers who receivedtopical application of PGE1 via an atomizer whichwas calibrated to deliver doses of 37, 50, 75 and100 ,ug to one nostril. All the doses caused anincrease in the patency of the nasal airway and avisible blanching of the nasal mucosa. The effectlasted from i hr at the lower dose to 10-14 hr at the75 jig dose. The 100 ,ug dose caused subjectiveirritation in all subjects, but no change in pulserate or blood pressure was noted. Anggard (1969)also reported on the effects of topically applied dosesof 10-15 jig of PGEi, PGE2 and PGFIa on nasalairway resistance in seven normal men and women.Clear-cut increase in nasal patency was observedin four of the subjects following administration ofthe PGEs, but no effect was noted with PGF1I.Inhibition of gastric secretionAs Horton (1969) pointed out, gastric secretion in

response to a variety of secretagogues is believed tobe mediated at least in some species via cyclic AMPformation and it would be expected that PGE1would inhibit gastric secretion by blocking adenylcyclase in the gastric parietal cells. While 'predic-tions' of the influence of prostaglandins on adenyl

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cyclase-mediated systems is not always straightforward (Butcher, 1969), it has been shown that indogs (Robert, Nezamis & Phillips, 1967) and inrats (Shaw & Ramwell, 1968) prostaglandinsinhibit gastric acid secretion induced by histamine orpentagastrin. Prostaglandins are known also tobe released into the lumen of the rat stomachspontaneously and in response to various stimuli(Coceani, Pace-Asciak & Wolfe, 1968). They havebeen found in the gastro-intestinal wall of man(Bennett, Murray & Whyllie, 1968b), and they mayplay a physiological role in the control of intestinalmotility (Bennett, Eley & Scholes 1968a). Orallyadministered PGE1 caused increased intestinalmotility resulting in loose faeces in man (Hortonet al., 1968). The possible significance of this inrelation to the diarrhoea associated with sometumors has been considered (Sandler et al., 1968;Misiewicz et al., 1969).

Robert, Nezamis & Phillips (1967) have shown thatPGEi, infused intravenously at rates of 0-5 to 1-0,ug/kg/min, markedly inhibited gastric secretion indogs stimulated by food, histamine, pentagastrin, or2-deoxyglucose. Maximum inhibition was achievedafter 30-45 min, and was maintained throughoutthe infusion period. PGE2 inhibited gastric secretionstimulated by food or histamine, and the ED50,i.e., the dose reducing gastric secretion by 50%,was the same as for PGE1. PGA1 strongly inhibitedfood-induced secretion with an ED50 of 0-08-0-1,ug/kg/min. With all three compounds, gastric secre-tion rose and reached normal levels about 2 hr afterthe infusion was stopped. PGF2a (10 ig/kg/min) hadno influence on histamine-induced gastric secretion.

Similarly, Robert, Nezamis& Phillips (1968) inhibi-ted gastric secretion in rats with PGE1 given either bysingle subcutaneous injection or constant subcutan-eous infusion. PGE_, infused subcutaneously, strong-ly inhibited both Shay ulcers and steroid-inducedulcers in rats. Regarding the mechanism of action,Jacobson (1970) concluded from studies in con-scious dogs that PGE1 reduced secretion by a primarymechanism other than restriction of gastric mucosalblood flow. PGE1 did cause a decrease in blood flow,but this appeared to be the result rather than thecause of gastric secretory inhibition.Thus far only very limited and preliminary

studies in man have been reported. Horton et al.(1968) administered oral doses of 10-40 ,rg/kgto three human subjects and observed no inhibitionof pentagastrin-induced gastric secretion. On theother hand, Wilson, Phillips & Levine (1970) havefound that PGA, infused at the rate of 0-5-1-25,ug/kg/min i.v. for 30 min decreased mean volume andacidity in eleven healthy volunteers after inducinggastric secretion by intravenous administration ofsub-maximal doses of histamine.

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BENNETT, A., ELEY, K.G. & SCHOLES, G.B. (1968a) Effect ofprostaglandins E1 and E2 on intestinal motility in theguinea-pig and rat. British Journal ofPharmacology, 34, 369.

BENNETT, A., MURRAY, J.G. & WYLLIE, J.H. (1968b)Occurrence of prostaglandin E2 in the human stomach,and a study of its effects on human isolated gastric muscle.British Journal of Pharmacology and Chemotherapy,32, 339.

BERGSTROM, S. (1967) Prostaglandins: Members of a newhormonal system. Science, 157, 382.

BERGSTR6M, S., CARLSON, L.H., EKELUND, L.-G. & OR6, L.(1965) Cardiovascular and metabolic response to infusionsof prostaglandin E1 and to simultaneous infusions ofnoradrenaline and prostaglandin E1 in man. Acta Physio-logica Scandinavica, 64, 332.

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BERGSTROM, S., DUNER, H., EULER, U.S.v., PERNOW, B. &SJOVALL, J. (1959) Observations of the effects of infusionof prostaglandin E in man. Acta Physiologica Scandina-vica, 45, 145.

BERGSTROM, S. & SJOVALL, J. (1960) The isolation of prosta-glandin F [and prostaglandin El from sheep prostateglands. Acta Chemica Scandinavica, 14, 1693, [17011.

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BYGDEMAN, M., KWON, S.U., MUKHERJEE, T., ROTH-BRAN-DEL, U. & WIQVIST, N. (1970) The effect of the prostaglandinF compounds on the contractility of the pregnant humanuterus. American Journal of Obstetrics and Gynecology,106, 567.

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LEE, J.B. (1967) Chemical and physiological properties ofrenal prostaglandins: The antihypertensive effects ofmedullin in essential human hypertension. p. 197. NobelSymposium 2, Prostaglandins (Ed. by S. Bergstrom and B.Samuelsson). Almqvist and Wiksell, Stockholm.

LEE, J.B., COVINO, B.G., TAKMAN, B.H. & SMITH, E.R.(1965) Renomedullary vasodepressor substance, medullin:isolation, chemical characterization and physiologicalproperties. Circulation Research, 17, 57.

LEE, J.B., CROWSHAW, K., TAKMAN, B.H., ATTREP, K.A.& GOUGOUTAS, J.Z. (1967) The identification of prosta-glandins E2, F2a, and A2 from rabbit kidney medulla.Biochemical Journal, 105, 1251.

LEE, J.B., GOUGOUTAS, J.Z., TAKMAN, B.H., DANIELS, E.G.,GROSTIC, M.F., PIKE, J.E., HINMAN, J.W. & MUIRHEAD,E.E. (1966) Vasodepressor and antihypertensive prosta-glandins of PGE type with emphasis on the identification ofmedullin as PGE--217. Journal of Clinical Investigation,45, 1036.

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