METHOD OF TREATING HYPERTENSION IN PREGNANT MAMMALS

Abstract: A method of treating a pregnant mammal (including a human) which comprises administering IGF-1 or an analogue thereof or another hormone (such as growth hormone) which elevates maternal IGF-1 to thereby illicit a reduction of maternal blood pressure and/or to promote fetal growth and placental function.

Description: "METHOD OF TREATING HYPERTENSION IN PREGNANT MAMMALS" TECHNICAL FIELD The present invention relates to a method of treating high blood pressure or a tendency to be hypertensive in pregnant mammals including humans which aids fetal development. BACKGROUND ART Hypertension in pregnancy is, both in man and in other nnmιnι«l g associated with impaired fetal growth. In man it is frequently associated with a syndrome of proteinuria and edema which is termed "toxaemia of pregnancy" or preeclampsia. These pregnancies are compUcated by placental insufficiency and fetal growth retardation. Current therapy is essentially restricted to common anti-hypertensive agents and bed rest which, while reducing the risk of hypertensive crises in the mother, do not correct the fetal growth retardation and reduce the consequent risk of fetal death, stillbirth and the neonatal complications of infrauterine growm retardation. The essence of this invention is that we have found that the adrninistration of IGF- 1 in pregnant hypertensive mammals reduces maternal blood pressure and improves placental function and fetal development We have previously disclosed mat the adnunistration of IGF- 1 through part or whole of pregnancy to a maternal mammal overcomes maternal cx)nstτaint on fetal growth (IGF- 1 in Pregnancy: PCT Europe 91912874.4, USA 07/969229, Japan 3-511969, Australia 82052/91, Canada 2087030). We have observed such administration of IGF- 1 promoting fetal growm and placental function. However mere is nothing in the prior art that would have led us to conclude that there would be a lowering effect on blood pressure. Elsewhere we have disclosed mat in non-pregnant animals IGF- 1 promotes cardiac output (Ambler et al J Cardiovascular Research 27 1368-1373 1993) and this is associated with maintenance of blood pressure. In pregnant mammals with lypeitensionand apiedisposMon to to growm retarded fetuses with disproportionatery large placentas, we have now observed that IGF-1 adrninistration to the mother reverses these changes. DISCLOSURE OF INVENTION In a first aspect the present invention consists in a method of treatment by which IGF-1 is administered to pregnant mammals with hypertension to promote fetal growth and placental function. In a further aspect the invention consists in a method of treatment by which IGF-1 is administered to pregnant mammals with hypertension to reduce maternal blood pressure. In still a further aspect the invention consists in a method of treatment by which maternal levels of IGF-1 are elevated either directly by administration of IGF-1 or indirectly by the administration of other hormones which elevate maternal IGF-1 such as growth hormone. In yet a further aspect the invention consists in a method of treatment where preferably the IGF-1 administered is recombinant human IGF-1 or one of its analogues with alterations to the amino terminal (eg des 1-3 N IGF-1). In yet a further aspect the invention consists in a method of treatment where the IGF-1 may be aάπύmstered alone or in combination with binding proteins to alter its half life and bioavailability or in combination with growth hormone. In still a further aspect the present invention consists in a method of treatment where IGF-1 is administered during the latter phase of pregnancy when hypertension is present In yet a further aspect the invention consists in a method of treatment where IGF- 1 is administered at a dose of 40 to 2000 μg/kg body weight per day to a pregnant mammal and preferentially in humans at a dose of 40 to 200 μg kg body weight per day. In yet a further aspect the invention consists in a mode of treatment by which the IGF-1 is administered to a pregnant mammal either continuously by implant or mtcrmittently by subcutaneous or intramuscular, intranasal or oral routes of administration. In still a further aspect the invention consists in a method of treatment where preferably IGF-1 itself is administered subcutaneously but forms of IGF- 1 with increased stability may be given by oral or intranasal route. In yet a further aspect the invention consists in a mode of treatment where IGF-1 is administered alone or in combination with other antihypertensive treatments. This mvention may also be said broadly to consist in the parts, dements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more of said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which is mvention relates, such known equivalents are deemed to be incorporated herein as if individually set forth. BRIEF DESCRIPTION OF DRAWINGS The invention consists in the foregoing and also envisages constructions of which the following gives examples. One preferred form of the present invention will now be described with reference to a non limiting example. Spontaneously hypertensive rats (SHR) are a defined and well studied strain of rat vvim a rjropαisity to lωve ghblcrod pressure. They have been extensively used to model human hypertension. They are derived from a Wistar Kyoto (WKY) strain of rat and the appropriate control line is the WKY rat (Wistar Kyoto rat) which is the strain f om which the SHR was derived. SHR or WKY rats were mated under laboratory conditions so mat the day of mating was known. At day 10 after mating animals were divided into two groups (n= 10 each) to receive either saline or IGF-1. Of these four groups of animals several were determined to be non pregnant leaving reduced numbers in each group. The final numbers in each group were; WKY saline n=7, WKY IGF-1 n=7, SHR saline n=5, SHR IGF-1 n=5. The daily dose of IGF-1 administered was 2 μg/gm body weight per day. This dose was divided into three equal doses and admώistered to the mother subcutaneously at 8.00am, 4.00pm and 10.00pm dairy. The IGF-1 used was recombinant human IGF-1 provided by Dr Linda Fryklund of Pharmacia AB Stockholm Sweden. The saline or IGF-1 treatment was continued until day 20 of pregnancy. At that age the animals were sacrificed to obtain maternal weights, fetal and placental weights. On day twenty blood pressure measurements were recorded via a carotid arter cannula on all animals under halothane anaesthetic prior to sacrifice. 10 mins equilibration was allowed to overcome the depressive influence of the anaesthetic. The following observations were made. 1. Maternal, Placental and Fetal Size. IGF-1 treatment in SHR rats significantly increases circulating IGF- 1 concentration (p=0.031) from 288.92 ± 87.27 ng ml in saline treated rats to 437.47 ± 102.42 ng ml in IGF-1 treated rats. IGF-1 treatment increased mean fetal weight in the SHR rats from 1.79 ± 0.039g i the saline treated SHR rats to 1.90 ± 0.053g in the IGF-1 TxSHR rats (p=0.054). A similar trend was observed in fetuses of the saline WKY rats. IGF-1 treatment in the SHR rats tended to cause a reduction in placental weight compared to that seen in the saline SHR placentae (p=0.096) such that they were of a similar placental weight to that seen in saline treated WKY rats. Placental weight in the saline SHR group was 0.43 ± 0.023g versus 0.38 ± 0.012g in the SHR IGF-1 treated group. The saline WKY placenta weight was 0.32g ± 0.008g. The ratio of fetal to placental weight was significantly increased (pθ.05) from 4.23 ± 0.13 in the saline SHR rats to 5.04 ± 0.14 in IGF-1 treated SHR rats. This was closer to the ratio observed in the saline WKY rats (6.70 ± 0.15) which is presumed to be normal for this strain of rat. The experimentation was repeated and the Fetal Weight and Placental Weight date can be summarised as follows. p values are group comparisons between saline and IGF-1 treatment in each breed. 2. Blood Pressure. In WKY rats, IGF-1 had no effect on blood pressure or heart rate. Systolic BP Diastolic BP Mean BP Heart Rate WKY saline 110 ± 2.0 84.1 ± 2.0 93.6 ± 1.37 360.88 ± 7.16 I WKY IGF-1 113.6 ± 3.4 87.8 ± 5.3 96.3 ± 4.6 331 ± 12.4 In contrast in SHR rats, IGF-1 reduced systolic, diastolic and mean blood pressure but had no effect on heart rate. Systolic BP Diastolic BP Mean BP Heart Rate SHR saline 141 ± 6.9 109 ± 4 119.6 ± 4.9 305 ± 17.2 SHR IGF-1 128 ± 7.47 92.6 ± 10.1 104 ± 9.2 308.4 ± 12.2 This treatment of the SHR rat through the later phase of pregnancy lowered maternal blood pressure, increased fetal growth and increased fetal:placental weight ratio towards that seen in the control WKY strain. The mode of action of IGF- 1 to lower blood pressure is not known. Nor is it known whether it is directly linked to die effects of maternally administered IGF-1 on fetal growth and placental function. It is well known to those skilled in the art that IGF- 1 does not traverse die placenta from the maternal to fetal compartment and thus any effect on fetal development is indirect. However the combination of these effects whether interdependent or not is clearly advantageous for fetal development and maternal well being and represents a combination of biological effects which are unique and readily applicable to hypertension of human pregnancy either directly or indirectly.

Claims: CLAIMS 1. A method of treatment by which IGF-1 is administered to pregnant mammals with hypertension to promote fetal growth and placental function. 2. A method of treatment by which IGF- 1 is administered to pregnant m als with hypertension to reduce maternal blood pressure. 3. A memod of treatment by which maternal levels of IGF- 1 are elevated either directiy by administration of IGF- 1 or indirectly by the administration of other hormones which elevate maternal IGF-1. 4. A method of claim 3 wherein growth hormone is administered. 5. A method of claim 3 where IGF- 1 administered. 6. A method of claim 3 wherein an analogue of IGF- 1 with alterations to the amino treatment. 7. A method of claim 6 wherein des 1-3 N IGF- 1 is administered. 8. A method of claim 5, 6 or 7 where the IGF-1 or analogue thereof is administered alone or in combination with binding proteins to alter its half life and bioavailability or in combination with growth hormone. 9. A memod of any one of claims 3 to 8 where IGF-1 is administered during the latter phase of pregnancy when hypertension is present. 10. A method of any one of claims 3 to 9 wherein die mammal is human and the treatment is to promote fetal growth and placental function and/or reduce maternal blood pressure. 11. A method of claim 10 wherein IGF- 1 is administered at a dose of 40 to 200 μg/kg bodyweight per day. 12. A method of treatment where IGF-1 is administered at a dose of 40 to 2000 μg/kg body weight per day to a pregnant mammal. 13. A mode of treatment by which the IGF-1 is administered to a pregnant mammal either continuously by implant or intermittently by subcutaneous or intramuscular, intranasal or oral routes of administration. 14. A mode of treatment of claim 13 where IGF-1 is administered alone or in combination with other antihypertensive treatments. 15. A mediod of treatment preferably IGF- 1 itself is administered subcutaneously or a form of IGF- 1 with increased stability is administered by the oral or intranasal route.

Inventors: BASSETT NICOLE SUSAN, GLUCKMAN PETER DAVID, JOHNSTON BARBARA MADELEINE, BASSETT, NICOLE, SUSAN, GLUCKMAN, PETER, DAVID, JOHNSTON, BARBARA, MADELEINE
Applicants: BASSETT NICOLE SUSAN, GLUCKMAN PETER DAVID, JOHNSTON BARBARA MADELEINE, PHARMACIA AB, BASSETT, NICOLE, SUSAN, GLUCKMAN, PETER, DAVID, JOHNSTON, BARBARA, MADELEINE
Application year: 1995
Main classification: A61K38
IPC codes: A61K38, A61P9