EP3344237A1 - Prophylaxis of hypertension and cardiovascular diseases - Google Patents

Prophylaxis of hypertension and cardiovascular diseases

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Publication number
EP3344237A1
EP3344237A1 EP16757650.3A EP16757650A EP3344237A1 EP 3344237 A1 EP3344237 A1 EP 3344237A1 EP 16757650 A EP16757650 A EP 16757650A EP 3344237 A1 EP3344237 A1 EP 3344237A1
Authority
EP
European Patent Office
Prior art keywords
resveratrol
compound
offspring
metabolite
hypertension
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16757650.3A
Other languages
German (de)
French (fr)
Inventor
Euridice CASTANEDA GUTIERREZ
Catherine Mace
Paul David TAYLOR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe des Produits Nestle SA
Original Assignee
Nestec SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nestec SA filed Critical Nestec SA
Publication of EP3344237A1 publication Critical patent/EP3344237A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a compound for use in the prophylaxis of
  • cardiovascular diseases In particular the present invention relates to the prophylaxis of cardiovascular diseases and hypertension in the offspring, through administration of the compound pre-pregnancy, during pregnancy and/or during lactation.
  • cardiovascular disease is the primary cause of premature death.
  • Resveratrol (3,5,4'-trihydroxystilbene) is a natural plant polyphenol, which is produced by certain plants such as Japanese knotweed, peanuts, and in the skins of grapes, blueberries and raspberries. Resveratrol exists as two double-bond isomers, cis -resveratrol and trans -resveratrol, having the formulae:
  • Dihydroresveratrol is a metabolite of resveratrol.
  • Trans- and czs-resveratrol, as well as dihydroresveratrol have been described in the literature as having a number of pharmacological activities, including antioxidant-, anticancer-, antiplatelet-, and estrogen modulating activities.
  • Resveratrol (particularly the trans-isomer) has been shown to improve metabolic outcomes in humans and animal models.
  • resveratrol has been proposed as having a beneficial effect in obesity-related conditions, including blood sugar control, and preventing leptin resistance.
  • low dose resveratrol has been shown to reverse cardiac impairment in obese-prone rats [Louis, XL, et al, J.
  • WO2009/003798 discloses a food product composition comprising trans-resveratrol that can be used to control blood pressure.
  • resveratrol is able to exert an antihypertensive effect in the offspring of overweight or obese females.
  • resveratrol when administered to the mother during pregnancy and/or during lactation may prevent, or reduce the risk of, blood pressure elevation in the offspring.
  • cardiovascular health in an offspring e.g. for humans: at the fetal, neonatal, infant and potentially the child stages or beyond
  • an offspring e.g. for humans: at the fetal, neonatal, infant and potentially the child stages or beyond
  • the present invention provides a compound of Formula 1 :
  • Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a pregnant and/or lactating female subject (i.e. the mother of the offspring), wherein the subject is overweight or obese.
  • the compounds may be alternatively or additionally administered to the female subject pre-pregnancy.
  • Formula 1 encompasses the compound wherein wavy bond represents double bond substituents being in the cw-configuration (cz ' s-resveratrol) or in the trans-configuration (trans-resveratrol).
  • the present invention provides a compound of Formula 1 :
  • Formula 1 or a metabolite thereof, for use as a pre-pregnancy, pregnancy or lactation supplement in an overweight or obese female subject, in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring.
  • the compound of Formula 1 may particularly be trans-resveratrol having the formula 1A:
  • the invention further provides a compound of Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a pregnant female subject, wherein the subject is overweight or obese.
  • the invention further provides a compound of Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a lactating female subject, wherein the subject is overweight or obese.
  • the compound of Formula 1 or a metabolite thereof can be administered in any dose that is effective in achieving the objective of the present invention.
  • dose refers to a daily quantity that is administered to a subject.
  • any dose having a positive i.e. antihypertensive, effect on the blood pressure of the offspring of a subject, in particular an overweight or obese subject, to whom it is administered may be considered an effective dose.
  • an effective dose may depend on the age, size and health status of the subject, on the subject's lifestyle, as well as on the subject's genetic heritage.
  • Preferred doses in mammals, including cats, dogs and humans, and in particular humans may be 0.1 to 3g, or 0.2 to 2g, or 0.3 to 1.5g, or 0.4 to 1.2g, or 0.4 to lg.
  • particularly useful doses in mammals including cats, dogs and humans, and in particular humans, may be 6-17 mg/kg of body weight, in particular 6 to 10 mg/kg of body weight, more particularly 7 to 9 mg/kg of body weight, and even more particularly 8 to 8.5 mg/kg of body weight.
  • the dose may be administered all at once or it may be spread out over several administrations throughout a day.
  • the invention provides a compound of Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound during pregnancy and lactation.
  • a further aspect of the invention provides a compound of Formula 1 or a metabolite thereof, for use in the in utero prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to an overweight or obese pregnant female subject.
  • the hypertension and/or cardiovascular disease in the offspring may be associated with maternal overweight or maternal obesity.
  • the prophylaxis of hypertension and/or cardiovascular disease may comprise a reduction in the systolic and/or the diastolic blood pressure. Particularly the prophylaxis of hypertension and/or cardiovascular disease may comprise a reduction in the systolic blood pressure of the offspring, or may comprise a prevention of the onset of hypertension in the offspring.
  • the hypertension may be associated with, or is a consequence of, maternal overweight or obesity.
  • the prophylaxis of hypertension may reduce, or prevent the risk of, the development of an associated cardiovascular disease in the offspring.
  • the cardiovascular disease may be a disease or disorder associated with, or caused by hypertension.
  • the cardiovascular disease may be selected from the group consisting of hypertensive heart disease as well as diseases of the cardiovascular system.
  • Cardiovascular disease include arteriosclerosis and associated diseases including angina, heart failure, peripheral artery disease, retinal vascular diseases, aneurysm, hypertensive renal damage and failure, cognitive impairment due to restricted blood flow, transient ischemic attack, ischemic heart disease, stroke; coronary artery disease, arrhythmias, left ventricular hypertrophy, heart failure, blood clots, myocardial infarction and diabetic vascular diseases.
  • arteriosclerosis and associated diseases including angina, heart failure, peripheral artery disease, retinal vascular diseases, aneurysm, hypertensive renal damage and failure, cognitive impairment due to restricted blood flow, transient ischemic attack, ischemic heart disease, stroke; coronary artery disease, arrhythmias, left ventricular hypertrophy, heart failure, blood clots, myocardial infarction and diabetic vascular diseases.
  • the offspring of the female subject may be the fetus, neonate, infant, child, or adult in the case of a human, or the fetus, infant or adult in the case of other mammals (for example cats and dogs).
  • the prophylaxis of hypertension or cardiovascular disease in humans is especially applicable to offspring at the fetal, neonatal, infant or child stage, or at the neonatal, infant or child stage.
  • the effect of resveratrol in the prevention of hypertension, or the reduction in the risk of onset of hypertension, in the offspring may also have a prophylactic effect on hypertension and/or cardiovascular disease at future stages of development beyond infancy and childhood (e.g. adulthood).
  • the female subject to which the compound of Formula 1 or a metabolite thereof, is administered is obese as defined herein.
  • the female subject may have a pre-pregnancy BMI of > 25 kg/m 2 , or may have a pre-pregnancy BMI of > 30 kg/m 2 .
  • the present invention also encompasses a composition comprising a compound of Formula 1 :
  • composition may comprise a compound of Formula 1A (i.e. trans-resveratrol) or a metabolite thereof.
  • the composition may be selected from the group consisting of a pharmaceutical composition, a food product, a food extract, drink, food additive, a pet care product, a nutraceutical, and a nutritional supplement, in particular a maternal supplement.
  • the compound of formula 1 or 1 A, or a metabolite thereof, according to any embodiment of the invention may be obtained from a plant source.
  • plant extracts selected from the group consisting of: apple, berries [preferably acai, bilberry, blackberry, blackcurrant, blueberry, cherry, chokeberry, cloudberry, cranberry, crowberry, grape (particularly grape skins), lingonberry, mulberry, raspberry, redcurrant, rowanberry, whortleberry], purple corn, purple potato, cocoa bean, purple carrot, sweet potato, red cabbage, aubergine, grape, peanut, pomegranate, pistachio (Pistacia vera), rhubarb (Rheum rabarbarum) and hop (Humulus lupulus), eucalyptus and spruce trees, plants of the Polygonaceae (knotweed - e.g. Japanese knotweed) and Vitaceae families and Pin us strobus, white hellebore (Veratrum album
  • Poligonum cuspidatum, Bauhinia racemosa, or red/white wine extract may be used.
  • the invention further provides a method for the prophylaxis of hypertension in an offspring comprising administering a therapeutically active amount of a compound of Formula 1 or a metabolite thereof, to a pregnant and/or lactating female subject, wherein the female subject is overweight or obese.
  • FIGURES Figures 1A and IB: Systolic and diastolic blood pressure of control (Ctrl) and obese (Ob) pregnant dams at day 10 of gestation.
  • Figures 2A and 2B Systolic and diastolic blood pressure of obese pregnant dams with (Ob+R) or without (Ob) resveratrol supplementation at day 10 of gestation.
  • Figs 3A and 3B Systolic blood pressure of the male (3 A) and female (3B) offspring at 90d.
  • OffCon offspring of lean dams;
  • OffOb offspring of obese dams.
  • references to “resveratrol” encompasses to trans-resveratrol and czs-resveratrol.
  • references to “resveratrol” encompasses to trans-resveratrol and czs-resveratrol.
  • the term “resveratrol” encompasses to trans-resveratrol and czs-resveratrol.
  • Formula 1 such that: when the wavy line represents a trans double bond, Formula 1 represents trans-resveratrol (i.e. Formula 1 A); when the wavy line represents a cz ' s-double bond, Formula 1 represents czs-resveratrol.
  • the compound of Formula 1 may preferably be trans-resveratrol.
  • a metabolite of compounds of Formula 1 include any active metabolite of the compounds of Formula 1 (i.e. metabolites of trans-resveratrol and cz ' s-resveratrol) that is effective in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring, when administered to a pregnant and/or lactating overweight or obese female subject.
  • active metabolite of the compounds of Formula 1 i.e. metabolites of trans-resveratrol and cz ' s-resveratrol
  • preferred metabolites of the compounds of Formula 1 include: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0- glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide, resveratrol disulfate, piceatannol (i.e. (3-hydroxyresveratol or 3,4',5- trihydroxystilbene), astringin (piceatannol glucoside), which (when the double bond is present) may be in the cis- or trans-configurations.
  • more preferred metabolites of the compounds of Formula 1 may be selected from the group consisting of: dihydroresveratrol, resveratro 1-3-0- glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0- sulfate, resveratrol sulfate glucuronide and resveratrol disulfate, which (when the double bond is present) may be in the cis- or trans-configurations.
  • Particularly preferred metabolites of the compounds of Formula 1 according to any aspect or embodiment of the present invention are those selected from the group consisting of: dihydroresveratrol, resveratro 1-3 -O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate, in which (when the double bond is present) are in the transconfiguration.
  • the compound is selected from the group consisting of: cz ' s-resveratrol, trans-resveratrol and the metabolites: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate (wherein when the double bond is present in the metabolites, may be in the cis- or trans-configurations).
  • the compound is selected from the group consisting of trans- resveratrol, and the metabolites: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate (wherein when the double bond is present in the metabolites, are in trans-configuration).
  • the compound for use in accordance with any embodiment of the invention is selected from the group consisting of trans-resveratrol, cz ' s-resveratrol and dihydroresveratrol, or preferably is selected from the group consisting of transz resveratrol or c s-resveratrol.
  • resveratrol refers to trans- resveratrol, having Formula 1A:
  • the term offspring encompasses the offspring of the female subject at any stage of development including fetus, neonate, infant, child and adult.
  • the term offspring in relation to a human refers to the neonate, infant and child stages, and more preferably the neonate and infant stages.
  • the term offspring in relation to other mammals e.g. cats and dogs, refers to a neonate or infant stage.
  • subject refers to a pregnant mammal and more particularly a pregnant cat, a pregnant dog or a pregnant human.
  • Cardiovascular disease refers to a mammal and more particularly a pregnant cat, a pregnant dog or a pregnant human.
  • cardiovascular disease includes cardiovascular diseases associated with, caused by, or resulting from hypertension. Particularly the cardiovascular disease is caused by hypertension.
  • cardiovascular diseases include those well-known in the literature to be attributable to long-term or uncontrolled hypertension, i.e. arteriosclerosis, angina, heart failure, peripheral artery disease, retinal vascular diseases, aneurysm, hypertensive renal damage and failure, cognitive impairment due to restricted blood flow, transient ischemic attack, ischemic heart disease, cerebral apoplexy (stroke), coronary artery disease, arrhythmias, left ventricular hypertrophy, blood clots, myocardial infarction and diabetic vascular diseases.
  • Hypertension is associated with raised systolic and/or diastolic blood pressure.
  • hypertension may be associated with at least a raised systolic blood pressure.
  • prophylaxis refers to preventing a disorder, as well as reducing the risk of development or preventing the onset of a disorder.
  • prophylaxis of hypertension includes preventing high blood pressure (whether systolic and/or diastolic), as well as reducing the risk of
  • the prophylaxis of hypertension includes preventing the onset of, or reducing the risk of development of, high blood pressure such as high systolic blood pressure.
  • prophylaxis of a particular condition includes a reference to reducing the risk of development of the condition or preventing the onset of the condition.
  • a reference to prophylaxis of cardiovascular disease (CVD), wherein the CVD is associated with, or results from, hypertension includes a reduction or prevention in the risk of a subject (e.g. offspring) developing the CVD due to hypertension.
  • Body mass index is calculated by dividing body weight in kilograms by the square of the height in centimetres.
  • the terms “obesity” and “overweight” refer to conditions in which a mammal accumulates excess body fat to the extent that it has a negative impact on health.
  • WHO World Health Organization
  • an adult human is considered to be overweight (pre-obese), if the BMI is between 25 kg/m 2 and 30 kg/m 2 .
  • An adult human is considered to be obese if the BMI is greater than 30 kg/m 2 .
  • certain geographical regions may apply different definitions for overweight and obese.
  • the Japan Society for the Study of Obesity has modified the WHO classification of obesity:
  • overweight and obese as set out in the above table as applicable to the female subject are encompassed.
  • a clinical diagnosis of overweight or obesity may be assessed by methods in addition to, or instead of, BMI, such as by comparison with standard body weights, physique index and determination of subcutaneous fat thickness. For example, mammals having a weight that exceeds the 85th percentile may be diagnosed as being overweight, and those exceeding the 95th percentile may be diagnosed as obese.
  • Other determinations of obesity include waist circumference and waist-hip ratio (circumference of the waist divided by that of the hips).
  • central (abdominal) obesity is defined as a waist circumference of > 80 cm in non-pregnant women; in the US, central obesity is defined as a waist circumference of > 88 cm in women, or waist-hip ratio of > 0.85 (women). All such definitions of overweight or obese are included. A healthcare practitioner would readily be able to determine whether a subject is overweight or obese using one or more of the established criteria.
  • obese or overweight in humans may particularly refer to a subject having a BMI of > 25 kg/m 2 .
  • the term obese includes subjects having a BMI > 25.0 kg/m 2 (JASSO definition for Asian populations) or subjects having a BMI of > 30.0 kg/m 2 (WHO definition).
  • the term obese may be considered to encompass the WHO obese classes I-III and the JASSO obese classes 1-4.
  • obese or overweight may alternatively refer to a subject, especially a human, having a BMI of > 30 kg/m 2 , particularly > 35 kg/m 2 or > 40 kg/m 2 .
  • overweight and obesity in relation to a pregnant or lactating female is generally determined by the BMI, weight and/or other indicators prior to pregnancy, for example by determination of pre-pregnancy BMI.
  • BMI BMI
  • weight and/or other indicators prior to pregnancy for example by determination of pre-pregnancy BMI.
  • excessive weight gain occurring during pregnancy in a female subject having a "normal" weight (WHO or JASSO classification) prior to pregnancy prior to the pregnancy may lead to the pregnant female being classified/diagnosed as overweight or obese.
  • WHO or JASSO classification "normal" weight
  • the BMI or other indicator of overweight or obesity can be determined by taking into account the estimated fetal, placental and amniotic fluid weight.
  • An assessment of overweight or obesity in a pregnant female subject can be readily made by a healthcare practitioner. For example, the following weight gain goals during pregnancy in humans have been suggested [Cunningham, F.G., et al, Prenatal care: William's Obstetrics, 21 st Ed., New York, Appleton and Lange: 2001 :232]:
  • obesity or overweight in pregnancy can be defined as a percentage range above the ideal body weight for a particular breed and taking into account the size of the litter.
  • overweight can be defined as a body weight of 10-20% or 15-25% above the ideal weight for the particular breed, and obesity may be or obesity may be defined as a body weight of over 25%, or over 30% above the ideal weight for the particular breed. It will be appreciated that an assessment of overweight or obesity in a pregnant mammals other than humans (and particularly cats and dogs), can be readily made by a veterinary practitioner.
  • Hypertension Hypertension may be determined by a clinician or other healthcare professional. For example, a neonate may be considered to have hypertension if the systolic blood pressure is above the 95th percentile of blood pressure for infants of similar gestational or postconceptional age and size. Hypertension in infants or children may be diagnosed if a systolic and/or diastolic pressure above the 95th percentile for age, gender, and height is found on three separate occasions [Pediatrics (2004), 114: 555- 557].
  • the data herein shows that obesity or overweight in the mother during pregnancy gives rise to a significant elevation in both systolic and diastolic blood pressure of the offspring, which is associated with, or is a consequence of, maternal overweight or obesity.
  • the data further shows that this hypertension in the offspring can be prevented or ameliorated by the administration of a compound of Formula 1 to the mother during pregnancy and/or lactation.
  • the present invention provides a method for prophylaxis of such cardiovascular diseases in the offspring.
  • the protective effect of the resveratrol may extend to well beyond the infant and childhood stages of offspring development.
  • Blood pressure can be determined by non-invasive or invasive methods as appropriate for the subject and setting.
  • non-invasive methods include auscultatory (such as a sphygmomanometer or stethoscope) or oscillometric measurement devices, which are routinely used by healthcare professionals.
  • auscultatory such as a sphygmomanometer or stethoscope
  • oscillometric measurement devices which are routinely used by healthcare professionals.
  • Invasive methods typically measure intra-arterial blood pressure via insertion of a catheter into an artery, and are particularly suitable for prenatal blood pressure monitoring of the fetus. In other mammals, such as cats and dogs, blood pressure can be readily measured, and hypertension can be assessed, by a veterinary practitioner (e.g. see guidance in: S. Brown, et al, J. Vet. Intern. Med. 2007, 21, 542-558).
  • the compound of Formula 1 or a metabolite thereof may be administered during pregnancy alone, during lactation alone or during pregnancy and lactation.
  • the compound of Formula 1 or a metabolite thereof may be alternatively or additionally administered pre-pregnancy.
  • the compound of Formula 1 or a metabolite thereof may for example be administered to a woman desiring to get pregnant, for example during at least 1, 2, 3 or 4 months preceding the pregnancy or desired pregnancy.
  • Pre-pregnancy administration of the compound of Formula 1 or a metabolite thereof may impact the intrauterine environment and in consequence may also have an antihypertensive effect on the blood pressure of the offspring of a subject to whom it is administered.
  • a reference to administration of a compound of Formula 1 or a metabolite thereof, during pregnancy particularly refers to administration of the compound during any part of, or the whole of, the gestation period.
  • administration of the compound of Formula 1 or a metabolite thereof may be initiated as soon as possible following conception until at least the end of the period of embryogenesis.
  • the embryogenesis period encompasses the first 8 weeks of development (10 weeks of gestation).
  • the compounds of Formula 1 or a metabolite thereof may be administered during substantial part of the gestation period.
  • administration of the compound of Formula 1 or a metabolite thereof can be within: the first week, the first two weeks, the first month, the first trimester, the second trimester or the third trimester of pregnancy.
  • the administration may be continued until at least the birth of the offspring.
  • administration of a compound of Formula 1 or a metabolite thereof, during pregnancy refers to administration as soon as possible from conception (as defined above) until birth, i.e. during the full gestation period.
  • the administration may be for a period of from: about 1 week to birth, about 2 weeks to birth, about 4 weeks to birth, about 8 weeks to birth, about 12 weeks to birth, about 18 weeks to birth.
  • Formula 1 or a metabolite thereof, to the overweight or obese pregnant female subject may be initiated prenatally prior to any diagnosis of hypertension in the fetus, thereby preventing the onset of, or reducing the risk and severity of, fetal hypertension arising from maternal overweight or maternal obesity.
  • prenatal administration of the compound of Formula 1 or a metabolite thereof, to the overweight or obese mother provides a method for the in utero prophylaxis of hypertension and/or a cardiovascular disease in the offspring.
  • the compound of Formula 1 or a metabolite thereof may additionally be administered pre-pregnancy to the overweight or obese female subject as well as during pregnancy and/or during lactation.
  • a reference to administration of a compound of Formula 1 or a metabolite thereof, during lactation particularly includes administration of the compound postnatally at any time during which the offspring is exclusively or partially ingesting the maternal milk (the subject's breast milk).
  • administration during lactation may be for the period starting from onset of lactation until the end of the weaning process, i.e. when the offspring has ceased to ingest the maternal milk. During this period, the offspring may be exclusively or partially ingesting the maternal milk.
  • administration of the compound of Formula 1 or a metabolite thereof, during lactation may refer to administration: for two weeks following the onset of lactation when the offspring is exclusively or partially ingesting the maternal milk.
  • the administration of the compound of Formula 1 or a metabolite thereof, during lactation may also include administration for a period of 1-24 months, 2-20 months, 3-18 months, 6-12 months, 4-12 months or 4-8 months following the onset of lactation during which the offspring is exclusively or partially ingesting the maternal milk.
  • Administration of the compounds of Formula 1 or a metabolite thereof, to the overweight or obese female subject may also be initiated postpartum, i.e. not during pregnancy, but instead from the onset of lactation.
  • the administration of the compound of formula 1 or a metabolite thereof, during lactation may also include administration for a period of 1-24 months, 2-20 months, 3-18 months, 6-12 months, 4-12 months or 4-8 months following the onset of lactation during which the offspring is exclusively or partially ingesting the maternal milk.
  • the administration may be initiated from the onset of lactation until the end of the weaning process, i.e. when the offspring has ceased to ingest the maternal milk.
  • the compound of Formula 1 or a metabolite thereof may be administered both prenatally, i.e. at any period from conception to birth, as well as postnatally during lactation, i.e.
  • the compound of Formula 1 or a metabolite thereof may be administered both prenatally for any period as defined above in relation to prenatal administration, as well as postnatally for any period as defined above in relation to the lactation period, and any combination of these periods as described above.
  • the offspring is not directly administered the compound of Formula 1 or a metabolite thereof.
  • the compounds of the present invention when administered prenatally to an overweight or obese pregnant female subject are indirectly transmitted to the developing embryo or fetus e.g. via the placenta or amniotic fluid.
  • the exposure of the offspring to the compound of Formula 1 or a metabolite thereof is in utero when the compounds are administered to the mother during pregnancy.
  • the compound of Formula 1 or a metabolite thereof when administered postnatally to an overweight or obese lactating female, are indirectly transmitted to the neonate or infant via the ingestion of maternal milk, i.e. the exposure of the offspring to the compound is solely via the mother's milk.
  • the compound of Formula 1 or a metabolite thereof may be used as a pre-pregnancy, pregnancy or lactation dietary supplement in an overweight or obese female subject, in the prophylaxis of hypertension and/or cardiovascular disease in the offspring or future offspring.
  • pre-pregnancy supplementation or administration preferably refers to administration from about 1-24 months, 1-18 months, 1-12 months, 1-6 months, or 1-3 months prior to pregnancy.
  • the present invention provides a composition comprising a compound of Formula 1 :
  • Formula 1 for use in the prophylaxis of hypertension and/or a
  • cardiovascular disease in an offspring comprising administration of the compound to a pregnant and/or lactating female subject, wherein the subject is overweight or obese.
  • the composition can be selected from the group consisting of a pharmaceutical composition, a food product, a food extract, drink, food additive, a pet food product, a nutraceutical, and a nutritional or dietary supplement, in particular a maternal supplement.
  • the composition may also comprise vitamins and minerals.
  • vitamins and minerals recommended by a governmental body, such as USRDA for supplementation in pregnancy or during lactation e.g. calcium, magnesium, phosphorus, iron, zinc, copper, iodine, selenium, vitamin A or retinol activity equivalent (RAE) e.g. beta carotene or a mix of carotenoids, vitamin C, vitamin Bl, niacin, folic acid, biotin, vitamin E, vitamin B2, vitamin B 12, vitamin B6, and vitamin D.
  • the composition may also comprise other ingredients commonly used in the form in which it is employed e.g. in the form of a nutritional supplement, or a food product.
  • Non limiting examples of such ingredients include: other nutrients, for instance, selected from the group of lipids (optionally in addition to DHA and ARA), carbohydrates, and protein, micronutrients (in addition to those set out above), pharmaceutically active agents, conventional food additives such as anti-oxidants, stabilizers, emulsifiers, acidulants, thickeners, buffers or agents for pH adjustment, chelating agents, colorants, excipients, flavor agents, osmotic agents, pharmaceutically acceptable carriers, preservatives, sugars, sweeteners, texturizers, emulsifiers, water and any combination thereof.
  • pharmaceutically active agents conventional food additives such as anti-oxidants, stabilizers, emulsifiers, acidulants, thickeners, buffers or agents for pH adjustment, chelating agents, colorants, excipients, flavor agents, osmotic agents, pharmaceutically acceptable carriers, preservatives, sugars, sweeteners, texturizers, emulsifiers, water and any combination
  • the compound of Formula 1 or a metabolite thereof can be prepared by synthetic or semi- synthetic means, or alternatively the compound of Formula 1 or a metabolite thereof, is extracted from a plant.
  • Suitable plants that contain the compound of Formula 1 and/or a metabolite thereof include: apple, berries (preferably acai, bilberry, blackberry, blackcurrant, blueberry, cherry, chokeberry, cloudberry, cranberry, crowberry, grape, lingonberry, mulberry, raspberry, redcurrant,
  • the compound of Formula 1 or a metabolite thereof may be in the form of an extract (for example, an extract obtained from the processing of the plant source) which contains enriched
  • the present invention also encompasses a method for the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administering a
  • Female Sprague Dawley rat were divided into two groups - a first, control ("lean dams”) group and a second (“obese dams”) group.
  • the lean dams group Six weeks prior to mating, the lean dams group were fed a control diet. At the same time, in the obese group, obesity was induced in the rats by feeding an obesogenic diet (high fat, high sugar + sweetened condensed milk ad libitum). Prior to diet assignment, a telemetry transmitter was implanted in the aorta of each rat.
  • the lean dams group were divided into two subgroups. In the first subgroup (Con) lean dams continued to receive control diet and received control vehicle and in the second subgroup (Con+Res) the lean dams continued to receive control diet but were supplemented with resveratrol (trans-resveratrol) during pregnancy and lactation.
  • Con first subgroup
  • Con+Res second subgroup
  • resveratrol trans-resveratrol
  • the obese dams group were divided into two subgroups of five.
  • the first subgroup (Ob) continued to be fed the obesogenic diet and were assigned to vehicle.
  • the second subgroup (Ob+Res) continued to be fed the obesogenic diet and were assigned resveratrol.
  • Resveratrol was supplemented during pregnancy and lactation in a gelatin pellet (50 mg/kg/d).
  • Con+R Lean dams on the control diet receiving resveratrol (50 mg/kg) from mating until weaning (21 days after birth)
  • Obese dams on the obesogenic diet receiving vehicle only i.e. no resveratrol
  • OffCon+R Ob (OffOb) and Ob+R (Off Ob+R) were separated from the dams and the offspring were weaned to a laboratory chow diet.
  • a telemetery transmitter was implanted on the abdominal aorta of the offspring for assessment of cardiovascular function.

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Abstract

A compound of Formula 1 : or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring, comprising administration of the compound to a pregnant and/or lactating female subject, wherein the subject is overweight or obese.

Description

Prophylaxis of hypertension and cardiovascular diseases FIELD OF INVENTION
The present invention relates to a compound for use in the prophylaxis of
cardiovascular diseases. In particular the present invention relates to the prophylaxis of cardiovascular diseases and hypertension in the offspring, through administration of the compound pre-pregnancy, during pregnancy and/or during lactation.
BACKGROUND
Worldwide, there is a high incidence of obesity among women of reproductive age. A study covering the period 1999-2008 reports that in the US, 35% of pregnant women are obese [Flegal, K.M., et al, Prevalence and trends in obesity among US adults, 1999-2008. JAMA, 2010. 303(3): p. 235-241]. A study over the period 1989-2007 reports that the incidence of maternal obesity in the UK is 15.6 %, and a higher incidence of maternal overweight at 26% [Heslehurst, N., et al, A Nationally Representative Study of Maternal Obesity in England, UK: Trends in Incidence and Demographic Inequalities in 619323 Births, 1989-2007. Int J Obes. 34(3): p. 420- 428]. Epidemiological evidence indicates that maternal obesity during pregnancy increases premature death and hospital admission by cardiovascular events in their progeny [Reynolds, R.M., et al., Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. Vol. 347, 2013].
A number of studies have provided evidence of a strong link between the negative influence of maternal obesity on fetal, neonatal and subsequent childhood
development and health. For example, maternal obesity has been associated with an increased risk of stillbirth, congenital abnormalities, fetal macrosomia, and moreover is a contributing factor in the development of childhood obesity, diabetes and cardiovascular disease. Hypertension is generally regarded as the most significant risk factor in morbidity and mortality in cardiovascular diseases such as coronary heart disease and stroke. The control of blood pressure is therefore considered to play a primary role in the prevention of cardiovascular disease [Izzo, J.L. Mechanisms and management of hypertensive heart disease: from left ventricular hypertrophy to heart failure, Med. Clin. N. Am. 88 (2004): 1257-1271]. According to the World Health Organization (WHO), cardiovascular disease is the primary cause of premature death.
Resveratrol (3,5,4'-trihydroxystilbene) is a natural plant polyphenol, which is produced by certain plants such as Japanese knotweed, peanuts, and in the skins of grapes, blueberries and raspberries. Resveratrol exists as two double-bond isomers, cis -resveratrol and trans -resveratrol, having the formulae:
trans -resveratrol cis -resveratrol
Cz's-resveratrol is also found in red wine, along with dihydroresveratrol, a derivative of resveratrol in which the double bond is saturated:
dihydroresveratrol Dihydroresveratrol is a metabolite of resveratrol. Trans- and czs-resveratrol, as well as dihydroresveratrol have been described in the literature as having a number of pharmacological activities, including antioxidant-, anticancer-, antiplatelet-, and estrogen modulating activities. Resveratrol (particularly the trans-isomer) has been shown to improve metabolic outcomes in humans and animal models. For example, resveratrol has been proposed as having a beneficial effect in obesity-related conditions, including blood sugar control, and preventing leptin resistance. Moreover, low dose resveratrol has been shown to reverse cardiac impairment in obese-prone rats [Louis, XL, et al, J. Nutr. Biochem, 2012, Sep 23(9): 1163-1169]. Some preclinical studies have shown that resveratrol reduces blood pressure in animal models of hypertension and metabolic disease [Zordoky, B.N., I.M. Robertson, and J.R. Dyck, Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases, Biochim Biophys Acta, 11/2014]. WO2009/003798 discloses a food product composition comprising trans-resveratrol that can be used to control blood pressure.
The effect of resveratrol administration on blood pressure arising from overweight or obese subjects has to date received little or no attention. The negative impact of maternal overweight or obesity on the prenatal and postnatal health of the offspring and potentially the future health of the child or adult is well documented. It is therefore highly desirable to seek improved treatments that enable commencement of therapy at the earliest opportunity in order prevent, reduce the risk of, or reverse the potential adverse effect of maternal overweight or maternal obesity on the health of the developing offspring.
SUMMARY OF THE INVENTION
We have surprisingly found that resveratrol is able to exert an antihypertensive effect in the offspring of overweight or obese females. In particular, we have found that resveratrol when administered to the mother during pregnancy and/or during lactation, may prevent, or reduce the risk of, blood pressure elevation in the offspring. Thus we have uncovered a potential use of resveratrol as programming agent for
cardiovascular health in an offspring (e.g. for humans: at the fetal, neonatal, infant and potentially the child stages or beyond), when supplemented to the mother during pregnancy and/or lactation or prior to conception.
Thus, in a first aspect, the present invention provides a compound of Formula 1 :
Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring, comprising administration of the compound to a pregnant and/or lactating female subject (i.e. the mother of the offspring), wherein the subject is overweight or obese. The compounds may be alternatively or additionally administered to the female subject pre-pregnancy.
It will be appreciated that Formula 1 encompasses the compound wherein wavy bond represents double bond substituents being in the cw-configuration (cz's-resveratrol) or in the trans-configuration (trans-resveratrol).
In a second aspect, the present invention provides a compound of Formula 1 :
Formula 1 or a metabolite thereof, for use as a pre-pregnancy, pregnancy or lactation supplement in an overweight or obese female subject, in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring. The compound of Formula 1 may particularly be trans-resveratrol having the formula 1A:
Formula 1A.
The invention further provides a compound of Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a pregnant female subject, wherein the subject is overweight or obese.
The invention further provides a compound of Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a lactating female subject, wherein the subject is overweight or obese.
The compound of Formula 1 or a metabolite thereof, can be administered in any dose that is effective in achieving the objective of the present invention.
The term "dose" as used herein refers to a daily quantity that is administered to a subject.
Any dose having a positive i.e. antihypertensive, effect on the blood pressure of the offspring of a subject, in particular an overweight or obese subject, to whom it is administered, may be considered an effective dose. Typically, an effective dose may depend on the age, size and health status of the subject, on the subject's lifestyle, as well as on the subject's genetic heritage. Preferred doses in mammals, including cats, dogs and humans, and in particular humans, may be 0.1 to 3g, or 0.2 to 2g, or 0.3 to 1.5g, or 0.4 to 1.2g, or 0.4 to lg.
If a dose is worked out by the weight of a subject, then particularly useful doses in mammals, including cats, dogs and humans, and in particular humans, may be 6-17 mg/kg of body weight, in particular 6 to 10 mg/kg of body weight, more particularly 7 to 9 mg/kg of body weight, and even more particularly 8 to 8.5 mg/kg of body weight.
The dose may be administered all at once or it may be spread out over several administrations throughout a day.
In another aspect, the invention provides a compound of Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound during pregnancy and lactation.
A further aspect of the invention provides a compound of Formula 1 or a metabolite thereof, for use in the in utero prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to an overweight or obese pregnant female subject.
The hypertension and/or cardiovascular disease in the offspring may be associated with maternal overweight or maternal obesity. The prophylaxis of hypertension and/or cardiovascular disease may comprise a reduction in the systolic and/or the diastolic blood pressure. Particularly the prophylaxis of hypertension and/or cardiovascular disease may comprise a reduction in the systolic blood pressure of the offspring, or may comprise a prevention of the onset of hypertension in the offspring. The hypertension may be associated with, or is a consequence of, maternal overweight or obesity. The prophylaxis of hypertension may reduce, or prevent the risk of, the development of an associated cardiovascular disease in the offspring. The cardiovascular disease may be a disease or disorder associated with, or caused by hypertension. The cardiovascular disease may be selected from the group consisting of hypertensive heart disease as well as diseases of the cardiovascular system.
Cardiovascular disease include arteriosclerosis and associated diseases including angina, heart failure, peripheral artery disease, retinal vascular diseases, aneurysm, hypertensive renal damage and failure, cognitive impairment due to restricted blood flow, transient ischemic attack, ischemic heart disease, stroke; coronary artery disease, arrhythmias, left ventricular hypertrophy, heart failure, blood clots, myocardial infarction and diabetic vascular diseases.
In any embodiment of the present invention, the offspring of the female subject may be the fetus, neonate, infant, child, or adult in the case of a human, or the fetus, infant or adult in the case of other mammals (for example cats and dogs). Particularly, the prophylaxis of hypertension or cardiovascular disease in humans is especially applicable to offspring at the fetal, neonatal, infant or child stage, or at the neonatal, infant or child stage. The effect of resveratrol in the prevention of hypertension, or the reduction in the risk of onset of hypertension, in the offspring may also have a prophylactic effect on hypertension and/or cardiovascular disease at future stages of development beyond infancy and childhood (e.g. adulthood).
The effect of resveratrol in the reduction of blood pressure can be observed in the offspring of the female subject to which resveratrol is administered, and can be seen in both male and female offspring, and particularly in the female offspring. In any embodiment of the present invention, the female subject to which the compound of Formula 1 or a metabolite thereof, is administered, is obese as defined herein. For example, in humans, the female subject may have a pre-pregnancy BMI of > 25 kg/m2, or may have a pre-pregnancy BMI of > 30 kg/m2. The present invention also encompasses a composition comprising a compound of Formula 1 :
Formula 1 or a metabolite thereof, as an active agent for use in accordance with any aspect or embodiment as described herein. Particularly, the composition may comprise a compound of Formula 1A (i.e. trans-resveratrol) or a metabolite thereof.
The composition may be selected from the group consisting of a pharmaceutical composition, a food product, a food extract, drink, food additive, a pet care product, a nutraceutical, and a nutritional supplement, in particular a maternal supplement.
The compound of formula 1 or 1 A, or a metabolite thereof, according to any embodiment of the invention may be obtained from a plant source. For example plant extracts selected from the group consisting of: apple, berries [preferably acai, bilberry, blackberry, blackcurrant, blueberry, cherry, chokeberry, cloudberry, cranberry, crowberry, grape (particularly grape skins), lingonberry, mulberry, raspberry, redcurrant, rowanberry, whortleberry], purple corn, purple potato, cocoa bean, purple carrot, sweet potato, red cabbage, aubergine, grape, peanut, pomegranate, pistachio (Pistacia vera), rhubarb (Rheum rabarbarum) and hop (Humulus lupulus), eucalyptus and spruce trees, plants of the Polygonaceae (knotweed - e.g. Japanese knotweed) and Vitaceae families and Pin us strobus, white hellebore (Veratrum album),
Poligonum cuspidatum, Bauhinia racemosa, or red/white wine extract, may be used. The invention further provides a method for the prophylaxis of hypertension in an offspring comprising administering a therapeutically active amount of a compound of Formula 1 or a metabolite thereof, to a pregnant and/or lactating female subject, wherein the female subject is overweight or obese.
DESCRIPTION OF FIGURES Figures 1A and IB: Systolic and diastolic blood pressure of control (Ctrl) and obese (Ob) pregnant dams at day 10 of gestation. Figures 2A and 2B: Systolic and diastolic blood pressure of obese pregnant dams with (Ob+R) or without (Ob) resveratrol supplementation at day 10 of gestation.
Figs 3A and 3B. Systolic blood pressure of the male (3 A) and female (3B) offspring at 90d. OffCon: offspring of lean dams; OffOb: offspring of obese dams.
Figure 4. Female Offspring Systolic BP at 3 months (mean of 12 hourly averages for each light/dark cycle over 1 week) Con (n=10), Con+RES (n=5), Ob (n=6), Ob+RES (n=4). Random effects GLS regression analysis; main effect of maternal obesity (P=0.008), significant interaction (P<0.05) with 8mmHg reduction in BP in OffOb+RES (**P=0.006), no effect in controls.
Figure 5. Male Offspring Systolic BP at 3 months (mean of 12 hourly averages for each light/dark cycle over 1 week) Con (n=12), Con+RES (n=5), Ob (n=5), Ob+RES (n=5). Random effects GLS regression analysis; main effect of maternal obesity (P=0.016), significant interaction with Resveratrol (P=0.033). Resveratrol Tx significantly elevated blood pressure in offspring of controls by 5 mmHg (*P=0.017), and effected a non significant reduction in OffOb.
DETAILED DESCRIPTION OF THE INVENTION
Resveratrol
As used herein, unless otherwise indicated, references to "resveratrol" encompasses to trans-resveratrol and czs-resveratrol. In particular, the term "resveratrol"
encompasses compounds having the Formula 1 :
Formula 1 such that: when the wavy line represents a trans double bond, Formula 1 represents trans-resveratrol (i.e. Formula 1 A); when the wavy line represents a cz's-double bond, Formula 1 represents czs-resveratrol. In any embodiment of the present invention, the compound of Formula 1 may preferably be trans-resveratrol.
As used herein, reference to a metabolite of compounds of Formula 1 include any active metabolite of the compounds of Formula 1 (i.e. metabolites of trans-resveratrol and cz's-resveratrol) that is effective in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring, when administered to a pregnant and/or lactating overweight or obese female subject. In accordance with any aspect or embodiment of the present invention, preferred metabolites of the compounds of Formula 1 include: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0- glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide, resveratrol disulfate, piceatannol (i.e. (3-hydroxyresveratol or 3,4',5- trihydroxystilbene), astringin (piceatannol glucoside), which (when the double bond is present) may be in the cis- or trans-configurations. In any embodiment of the present invention, more preferred metabolites of the compounds of Formula 1 may be selected from the group consisting of: dihydroresveratrol, resveratro 1-3-0- glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0- sulfate, resveratrol sulfate glucuronide and resveratrol disulfate, which (when the double bond is present) may be in the cis- or trans-configurations. Particularly preferred metabolites of the compounds of Formula 1 according to any aspect or embodiment of the present invention are those selected from the group consisting of: dihydroresveratrol, resveratro 1-3 -O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate, in which (when the double bond is present) are in the transconfiguration.
Preferably in any embodiment of the present invention, the compound is selected from the group consisting of: cz's-resveratrol, trans-resveratrol and the metabolites: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate (wherein when the double bond is present in the metabolites, may be in the cis- or trans-configurations). More preferably, in any embodiment of the present invention, the compound is selected from the group consisting of trans- resveratrol, and the metabolites: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate (wherein when the double bond is present in the metabolites, are in trans-configuration).
Alternatively, the compound for use in accordance with any embodiment of the invention is selected from the group consisting of trans-resveratrol, cz's-resveratrol and dihydroresveratrol, or preferably is selected from the group consisting of transz resveratrol or c s-resveratrol.
Preferably, in any embodiment of the present invention, resveratrol refers to trans- resveratrol, having Formula 1A:
Formula 1A As used herein, unless otherwise indicated, the term offspring encompasses the offspring of the female subject at any stage of development including fetus, neonate, infant, child and adult. Preferably, in any embodiment of the present invention, the term offspring in relation to a human, refers to the neonate, infant and child stages, and more preferably the neonate and infant stages. Preferably, in any embodiment of the present invention, the term offspring in relation to other mammals (e.g. cats and dogs), refers to a neonate or infant stage.
The term "subject" as used herein refers to a pregnant mammal and more particularly a pregnant cat, a pregnant dog or a pregnant human. Cardiovascular disease
As used herein, unless otherwise indicated, a reference to cardiovascular disease includes cardiovascular diseases associated with, caused by, or resulting from hypertension. Particularly the cardiovascular disease is caused by hypertension. Such cardiovascular diseases include those well-known in the literature to be attributable to long-term or uncontrolled hypertension, i.e. arteriosclerosis, angina, heart failure, peripheral artery disease, retinal vascular diseases, aneurysm, hypertensive renal damage and failure, cognitive impairment due to restricted blood flow, transient ischemic attack, ischemic heart disease, cerebral apoplexy (stroke), coronary artery disease, arrhythmias, left ventricular hypertrophy, blood clots, myocardial infarction and diabetic vascular diseases. Particularly, cardiovascular diseases that may be prevented or ameliorated by control of hypertension according to the present invention may be arteriosclerosis, angina, heart failure, peripheral artery disease, aneurysm, transient ischemic attack, ischemic heart disease, cerebral apoplexy (stroke), coronary artery disease, arrhythmias, left ventricular hypertrophy, heart failure, and myocardial infarction.
Hypertension is associated with raised systolic and/or diastolic blood pressure.
Particularly, hypertension may be associated with at least a raised systolic blood pressure.
As used herein, unless otherwise indicated, prophylaxis refers to preventing a disorder, as well as reducing the risk of development or preventing the onset of a disorder. For example, prophylaxis of hypertension includes preventing high blood pressure (whether systolic and/or diastolic), as well as reducing the risk of
development of high blood pressure (whether systolic and/or diastolic). Particularly, the prophylaxis of hypertension includes preventing the onset of, or reducing the risk of development of, high blood pressure such as high systolic blood pressure.
The term "prophylaxis" of a particular condition includes a reference to reducing the risk of development of the condition or preventing the onset of the condition. For example, a reference to prophylaxis of cardiovascular disease (CVD), wherein the CVD is associated with, or results from, hypertension includes a reduction or prevention in the risk of a subject (e.g. offspring) developing the CVD due to hypertension.
Obesity and overweight
Body mass index (BMI) is calculated by dividing body weight in kilograms by the square of the height in centimetres.
The terms "obesity" and "overweight" refer to conditions in which a mammal accumulates excess body fat to the extent that it has a negative impact on health. For example, according to the World Health Organisation (WHO), an adult human is considered to be overweight (pre-obese), if the BMI is between 25 kg/m2 and 30 kg/m2. An adult human is considered to be obese if the BMI is greater than 30 kg/m2. However, it is to be understood that certain geographical regions may apply different definitions for overweight and obese. For example, the Japan Society for the Study of Obesity (JASSO) has modified the WHO classification of obesity:
It will be appreciated that all definitions of overweight and obese as set out in the above table as applicable to the female subject are encompassed. It will also be appreciated that a clinical diagnosis of overweight or obesity may be assessed by methods in addition to, or instead of, BMI, such as by comparison with standard body weights, physique index and determination of subcutaneous fat thickness. For example, mammals having a weight that exceeds the 85th percentile may be diagnosed as being overweight, and those exceeding the 95th percentile may be diagnosed as obese. Other determinations of obesity include waist circumference and waist-hip ratio (circumference of the waist divided by that of the hips). For example, in Europe, central (abdominal) obesity is defined as a waist circumference of > 80 cm in non-pregnant women; in the US, central obesity is defined as a waist circumference of > 88 cm in women, or waist-hip ratio of > 0.85 (women). All such definitions of overweight or obese are included. A healthcare practitioner would readily be able to determine whether a subject is overweight or obese using one or more of the established criteria.
Nevertheless, in any embodiment of the present invention, obese or overweight in humans may particularly refer to a subject having a BMI of > 25 kg/m2. As set out in the above table, the term obese includes subjects having a BMI > 25.0 kg/m2 (JASSO definition for Asian populations) or subjects having a BMI of > 30.0 kg/m2 (WHO definition). Hence, in general, the term obese may be considered to encompass the WHO obese classes I-III and the JASSO obese classes 1-4.
In any embodiment of the present invention, obese or overweight may alternatively refer to a subject, especially a human, having a BMI of > 30 kg/m2, particularly > 35 kg/m2 or > 40 kg/m2.
It will be appreciated that overweight and obesity in relation to a pregnant or lactating female, especially in humans, is generally determined by the BMI, weight and/or other indicators prior to pregnancy, for example by determination of pre-pregnancy BMI. Alternatively, excessive weight gain occurring during pregnancy in a female subject having a "normal" weight (WHO or JASSO classification) prior to pregnancy prior to the pregnancy, may lead to the pregnant female being classified/diagnosed as overweight or obese. Thus, the reference to overweight and obesity in pregnant female subjects includes subjects who were overweight or obese prior to becoming pregnant, as well as subjects that become overweight or obese due to excessive weight gain during pregnancy.
Where the overweight or obesity is due to excessive weight gain during pregnancy, the BMI or other indicator of overweight or obesity can be determined by taking into account the estimated fetal, placental and amniotic fluid weight. An assessment of overweight or obesity in a pregnant female subject can be readily made by a healthcare practitioner. For example, the following weight gain goals during pregnancy in humans have been suggested [Cunningham, F.G., et al, Prenatal care: William's Obstetrics, 21st Ed., New York, Appleton and Lange: 2001 :232]:
In other mammals, such as cats and dogs, obesity or overweight in pregnancy can be defined as a percentage range above the ideal body weight for a particular breed and taking into account the size of the litter. For example, overweight can be defined as a body weight of 10-20% or 15-25% above the ideal weight for the particular breed, and obesity may be or obesity may be defined as a body weight of over 25%, or over 30% above the ideal weight for the particular breed. It will be appreciated that an assessment of overweight or obesity in a pregnant mammals other than humans (and particularly cats and dogs), can be readily made by a veterinary practitioner.
Hypertension Hypertension may be determined by a clinician or other healthcare professional. For example, a neonate may be considered to have hypertension if the systolic blood pressure is above the 95th percentile of blood pressure for infants of similar gestational or postconceptional age and size. Hypertension in infants or children may be diagnosed if a systolic and/or diastolic pressure above the 95th percentile for age, gender, and height is found on three separate occasions [Pediatrics (2004), 114: 555- 557].
The data herein shows that obesity or overweight in the mother during pregnancy gives rise to a significant elevation in both systolic and diastolic blood pressure of the offspring, which is associated with, or is a consequence of, maternal overweight or obesity. The data further shows that this hypertension in the offspring can be prevented or ameliorated by the administration of a compound of Formula 1 to the mother during pregnancy and/or lactation. Thus, by controlling the blood pressure of the offspring at an early stage in its development, the risk of the offspring developing a hypertension related cardiovascular disease may be reduced. Hence, the present invention provides a method for prophylaxis of such cardiovascular diseases in the offspring. Moreover, the protective effect of the resveratrol may extend to well beyond the infant and childhood stages of offspring development.
Blood pressure can be determined by non-invasive or invasive methods as appropriate for the subject and setting. For example, non- invasive methods include auscultatory (such as a sphygmomanometer or stethoscope) or oscillometric measurement devices, which are routinely used by healthcare professionals. Invasive methods typically measure intra-arterial blood pressure via insertion of a catheter into an artery, and are particularly suitable for prenatal blood pressure monitoring of the fetus. In other mammals, such as cats and dogs, blood pressure can be readily measured, and hypertension can be assessed, by a veterinary practitioner (e.g. see guidance in: S. Brown, et al, J. Vet. Intern. Med. 2007, 21, 542-558).
Compound Administration
The compound of Formula 1 or a metabolite thereof, may be administered during pregnancy alone, during lactation alone or during pregnancy and lactation. The compound of Formula 1 or a metabolite thereof, may be alternatively or additionally administered pre-pregnancy. The compound of Formula 1 or a metabolite thereof, may for example be administered to a woman desiring to get pregnant, for example during at least 1, 2, 3 or 4 months preceding the pregnancy or desired pregnancy. Pre-pregnancy administration of the compound of Formula 1 or a metabolite thereof, may impact the intrauterine environment and in consequence may also have an antihypertensive effect on the blood pressure of the offspring of a subject to whom it is administered.
As used herein, unless otherwise indicated, a reference to administration of a compound of Formula 1 or a metabolite thereof, during pregnancy (i.e. prenatal administration), particularly refers to administration of the compound during any part of, or the whole of, the gestation period. In any embodiment of the present invention administration of the compound of Formula 1 or a metabolite thereof, may be initiated as soon as possible following conception until at least the end of the period of embryogenesis. For example, in humans, the embryogenesis period encompasses the first 8 weeks of development (10 weeks of gestation).
The compounds of Formula 1 or a metabolite thereof, may be administered during substantial part of the gestation period. In any embodiment of the present invention, administration of the compound of Formula 1 or a metabolite thereof, can be within: the first week, the first two weeks, the first month, the first trimester, the second trimester or the third trimester of pregnancy. Particularly, the administration may be continued until at least the birth of the offspring. Thus, for example, in any embodiment of the present invention, administration of a compound of Formula 1 or a metabolite thereof, during pregnancy refers to administration as soon as possible from conception (as defined above) until birth, i.e. during the full gestation period. In humans, the administration may be for a period of from: about 1 week to birth, about 2 weeks to birth, about 4 weeks to birth, about 8 weeks to birth, about 12 weeks to birth, about 18 weeks to birth. In any embodiment of the present invention, administration of the compound of
Formula 1 or a metabolite thereof, to the overweight or obese pregnant female subject may be initiated prenatally prior to any diagnosis of hypertension in the fetus, thereby preventing the onset of, or reducing the risk and severity of, fetal hypertension arising from maternal overweight or maternal obesity. Hence, prenatal administration of the compound of Formula 1 or a metabolite thereof, to the overweight or obese mother provides a method for the in utero prophylaxis of hypertension and/or a cardiovascular disease in the offspring. In any embodiment of the present invention, the compound of Formula 1 or a metabolite thereof, may additionally be administered pre-pregnancy to the overweight or obese female subject as well as during pregnancy and/or during lactation.
As used herein, unless otherwise indicated, a reference to administration of a compound of Formula 1 or a metabolite thereof, during lactation, particularly includes administration of the compound postnatally at any time during which the offspring is exclusively or partially ingesting the maternal milk (the subject's breast milk). For example administration during lactation may be for the period starting from onset of lactation until the end of the weaning process, i.e. when the offspring has ceased to ingest the maternal milk. During this period, the offspring may be exclusively or partially ingesting the maternal milk. More particularly, administration of the compound of Formula 1 or a metabolite thereof, during lactation may refer to administration: for two weeks following the onset of lactation when the offspring is exclusively or partially ingesting the maternal milk. The administration of the compound of Formula 1 or a metabolite thereof, during lactation may also include administration for a period of 1-24 months, 2-20 months, 3-18 months, 6-12 months, 4-12 months or 4-8 months following the onset of lactation during which the offspring is exclusively or partially ingesting the maternal milk. Administration of the compounds of Formula 1 or a metabolite thereof, to the overweight or obese female subject may also be initiated postpartum, i.e. not during pregnancy, but instead from the onset of lactation. The administration of the compound of formula 1 or a metabolite thereof, during lactation may also include administration for a period of 1-24 months, 2-20 months, 3-18 months, 6-12 months, 4-12 months or 4-8 months following the onset of lactation during which the offspring is exclusively or partially ingesting the maternal milk. The administration may be initiated from the onset of lactation until the end of the weaning process, i.e. when the offspring has ceased to ingest the maternal milk. In any embodiment of the present invention the compound of Formula 1 or a metabolite thereof, may be administered both prenatally, i.e. at any period from conception to birth, as well as postnatally during lactation, i.e. at any period from birth until the end of the weaning process, i.e. when the offspring has ceased to ingest the maternal milk. Further, in any embodiment of the present invention the compound of Formula 1 or a metabolite thereof, may be administered both prenatally for any period as defined above in relation to prenatal administration, as well as postnatally for any period as defined above in relation to the lactation period, and any combination of these periods as described above.
Preferably, in any embodiment of the present invention, the offspring is not directly administered the compound of Formula 1 or a metabolite thereof. Thus, the compounds of the present invention, when administered prenatally to an overweight or obese pregnant female subject are indirectly transmitted to the developing embryo or fetus e.g. via the placenta or amniotic fluid. In other words, the exposure of the offspring to the compound of Formula 1 or a metabolite thereof, is in utero when the compounds are administered to the mother during pregnancy.
Similarly, the compound of Formula 1 or a metabolite thereof, when administered postnatally to an overweight or obese lactating female, are indirectly transmitted to the neonate or infant via the ingestion of maternal milk, i.e. the exposure of the offspring to the compound is solely via the mother's milk.
In any embodiment of the present invention, the compound of Formula 1 or a metabolite thereof, may be used as a pre-pregnancy, pregnancy or lactation dietary supplement in an overweight or obese female subject, in the prophylaxis of hypertension and/or cardiovascular disease in the offspring or future offspring.
Preferably, in any aspect or any embodiment of the present invention, pre-pregnancy supplementation or administration preferably refers to administration from about 1-24 months, 1-18 months, 1-12 months, 1-6 months, or 1-3 months prior to pregnancy.
We have determined that prenatal administration of the compounds to the pregnant mother and/or postnatal administration to the lactating mother is able to bring about a marked decrease in blood pressure of the offspring, whilst having an insignificant effect on the blood pressure of the overweight or obese mother. We have further demonstrated that the antihypertensive effect is observed well beyond the period after which the offspring has ceased to ingest the mother's milk, i.e. well beyond the period after which the offspring is not longer exposed to the compound. Further, when employed as a pre-pregnancy supplement alone, or in combination as a pregnancy and/or lactation supplement, the compounds may provide an antihypertensive effect in the cardiovascular health of the future offspring. Compositions
The present invention provides a composition comprising a compound of Formula 1 :
Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a
cardiovascular disease in an offspring, comprising administration of the compound to a pregnant and/or lactating female subject, wherein the subject is overweight or obese.
The composition can be selected from the group consisting of a pharmaceutical composition, a food product, a food extract, drink, food additive, a pet food product, a nutraceutical, and a nutritional or dietary supplement, in particular a maternal supplement.
The composition may also comprise vitamins and minerals. For example, vitamins and minerals recommended by a governmental body, such as USRDA, for supplementation in pregnancy or during lactation e.g. calcium, magnesium, phosphorus, iron, zinc, copper, iodine, selenium, vitamin A or retinol activity equivalent (RAE) e.g. beta carotene or a mix of carotenoids, vitamin C, vitamin Bl, niacin, folic acid, biotin, vitamin E, vitamin B2, vitamin B 12, vitamin B6, and vitamin D. The composition may also comprise other ingredients commonly used in the form in which it is employed e.g. in the form of a nutritional supplement, or a food product. Non limiting examples of such ingredients include: other nutrients, for instance, selected from the group of lipids (optionally in addition to DHA and ARA), carbohydrates, and protein, micronutrients (in addition to those set out above), pharmaceutically active agents, conventional food additives such as anti-oxidants, stabilizers, emulsifiers, acidulants, thickeners, buffers or agents for pH adjustment, chelating agents, colorants, excipients, flavor agents, osmotic agents, pharmaceutically acceptable carriers, preservatives, sugars, sweeteners, texturizers, emulsifiers, water and any combination thereof.
The compound of Formula 1 or a metabolite thereof, can be prepared by synthetic or semi- synthetic means, or alternatively the compound of Formula 1 or a metabolite thereof, is extracted from a plant. Suitable plants that contain the compound of Formula 1 and/or a metabolite thereof, include: apple, berries (preferably acai, bilberry, blackberry, blackcurrant, blueberry, cherry, chokeberry, cloudberry, cranberry, crowberry, grape, lingonberry, mulberry, raspberry, redcurrant,
rowanberry, whortleberry), purple corn, purple potato, cocoa bean, purple carrot, sweet potato, red cabbage, aubergine, grape, peanut, pomegranate, pistachio nut, rhubarb and hop, eucalyptus and spruce, Japanese, plants of the Polygonaceae (knotweed) and Vitaceae families and Pin us strobus, white hellebore (Veratrum album), Poligonum cuspidatum, or wine extract. Thus, the compound of Formula 1 or a metabolite thereof, may be in the form of an extract (for example, an extract obtained from the processing of the plant source) which contains enriched
concentrations of the compound.
The present invention also encompasses a method for the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administering a
therapeutically active amount of a compound of Formula 1 or a metabolite thereof, to a pregnant and/or lactating female subject, wherein the female subject is overweight or obese.
The following examples serve to illustrate various features and embodiments of the present invention. It will be appreciated that the examples are non-limiting and that those skilled in the art will recognize that various modifications may be made to the foregoing description and the following examples without departing from the spirit and scope of the invention. EXAMPLES
MATERIAL AND METHODS
Female Sprague Dawley rat were divided into two groups - a first, control ("lean dams") group and a second ("obese dams") group.
Six weeks prior to mating, the lean dams group were fed a control diet. At the same time, in the obese group, obesity was induced in the rats by feeding an obesogenic diet (high fat, high sugar + sweetened condensed milk ad libitum). Prior to diet assignment, a telemetry transmitter was implanted in the aorta of each rat.
At mating, the lean dams group were divided into two subgroups. In the first subgroup (Con) lean dams continued to receive control diet and received control vehicle and in the second subgroup (Con+Res) the lean dams continued to receive control diet but were supplemented with resveratrol (trans-resveratrol) during pregnancy and lactation.
The obese dams group were divided into two subgroups of five. The first subgroup (Ob) continued to be fed the obesogenic diet and were assigned to vehicle. The second subgroup (Ob+Res) continued to be fed the obesogenic diet and were assigned resveratrol. Resveratrol was supplemented during pregnancy and lactation in a gelatin pellet (50 mg/kg/d).
Thus, in total there were 4 experimental groups: Lean dams on the control diet receiving vehicle only (i.e. no resveratrol) ("Con")
Lean dams on the control diet receiving resveratrol (50 mg/kg) from mating until weaning (21 days after birth) ("Con+R" or "Con+Res")
Obese dams on the obesogenic diet receiving vehicle only (i.e. no resveratrol)
(Ob)
• Obese dams on the obesogenic diet receiving resveratrol (50 mg/kg) from
mating until weaning (21 days after birth) ("Ob+R" or "Obs+Res") In 5 dams per group, systolic and diastolic pressures were measured at day 10 of gestation with a telemetry transmitter.
At birth, the litters were standardized to 8 pups (4 males and 4 females). For figure 4 (females) the numbers are as follows:
Con (n=10), Con+R (n=5), Ob (n=6), Ob+R (n=4).
For figure 5 (males) the numbers are as follows: Con (n=12), Con+R (n=5), Ob (n=5), Ob+R (n=5). From birth up to 21 days following birth, the pups were exclusively consuming the mother's milk. After 21 days, the offspring of the 4 groups, i.e., (OffCon),
(OffCon+R), Ob (OffOb) and Ob+R (Off Ob+R) were separated from the dams and the offspring were weaned to a laboratory chow diet. At 90 d of age, a telemetery transmitter was implanted on the abdominal aorta of the offspring for assessment of cardiovascular function.
RESULTS
Obesity caused an increase in systolic and diastolic blood pressure in pregnant dams (Figures 1A and IB). Surprisingly, supplementation with resveratrol, which has been reported in the literature as having antihypertensive effects, had no effect on the blood pressure of the obese pregnant dams (Figures 2 A and 2B). The applicant's findings support the well-known link between maternal obesity having a negative and potentially long term impact on the health of the offspring. For example, as can be seen from Figures 3 A and 3B, maternal obesity has a significant effect on the blood pressure of the offspring (OffOb vs OffCon) which was observed 90 days following birth, i.e. well beyond the gestation and lactation period. Without being bound by theory, this may be attributable to an epigenetic programming mechanism. Hence, potentially the hypertension and associated risk of cardiovascular disease in the offspring resulting from developmental programming due to maternal obesity may persist into childhood and later on into adulthood. Moreover, the results demonstrate that the effect of maternal obesity on blood pressure/hypertension can be seen in both female and male offspring.
We have found that resveratrol administration to pregnant obese dams during pregnancy and lactation has a significant antihypertensive effect on the blood pressure of the resulting offspring (OffOb+Res vs OffCon) (Figure 3). This effect was observed in both the male and female offspring of the obese dams (Figures 4 and 5), with a greater effect being observed in the female offspring (Figure 4). These results are particularly surprising because an antihypertensive effect (i.e. reduction of blood pressure) was not observed in the obese pregnant dams themselves following resveratrol administration (Figures 2 A and 2B). Moreover, the prevention of hypertension in the offspring was observed at 90 days, i.e. long after the gestation and lactation period (21 days) during which the offspring may have received indirect exposure to the resveratrol through its mother.
Thus, these results show that resveratrol supplementation of obese mothers during pregnancy and/or lactation is able to achieve a significant improvement on blood pressure in the offspring. Hence, it may be concluded that resveratrol administration in accordance with the present invention can effect a reversal of, or prevent hypertension programmed by maternal obesity.

Claims

1. A compound of Formula 1 :
Formula 1 or a metabolite thereof, for use in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring, comprising administration of the compound to a pregnant and/or lactating female subject, wherein the subject is overweight or obese.
A compound for use according to claim 1 , wherein the compound is selected from the group consisting of: cz's-resveratrol, trans-resveratrol, or a metabolite thereof selected from the group consisting of: dihydroresveratrol, resveratro 1-3- O-glucuronide, resveratro 1-4 '-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide, resveratrol disulfate, piceatannol or astringin wherein when the double bond is present, the metabolite may be in the cis- or trans-configuration; or wherein the compound is selected from the group consisting of cz's -resveratrol, trans-resveratrol, or a metabolite thereof selected from the group consisting of: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratro 1-4 '-O-glucuronide, resveratro 1-3-0- sulfate, resveratro 1-4 '-O-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate wherein when the double bond is present, the metabolite may be in the cis- or trans-configuration; or wherein the compound is selected from the group consisting of: cz's-resveratrol, trans-resveratrol, or a metabolite thereof selected from the group consisting of: dihydroresveratrol, resveratro 1-3 -O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate wherein when the double bond is present, the metabolite is in the trans-configuration; or wherein the compound is selected from the group consisting of: cz's -resveratrol, trans- resveratrol, or a metabolite thereof selected from the group consisting of: dihydroresveratrol, resveratrol-3-O-glucuronide, resveratrol-4'-0-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-0-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate wherein when the double bond is present, the metabolite may be in the cis- or trans-configuration; or wherein the compound is selected from the group consisting of: trans-resveratrol, dihydroresveratrol, resveratrol-3-O-glucuronide, resveratro 1-4 '-O-glucuronide, resveratro 1-3-0- sulfate, resveratro 1-4 '-O-sulfate, resveratrol sulfate glucuronide and resveratrol disulfate; or wherein the compound is selected from the group consisting of: trans-resveratrol, cz's-resveratrol and dihydroresveratrol; or wherein the compound is selected from the group consisting of trans-resveratrol or cis- resveratrol; or wherein the compound is trans-resveratrol or a metabolite thereof; or wherein the compound is trans-resveratrol having the Formula 1 A:
Formula 1A.
A compound for use according to claim 1 or claim 2 in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a lactating female subject, wherein the subject is overweight or obese.
A compound for use according to claim 1 or claim 2 in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to a female subject during pregnancy and lactation, wherein the subject is overweight or obese.
5. A compound according to claim 1 or claim 2 for use in the in utero, and/or postnatal prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administration of the compound to an overweight or obese pregnant and/or lactating female subject.
6. A compound according for use according to any of claims 1-5 further
comprising pre-pregnancy administration to the female subject.
7. A compound of Formula 1 or 1 A as defined in claim 1 or claim 2, for use as a pre-pregnancy supplement in an overweight or obese female subject, in the prophylaxis of hypertension and/or a cardiovascular disease in an offspring.
8. A compound for use according to any of claims 1-7 wherein the hypertension and/or cardiovascular disease in the offspring is associated with, or is a consequence of, maternal overweight or maternal obesity.
9. A compound for use according to any of claims 1-8 wherein the prophylaxis of hypertension and/or cardiovascular disease comprises preventing the onset of hypertension wherein the hypertension is associated with a high systolic and/or the diastolic blood pressure of the offspring, and preferably at least a high systolic blood pressure of the offspring.
10. A compound for use according to any of claims 1-9 wherein the cardiovascular disease is associated with, or caused by hypertension, preferably wherein the cardiovascular disease is selected from the group consisting of arteriosclerosis, angina, heart failure, peripheral artery disease, retinal vascular diseases, aneurysm, hypertensive renal damage and failure, cognitive impairment due to restricted blood flow, transient ischemic attack, ischemic heart disease, cerebral apoplexy (stroke), coronary artery disease, arrhythmias, left ventricular hypertrophy, blood clots, myocardial infarction and diabetic vascular diseases.
11. A compound for use according to any of claims 1-10 wherein the offspring is a fetus, neonate, infant or child, preferably a neonate or infant, preferably wherein the offspring is female.
12. A compound according to any of claims 1-11 wherein the female subject is obese, preferably wherein the female subject has a pre-pregnancy body mass index of > 25 kg/m2, and more preferably a pre-pregnancy body mass index of > 30 kg/m2.
13. A composition comprising a compound of Formula 1 :
Formula 1 or a metabolite thereof as defined in claim 1 or claim 2, for use in accordance with any preceding claim.
A composition according to claim 13 wherein the composition is selected from the group consisting of a pharmaceutical composition, a food product, a food extract, drink, food additive, a pet care product, a nutraceutical, and a nutritional supplement, preferably wherein the compound of formula 1 or 1 A and/or a metabolite thereof, is derived from a plant extract, such as apple, berries (preferably acai, bilberry, blackberry, blackcurrant, blueberry, cherry, chokeberry, cloudberry, cranberry, crowberry, grape, lingonberry, mulberry, raspberry, redcurrant, rowanberry, whortleberry), purple corn, purple potato, cocoa bean, purple carrot, sweet potato, red cabbage, aubergine, grape, peanut, pomegranate, pistachio nut, rhubarb and hop, eucalyptus and spruce, Japanese, plants of the Polygonaceae (knotweed) and Vitaceae families and Pinus strobus, white hellebore (Veratrum album), Poligonum cuspidatum, or wine extract. A method for the prophylaxis of hypertension and/or a cardiovascular disease in an offspring comprising administering a therapeutically active amount of a compound of Formula 1 or a metabolite thereof, to a pregnant and/or lactating female subject, wherein the female subject is overweight or obese.
EP16757650.3A 2015-09-02 2016-08-26 Prophylaxis of hypertension and cardiovascular diseases Withdrawn EP3344237A1 (en)

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Title
JUAN MANUEL GALLARDO ET AL: "Maternal obesity increases oxidative stress in the newborn : Maternal Obesity and Oxidative Stress", OBESITY RESEARCH, vol. 23, no. 8, 1 August 2015 (2015-08-01), US, pages 1650 - 1654, XP055616838, ISSN: 1930-7381, DOI: 10.1002/oby.21159 *

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