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WO1996003929A1 - Procede de prediction d'un accouchement premature a l'aide d'estetrol (e4) comme indicatuer - Google Patents

Procede de prediction d'un accouchement premature a l'aide d'estetrol (e4) comme indicatuer Download PDF

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Publication number
WO1996003929A1
WO1996003929A1 PCT/US1995/003442 US9503442W WO9603929A1 WO 1996003929 A1 WO1996003929 A1 WO 1996003929A1 US 9503442 W US9503442 W US 9503442W WO 9603929 A1 WO9603929 A1 WO 9603929A1
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Prior art keywords
concentration
estetrol
body fluid
tocolytic
treatment
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PCT/US1995/003442
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English (en)
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Vivian Dullien
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Biex, Inc.
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Priority to AU21034/95A priority Critical patent/AU2103495A/en
Publication of WO1996003929A1 publication Critical patent/WO1996003929A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/42—Gynaecological or obstetrical instruments or methods

Definitions

  • This invention is directed to a method for prediction of termination of pregnancy by premature labor resulting in premature delivery.
  • This invention also relates to techniques for determining when tocolytic therapy to prevent delivery should be initiated and to what extent and duration it should continue.
  • Estrogens which are 18-carbon steroids with an aromatic A ring, a phenolic hydroxyl group at position 3 of the A ring, and an oxygen functional group (either hydroxyl or carbonyl) at position 17 of the D ring, produce a wide variety of effects on specific target organs and on the body as a whole, working either alone or in conjunction with other hormones.
  • estradiol sometimes referred to as E ⁇ which refers to the presence of two hydroxyl groups
  • estradiol is not a useful indicator of onset of labor in pregnant humans, as discussed in Block eL ⁇ l-, Am. J. Obstet. Gvnecol. 150:716-22 (1984), which flatly states that pre-term delivery is not predicted by serum plasma estradiol (or progesterone) concentration measurements.
  • Estetrol (E 4 ) is predominantly made in the fetus where its main precursor is circulating estradiol. After reaching the fetal liver, estradiol undergoes hydroxylation at the 15 ⁇ and 16 ⁇ positions leaving E 4 .
  • the increased solubility in body fluids of estetrol relative to estradiol and its resulting appearance in unconjugated form in a variety of body fluids makes estetrol a desirable target for analysis, once a thorough understanding of its association with biological activity can be achieved.
  • Estetrol levels in plasma during normal pregnancy was studied by Tulchinsky et al. JCE&M. 40: 560-567 (1975). Measurement of plasma estetrol during pregnancy is described as useful for monitoring fetal well-being because of its production in the fetal liver. However, there are no proposals to relate estetrol concentrations to clinical situations other than fetal well-being.
  • Premature birth is the leading cause of infant morbidity and death in the United States and other developed countries.
  • an attending physician has the option of allowing the delivery to proceed or attempting to stop uterine contractions with tocolytic agents. While many factors will affect this decision, a primary factor is the gestational age of the fetus. Tocolytic agents are generally used between 24 and 32 weeks of gestation, as the goal of therapy ideally is to prolong gestation to or beyond 32 weeks. However, a delay of even one week during this time can be significant, because of the rapid development of the fetus and the greatly improved chances for survival with each additional week of prolonged gestation.
  • Criteria utilized include simple temporary arrest of uterine contractions, no further change in cervical dilation or effacement, as well as combinations of these clinical symptoms. However, in many cases an initial arrest of uterine contractions will be followed by additional contractions once therapy is halted. At the present time there are no clinical assays for determining the extent or duration of tocolytic therapy designed to prevent uterine contractions and thus premature birth. Accordingly, it is an object of this invention to establish the relationship of estetrol concentrations in various body fluids to underlying biological functions, notably premature delivery, and to provide diagnostic assays for estetrol to evaluate the existing and/or potential biological state of the patient from whom the estetrol sample has been obtained. It is another object of this invention to develop a clinical assay to provide * additional useful information to a physician who must decide whether to initiate, continue, decrease, increase, or halt tocolytic therapy.
  • estriol levels are predictive of premature onset of labor. See U.S. patent application serial No. 07/952,438, filed 28 September 1992. Additionally, the use of estriol measurement during labor to monitor the effectiveness of tocolytic agents was reported by the present inventor in U.S. patent application serial No. 08/136,219, filed October 13, 1993. However, the value of estetrol in monitoring onset of premature labor or in monitoring the effectiveness of tocolytic agents during labor has not previously been established.
  • the present invention provides a method for predicting/screening and detecting the onset of labor, especially labor associated with premature delivery, in a pregnant human, which comprises analyzing a body fluid of the pregnant human for estetrol concentration; correlating the concentration with a standard value selected from the group consisting of (1) a predetermined range of estetrol concentrations for the body fluid in normal pregnant humans or (2) a previously measured estetrol concentration of the body fluid of the pregnant human; and relating a higher concentration of estetrol relative to the standard value as an indication of potential onset of premature delivery.
  • the invention provides a method of monitoring tocolytic therapy, which comprises measuring a first concentration of estetrol in a body fluid of a pregnant patient undergoing or diagnosed as a candidate for undergoing treatment with a tocolytic agent; correlating the concentration with a pre-determined standard estetrol concentration; and either initiating, continuing, discontinuing, or modifying the tocolytic treatment in response to the relative values of the first estetrol concentration and the standard estetrol concentration.
  • the present invention provides a method for detecting the onset of labor, especially premature labor associated with delivery, in a pregnant human by simply measuring a body fluid for estetrol concentration.
  • This method is simpler than prior techniques and provides an assay that can be carried out by a patient at home, obviating the necessity of providing samples to a professional laboratory at a location distant from the patient and the resulting delay.
  • the assay can be carried out on a single saliva sample using a simple diagnostic kit with an enzyme label.
  • the assay can be carried out on any sample of body fluid, such as blood (or a blood fraction, especially serum or plasma), urine, cervical or vaginal secretions, sweat, or saliva.
  • Estetrol is sufficiently soluble in water so that it is distributed in fluids throughout the body. Saliva is preferred for simplicity of sampling and because, unlike in urine, detection is not complicated by the presence of estrogen conjugates.
  • a sample is the material being analyzed and is usually of direct biological origin, although pre- treatment may have removed some of the normal biological compounds normally associate with the analyte (such as red cells separated from plasma in a whole blood sample).
  • Assays are preferably directed to detection to free estetrol, since conjugated estetrol has reduced biological activity.
  • estetrol can be detected in the free form, while most estetrol in urine is present as a conjugate.
  • an estetrol conjugate is a compound formed by formation of a covalent linkage of a non-steroidal compound to estetrol. Linkage is typically through a hydroxyl group of the steroidal ring system.
  • the non-steroidal component can be inorganic (e.g., a sulfate group) or organic (e.g., a glucuronide group).
  • creatinine can be measured concurrently with estetrol in urine. Creatinine is produced at a constant rate in the kidneys, and measurement of creatinine concentration allows correction of volume errors in urine samples, as is well known in the art.
  • free estetrol can be separated from estetrol conjugates.
  • Techniques for such separations are known in the art. See, for example, Konbai et al.. Steroids 30:521-529 (1977), which describes such a separation as well as a radioimmunoassay useful for measuring plasma estetrol.
  • these separations are generally difficult, and assays that do not require separation, either because of the use of specific antibodies or other binding compounds that differentiate between free and conjugated estetrol, or because the sample is obtained from a source containing mostly free estetrol are preferred.
  • the concentration of estetrol in the fluid assayed is correlated with a standard value to determine when labor is imminent.
  • the standard is usually (1) a predetermined range of estetrol concentrations for the same body fluid in normal pregnant humans in the general population, either at the corresponding time in the pregnancy or a specific time relative to normal termination of pregnancy, or (2) a previously measured estetrol concentration of the same body fluid of the same pregnant human.
  • a measured higher concentration of estetrol relative to the standard value is an indication of potential onset of premature delivery.
  • the method of the invention does not require the measurement of any other substance, such as the progesterone concentration in the body fluid, or require the measurement of total estetrol production over a time interval.
  • the first general standard set out above namely a predetermined range of estetrol concentrations for the same body fluid in normal pregnant humans in general, is typically obtained by using the same assay technique that will be used in the application of the method to an individual being tested, in order to ensure the highest correlation.
  • Sufficient measurements are made in a normal population of pregnant women to produce a statistically significant range of normal values for the value to which a comparison will be made, which typically is at preselected time intervals during normal pregnancy. While comparison to a time immediately prior to normal delivery (38 to 40 weeks) is often used, other time periods can be used.
  • estetrol levels during a given week of an individual pregnancy can be compared to the normal range of concentrations for the same time period (e.g., the 20th week).
  • the minimum concentration indicative of possible onset of labor is considered to be at least 1 , preferably at least 2, more preferably at least 3, and most preferably at least 4, standard deviations above the mean estetrol concentration determined for any given body fluid for the selected comparison, such as for a time just prior to the onset of labor for normal pregnant humans.
  • one standard deviation is appropriate for an assay that is desired to sweep in for further evaluation all possible candidates who might be predisposed toward premature delivery, or this limit can be selected for patients known to have normal or low estetrol values and relatively little variation between samples.
  • One standard deviation can also be selected for a patient known to have problems with premature delivery in order to determine when to monitor the patient more closely under controlled conditions (such as by having a patient admitted to a hospital for constant monitoring).
  • Two standard deviations from the mean would encompass about 95% of normal samples; three standard deviations, about 99%; four standard deviations, more than 99%. These levels are more appropriate generally, especially for patients whose levels of estetrol are known to be normal or slightly above normal or to vary from sample to sample, as well as for assays with a high coefficient of variance.
  • estetrol levels that are sustained at or above a preselected elevated threshold are preferred as an indication of likely onset of labor. It is not necessary to express the lower limit of the indication of labor (upper limit of the normal range) in standard deviations. Any other system that can be used to provide a statistically significant indication of probable onset of labor can be used.
  • the limit can be set to be a concentration that is at least as high as the 95 th percentile concentration for normal patients for the same body fluid for a normal pregnancy. In many cases, it is preferred to select a normal level from the 38-42 week period for normal pregnancies, preferably at 40 weeks, and to monitor the concentration beginning at 30 weeks or earlier.
  • the actual estetrol level indicative of probable onset of premature delivery is best selected by the attending physician after collecting data from several samples from the patent during the initial portion of the pregnancy and taking into consideration the time at which the measurement is being made. For example, in a normal pregnancy at week 30, the change expected in the estetrol concentration prior to the onset of labor is smaller than 2 standard deviations from the mean concentration of estetrol at 30 weeks.
  • the method of the invention is preferably used for pregnancies during weeks 20 to 36, when prolonging pregnancy for even a short time is most efficacious in reducing the effects of premature birth.
  • the assay particularly when used to detect rate of increase, is still applicable for pregnancies terminated by labor and delivery after the end of 40 weeks, and measurements made during this time period are also considered to fall within the broadest scope of the invention.
  • the invention is normally practiced using the "self-comparison" method discussed in more detail below; i.e., by comparing the measurement at a given time with a measurement made earlier with the same patient.
  • an assay concentration of at least 1, preferably at least 2, more preferably at least 3, and most preferably at least 4, standard deviations above the mean normal concentration for the same stage of pregnancy can also be used as an indication of an abnormal pregnancy and thus as an indication of possible onset of labor, although the probability is lower if the measured level does not reach the levels considered normal for weeks 38-42. Standard values will vary with the specific body fluid whose concentration is being measured and with the specific assay being used (although to a lesser extent).
  • a previously measured estetrol concentration of the same body fluid of the same pregnant human can be used as a standard for comparison.
  • what is being determined is usually the rate of increase in estetrol concentration in the fluid being tested.
  • a positive assay i.e., indication of imminent onset of labor
  • the selection of a particular rate of increase to label as the lower limit of labor onset is best selected by the attending physician for the particular reason desired.
  • a screening test that is intended to collect potential problem patients into the hospital for further observation and study could select the 50% increase as its limit in order to avoid false negative results, while accepting the problems caused by including a relatively large number of false positives.
  • Higher percentage increases as the minimum positive indication are more acceptable for home assays and the like, in the same manner as described above for standard deviations from the normal population mean.
  • Increases in estetrol concentration that meet the standards of this paragraph and additionally reach levels previously indicated to be indicative of the onset of labor in normal populations of patients are particularly likely to indicate imminent onset of labor.
  • Standard enzyme-linked immunoassay techniques can be used for assaying estetrol.
  • Antibody production for use in such assays and the assays themselves are conventional and are not described here in detail. These techniques are well known in the literature and are exemplified by the publication Antibodies: A Laboratory Manual (1988) eds. Harlow and Lane, Cold Spring Harbor Laboratories Press, and U.S. Patent Nos. 4,381,292, 4,451,570, and 4,618,577.
  • For an example of production of antibodies specific for estradiol see Lasley et al. , Fertility and Sterility (1985) 43:861-867, and Munro ej_al., Abstract, Society for Gynecologic
  • Antibodies secreted by the immortalized cells are screened to determine the clones that secrete antibodies of the desired specificity.
  • the antibodies For monoclonal anti-estetrol antibodies, the antibodies must bind to estetrol.
  • Cells producing antibodies of the desired specificity are selected, cloned, and grown to produce the desired monoclonal antibodies.
  • Antibody can be attached to a solid surface for use in an assay of the invention using known techniques for attaching protein material to solid support materials.
  • the solid support can include plastic surfaces of test tubes or microtiter plates, polymeric beads, dip sticks, or filter materials.
  • the attachment methods include non-specific adsorption of the protein to the support and covalent attachment of the protein, typically through a free amino group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group.
  • the present invention provides a method for monitoring the efficacy of tocolytic treatments that reduce or eliminate uterine contraction in order to delay the onset of labor, especially pre-term labor, in a pregnant human.
  • Monitoring estetrol concentrations in a body fluid before or during treatment with a tocolytic agent allows a physician to reach better decisions on whether to begin or continue the tocolytic treatment or whether the treatment should be discontinued or modified.
  • the method involves measuring a first concentration of estetrol in a body fluid of a pregnant patient undergoing, or diagnosed as a candidate for undergoing, treatment with a tocolytic agent. This first concentration is compared to a standard, and various actions are taken depending on the relative value of the measured concentration and the standard, as well as on the history of the patient prior to the measurement in question.
  • a measured estetrol concentration above the standard value is an indication that tocolytic treatment should be initiated or, if already initiated, should be continued or increased in intensity.
  • estetrol concentration is below the standard value, tocolytic treatment will not be initiated or, if already initiated, will be decreased or halted depending on the measured concentration relative to the standard. Because estetrol measurement is straight-forward and can be carried out at the bedside, an attending physician can obtain quantitative results very rapidly, which is of great assistance in reaching a clinical decision.
  • the assay is the same as that described above for use in detecting potential onset of labor.
  • the concentration of estetrol in the fluid assayed is correlated with a standard value to determine when to initiate, increase, decrease, cease, or otherwise modify the tocolytic treatment.
  • the standard is usually (1) a predetermined range of estetrol concentrations for the same body fluid in normal pregnant humans in the general population, either at the corresponding time in the pregnancy or a specific time relative to normal termination of pregnancy, or (2) a previously measured estetrol concentration of the same body fluid of the same pregnant human.
  • a measured higher concentration of estetrol relative to the standard value is an indication of potential onset of pre-term labor and therefore an indication that tocolytic treatment should be initiated or, if already initiated, should be increased in intensity.
  • the method of the invention does not require the measurement of any other substance, such as the progesterone concentration in the body fluid, or require the measurement of total estetrol production over a time interval.
  • measurements of total estetrol over a given time period, such as 24 hours can be used with urine, if desired, and other substances important to fetal or maternal well being, such as progesterone, can be concurrently measured if desired.
  • estretrol concentrations can preferably be monitored at daily intervals for at least one week, then at weekly intervals, depending upon results.
  • tocolytic treatment can be halted.
  • tocolytic treatments should be continued, if appropriate when considered in combination with other clinical symptoms.
  • intensity of the tocolytic treatment can be either increased or decreased depending on the value of the estetrol concentration relative to the standard value. If the measured value is significantly higher than the standard and shows no sign of decreasing, then the intensity of the tocolytic treatments can be increased.
  • estetrol levels remain higher than normal, but have been reduced somewhat by the initial tocolytic treatment, then either the initial treatment can be continued at its initial intensity or the intensity of the treatment can be reduced, with continuous monitoring of the effect of the treatment of estetrol concentration.
  • the invention can be carried out with any tocolytic treatment, since it now appears that all such treatments are associated with modifications in the estetrol level in the body fluids of the mother.
  • a number of different classes of drugs that inhibit uterine concentration have been suggested and are discussed below by drug class.
  • the invention is not limited to the named tocolytic treatments, either individually or by class.
  • Isoxsuprine was the first J-sympathomimetic agent used to treat premature delivery, in 1961. Since then the functionally related compounds orciprenaline, metaproterenol, salbutamol, albuterol, nylidrin, terbutaline, ritodrine, hexoprenaline, and fenoterol have been used.
  • 3 Adrenergic receptors predominate in the heart, small intestine, and adipose tissue; 3 7 -adrenergic receptors are found in smooth muscle of the uterus, blood vessels, diaphragm, and bronchioles, ⁇ - Adrenergic agonists affect smooth muscle cells through membrane-mediated binding to ⁇ -adrenergic receptors that activates adenylate cyclase.
  • 0-Adrenergic agents cause many unwanted effects because ⁇ -adrenergic receptors are present in multiple organ systems.
  • the cardiovascular system is most often involved. However, effects are also seen on the pancreas, kidney, gastrointestinal tract, and liver. The most frequently observed maternal symptoms are nausea, vomiting, tremor, and palpitations. Women also experience headache, thirst, restlessness, and chest pain.
  • Heart rate systolic blood pressure
  • pulse pressure stroke volume
  • cardiac output There is a concomitant decrease in diastolic pressure and peripheral vascular resistance.
  • Cardiac output can increase up to 60% over baseline levels. Mean arterial pressure does not change significantly.
  • Cardiac arrhythmias have been reported. The most common is supraventricular tachycardia; the arrhythmias include atrial fibrillation, premature atrial contractions, and ventricular ectopy.
  • Pulmonary edema occurs in up to 5 % of patients treated with ⁇ - sympathomimetics. Pulmonary edema occurs with and without concurrent glucocorticoid therapy. Many cases are secondary effects of fluid overload resulting from the antidiuretic effect of high does of 3-sympathomimetics. Fluid overload can also be a secondary result of excessive administration of intravenous fluids.
  • Plasma renin and arginine vasopressin are increased during infusion of ⁇ - adrenergic agonists. This increase is associated with sodium and water retention, which predisposes to pulmonary edema. Pulmonary edema is more common in twin gestations. Infection may also play a role in the development of this complication. In the absence of underlying disease, most cases of pulmonary edema can be attributed to intravenous fluids and to ignoring signs of fluid overload. iS-Sympathomimetics increase maternal blood glucose about 40% with a concurrent increase in insulin secretion. The rise in glucose levels is even more pronounced in diabetes, probably because stimulation of glucagon secretion results in gluconeogenesis and glycogenolysis.
  • Serum potassium concentrations decrease rapidly at initiation of treatment with 3-sympathomimetics.
  • the potassium concentration is usually 0.6 to 1.5 mEq below pretreatment levels. This decrease in serum levels is probably due to a net flux of potassium from the extracellular to the intracellular space.
  • the hypokalemia is transient; replacement therapy is not indicated. Levels normalize within 24 hours of initiation of tocolysis.
  • Cardiovascular effects include fetal tachycardia, increased cardiac output and redistribution of fetal blood flow, increased thickness of the fetal ventricular septum, neonatal supraventricular tachycardia, myocardial ischemia, myocardial necrosis, hydrops, and hypoglycemia and hyperinsulinemia in the neonate.
  • Magnesium inhibits myometrial activity in vitro and in vivo. Magnesium inhibits uterine contractions induced by calcium and transiently inhibits further calcium response. The mechanism by which magnesium sulfate exerts its tocolytic effect is unknown. Presumably, myometrial contractility is depressed by modulating calcium uptake, binding, and distribution in smooth muscle cells, take, binding, and distribution in smooth muscle cells. In high concentrations magnesium blocks calcium influx by competing for calcium binding sites on the cellular membrane. Magnesium activates adenylate cyclase and increases cyclic adenosine monophosphate, thus reducing intracellular calcium. Serum concentrations of 4 to 8 mEq/L appear to be necessary for reduction of myometrial activity.
  • Dual-agent tocolysis after failure of single-agent therapy has also been reported in the scientific literature. Twenty-three patients were treated with a combination of magnesium sulfate and ritodrine or terbutaline. Delivery was delayed for >48 hours or more in 60.9% of patients, but pulmonary edema developed in 22% of the patients.
  • magnesium sulfate therapy is maintained in the non toxic range, maternal side effects are few. Nausea, vomiting, ileus, visual blurring, diplopia, headaches, weakness, lethargy, shortness of breath, pulmonary edema, alterations in calcium metabolism, and urinary retention have been reported. Hypermagnesemia can occur in the presence of impaired renal function. Excessive levels of serum magnesium have been associated with respiratory depression, subendocardial ischemia, cardia arrest and death.
  • oxytocin antagonists might provide effective tocolysis, because systemic side effects would be minimal because of organ specificity.
  • prostaglandin production probably plays a role in cervical ripening and may modulate uterine activity in labor.
  • Many birthing centers use prostaglandin Ej gel for cervical ripening.
  • Both prostaglandin E 2 and prostaglandin F ⁇ are used for induction of labor in the second trimester of pregnancy.
  • Prostaglandins exhibit uterine effects in two ways. First, they enhance production of myometrial gap junctions. Second, prostaglandin F ⁇ stimulates the influx of intracellular calcium and the release of calcium from the sarcoplasmic reticulum. This increase in intracellular calcium leads to activation of myosin light chain kinase and subsequent muscle contraction. Elevated levels of prostaglandins in plasma and amniotic fluid have been demonstrated during normal human parturition. Levels are low or absent in serum and amniotic fluid of patients not in labor at all states of pregnancy. Prostaglandin metabolites are significantly reduced in patients treated with indomethacin. They are also significantly higher in patients who are delivered pre-term than in patients with prolonged gestation.
  • All prostaglandin synthetase inhibitors act by inhibiting the enzyme cyclooxygenase. This enzyme is found throughout the body and in high concentrations in the myometrium. Cyclooxygenase converts arachidonic acid into the first prostaglandin intermediate prostaglandin G 2 . All subsequent prostaglandins are derived from this initial step. Aspirin causes irreversible inhibition of this enzyme by acetylation. Indomethacin competes with arachidonic acid for cyclooxygenase. Therefore it does not disrupt the enzyme. When indomethacin levels decrease, enzyme activity resumes. These drugs have anti-inflammatory, antipyretic, and analgesic properties. They also suppress formation of prostacyclin and thromboxane A 2 . Indomethacin, naproxen, and fenoprofen are more effective than aspirin as inhibitors of prostaglandin synthesis.
  • Nonsteroidal anti-inflammatory drugs differ in chemical structures, mechanisms of action, and side effects. Therefore one cannot assume that an effect observed with a particular agent will be found with another. These drugs effectively inhibit contractility of the pregnant and nonpregnant myometrium. They are more effective than the 3-sympathomimetics. There has been no report of suppression of uterine contractions with /S-adrenergic agonists after failed treatment with a prostaglandin inhibitor; but several studies show the opposite.
  • Prostaglandin inhibitors are not associated with serious adverse effects on mother or fetus. There were no major problems in the newborns of 297 women treated with indomethacin.
  • Indomethacin is used to treat persistent patency of the ductus arteriosus in the pre-term neonate.
  • Clinical response in the pre-term neonate is variable and not related to serum indomethacin concentration.
  • Prostaglandin inhibitors cause constriction of the fetal ductus arteriosus in utero. The constriction is transient and usually abates after cessation of the drug.
  • prolonged exposure to indomethacin may lead to persistent pulmonary hypertension and tricuspid insufficiency in the neonate.
  • fetal complications include impaired renal function with resultant oligohydramnios.
  • Indomethacin has also been used to treat polyhydramnios and normalize amniotic fluid volume. This drug may be especially useful for treating pre-term labor in patients with polyhydramnios.
  • indomethacin causes permanent renal impairment in the neonate; one case report documented a monozygotic twin gestation with polyhydramnios in which the mother was treated with indomethacin and the fetus had renal digenesis.
  • Calcium channel blockers inhibit spontaneous myometrial contractions and suppress prostaglandin- and oxytocin-induced uterine contractions in vitro and in vivo.
  • the main site of action is the cell membrane, where influx of extracellular calcium through voltage-dependent calcium channels is inhibited.
  • Verapamil but not nifedipine, impairs atrioventricular conduction and can cause cardiac dysfunction.
  • the use of verapamil for treating pre-term labor was first reported in 1972. Effectiveness of treatment could not be shown because dosage was limited after cardiovascular side effects.
  • the first study using nifedipine to treat premature delivery was reported in 1977.
  • Ten patients in pre-term labor were treated. Labor stopped in all patients. In a similar study of 20 patients, 15 had delivery delayed for > 3 days.
  • Calcium channel blockers produce vasodilation and decrease peripheral vascular resistance. Transient facial flushing is the most common side effect, but then can also cause nausea and headache. Maternal side effects appear to be less than with the 3-sympathomimetics. Nifedipine potentiates the toxicity of magnesium sulfate by causing neuromuscular blockade. It also causes maternal hepatotoxicity. Although no serious fetal or neonatal side effects have been reported, these drugs may diminish uteroplacental blood flow.
  • tocolytic treatments of the inventions can also involve combinations of the individual treatments listed above or other treatments not listed here.
  • Intensity of a given tocolytic treatment will generally be correlated to the concentration of the drug being administered, the duration of administration, or the frequency of administration.
  • a change in intensity can also refer to a change in the type of treatment from one generally considered less effective but with fewer side effects to one which is more potent but which has potentially greater side effects.

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Abstract

Un procédé de prédiction et de détection du début des contractions d'une femme enceinte consiste à analyser un fluide corporel de la patiente afin de déterminer la concentration en estétrol; à mettre en corrélation cette concentration avec une valeur étalon; et à mettre en relation une concentration plus élevée d'estétrol par rapport à la valeur étalon afin d'obtenir une indication sur l'éventualité d'un accouchement prématuré. La valeur étalon est généralement sélectionnée dans le groupe comprenant (1) une plage prédéterminée de concentrations d'estétrol dans le fluide corporel chez des femmes enceintes normales à un moment présélectionné par rapport à un accouchement normal à terme, ou (2) une concentration d'estétrol mesurée antérieurement du même fluide corporel de la même femme enceinte. L'invention concerne également un procédé de contrôle d'une thérapie tocolytique qui consiste à déterminer une première concentration d'estétrol dans un fluide corporel d'une femme enceinte soumise à un traitement avec un agent tocolytique ou à qui on prescrit un tel traitement et, en se basant sur la valeur de la première concentration par rapport à une valeur étalon, commencer, continuer, arrêter ou modifier le traitement.
PCT/US1995/003442 1994-08-04 1995-03-17 Procede de prediction d'un accouchement premature a l'aide d'estetrol (e4) comme indicatuer WO1996003929A1 (fr)

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AU21034/95A AU2103495A (en) 1994-08-04 1995-03-17 Method for prediction of premature delivery using estetrol (e4) as an indicator

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US28579694A 1994-08-04 1994-08-04
US08/285,796 1994-08-04

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US6174665B1 (en) 1999-09-10 2001-01-16 Biex, Inc. Hormone replacement therapy monitoring
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EP1260225A1 (fr) * 2001-05-18 2002-11-27 Pantarhei Bioscience B.V. Compositions pharmaceutiques pour le traitement hormonal substitutif
WO2002094276A1 (fr) * 2001-05-18 2002-11-28 Pantarhei Bioscience B.V. Composition pharmaceutique a utiliser en therapie de remplacement d'hormones
US6556977B1 (en) 1997-08-14 2003-04-29 Adeza Biomedical Corporation Methods for selecting, developing and improving diagnostic tests for pregnancy-related conditions
WO2009011576A1 (fr) * 2007-07-19 2009-01-22 Pantarhei Bioscience B.V. Traitement ou prévention de troubles de l'hypertension de grossesse ou d'un retard de croissance fœtal
US7732430B2 (en) 2001-05-23 2010-06-08 Pantarhei Bioscience B.V. Drug delivery system comprising a tetrahydroxilated estrogen for use in hormonal contraception
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US7923440B2 (en) 2002-06-11 2011-04-12 Pantarhei Bioscience B.V. Method of treating or preventing immune mediated disorders and pharmaceutical formulation for use therein
US7943604B2 (en) 2002-06-11 2011-05-17 Pantarhei Bioscience B.V. Method of treating human skin and a skin care composition for use in such a method
US8026228B2 (en) 2001-11-15 2011-09-27 Pantarhei Bioscience B.V. Estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy
US8236785B2 (en) 2007-01-08 2012-08-07 Pantarhei Bioscience B.V. Method of treating or preventing infertility in a female mammal and pharmaceutical kit for use in such method
US8987240B2 (en) 2002-10-23 2015-03-24 Pantarhei Bioscience B.V. Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy
US9034854B2 (en) 2002-07-12 2015-05-19 Pantarhei Bioscience B.V. Pharmaceutical composition comprising estetrol derivatives for use in cancer therapy
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11793760B2 (en) 2015-06-18 2023-10-24 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy

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US7228295B2 (en) 1997-08-14 2007-06-05 Adeza Biomedical Corporation Methods for selecting, developing and improving diagnostic tests for pregnancy-related conditions
WO2001020339A1 (fr) * 1999-09-10 2001-03-22 Biex, Inc. Surveillance d'un traitement hormonal substitutif
US6174665B1 (en) 1999-09-10 2001-01-16 Biex, Inc. Hormone replacement therapy monitoring
EP1700602A1 (fr) * 2001-05-18 2006-09-13 Pantarhei Bioscience B.V. Composition pharmaceutique à utiliser en thérapie de remplacement d'hormones
WO2002094276A1 (fr) * 2001-05-18 2002-11-28 Pantarhei Bioscience B.V. Composition pharmaceutique a utiliser en therapie de remplacement d'hormones
WO2002094275A1 (fr) * 2001-05-18 2002-11-28 Pantarhei Bioscience B.V. Utilisation de composes d'oestrogene pour accroitre la libido chez les femmes
EP1260225A1 (fr) * 2001-05-18 2002-11-27 Pantarhei Bioscience B.V. Compositions pharmaceutiques pour le traitement hormonal substitutif
US8048869B2 (en) * 2001-05-18 2011-11-01 Pantarhei Bioscience B.V. Pharmaceutical composition for use in hormone replacement therapy
US7723320B2 (en) 2001-05-18 2010-05-25 Pantarhei Bioscience B.V. Use of estrogen compounds to increase libido in women
US7732430B2 (en) 2001-05-23 2010-06-08 Pantarhei Bioscience B.V. Drug delivery system comprising a tetrahydroxilated estrogen for use in hormonal contraception
US7871995B2 (en) 2001-05-23 2011-01-18 Pantarhei Bioscience B.V. Drug delivery system comprising a tetrahydroxylated estrogen for use in hormonal contraception
US8026228B2 (en) 2001-11-15 2011-09-27 Pantarhei Bioscience B.V. Estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy
US7943604B2 (en) 2002-06-11 2011-05-17 Pantarhei Bioscience B.V. Method of treating human skin and a skin care composition for use in such a method
US7923440B2 (en) 2002-06-11 2011-04-12 Pantarhei Bioscience B.V. Method of treating or preventing immune mediated disorders and pharmaceutical formulation for use therein
US9040509B2 (en) 2002-06-11 2015-05-26 Pantarhei Bioscience B.V. Method of treating human skin and a skin care composition for use in such a method
US10201611B2 (en) 2002-07-12 2019-02-12 Donesta Bioscience B.V. Pharmaceutical composition comprising estetrol derivatives for use in cancer therapy
US9034854B2 (en) 2002-07-12 2015-05-19 Pantarhei Bioscience B.V. Pharmaceutical composition comprising estetrol derivatives for use in cancer therapy
US9561238B2 (en) 2002-10-23 2017-02-07 Donesta Bioscience B.V. Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy
US8987240B2 (en) 2002-10-23 2015-03-24 Pantarhei Bioscience B.V. Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy
US7776557B2 (en) * 2006-01-30 2010-08-17 Diagnostic Technologies Ltd. Method for monitoring tocolytic treatment
US8236785B2 (en) 2007-01-08 2012-08-07 Pantarhei Bioscience B.V. Method of treating or preventing infertility in a female mammal and pharmaceutical kit for use in such method
US8518923B2 (en) 2007-07-19 2013-08-27 Pantarhei Bioscience B.V. Treatment or prevention of hypertensive disorders of pregnancy or fetal growth retardation
WO2009011576A1 (fr) * 2007-07-19 2009-01-22 Pantarhei Bioscience B.V. Traitement ou prévention de troubles de l'hypertension de grossesse ou d'un retard de croissance fœtal
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US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
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US11666585B2 (en) 2018-04-19 2023-06-06 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms

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