WO1995012406A1 - Use of urinastatin-like compounds to prevent premature delivery - Google Patents
Use of urinastatin-like compounds to prevent premature delivery Download PDFInfo
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- WO1995012406A1 WO1995012406A1 PCT/US1994/012751 US9412751W WO9512406A1 WO 1995012406 A1 WO1995012406 A1 WO 1995012406A1 US 9412751 W US9412751 W US 9412751W WO 9512406 A1 WO9512406 A1 WO 9512406A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8114—Kunitz type inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Definitions
- This invention relates to the diagnosis and treatment of pregnant females at risk for preterm delivery.
- This invention is a method of diagnosing females at risk for preterm delivery and of treating such females with a combination of a tocolytic, a urinastatin-like compound, and an antibiotic.
- preterm births cannot be related to obvious causes, and even known causes may not necessarily be detectable or correctable.
- approximately one half of all preterm births occur in women who are pregnant for the first time and have no known risk factors for preterm delivery. Even when women complain of symptoms frequently associated with acute risk of preterm delivery, it is often difficult to distinguish harmless symptoms from those associated with imminent prematurity. Many symptoms such as uterine contractions, change in vaginal discharge, abdominal discomfort, pelvic heaviness or change in cervical dimensions (effacement and dilatation) may harmlessly occur as normal variants in some pregnancies, while similar symptoms in other pregnancies can be associated with impending preterm delivery.
- cervical dilatation is clinically important for determining risk of delivery (Morrison, Obstet. Gvnecol. 76 (Suppl. 1)55, 1990). Many clinical studies have demonstrated that cervical dilatation of greater than 3 cm is frequently associated with imminent delivery regardless of gestational age. Unfortunately, not all women with symptoms of threatened preterm delivery who ultimately deliver prematurely have advanced cervical dilatation when they present for emergency obstetrical care (Lockwood, N. En ⁇ l. J. Med. 325:669. 1991). Moreover, among the many clinical symptoms and signs associated with preterm labor or delivery, cervical dilatation is not necessarily the first clinical change noted.
- Kanayama Nahon Sanka Fuiinka Gakkai Zasshi. 4_4:110-15, 1992
- Kanayama Nahon Sanka Fuiinka Gakkai Zasshi. 4_4:110-15, 1992
- the tocolysis index is a relative index of delivery risk in which various risk factors for preterm delivery including status of amniotic membranes (rupture versus intact membranes) , presence or absence of vaginal bleeding, estimation of cervical dilatation, and frequency of uterine contractions are semi-quantitatively assessed and scored, as indicated below.
- Tocolvsis Index is a relative index of delivery risk in which various risk factors for preterm delivery including status of amniotic membranes (rupture versus intact membranes) , presence or absence of vaginal bleeding, estimation of cervical dilatation, and frequency of uterine contractions are semi-quantitatively assessed and scored, as indicated below.
- the final tocolysis score represents the sum of each factor's "score" and hypothetically correlates to risk for preterm delivery as well as potential for successful tocolytic treatment.
- a tocolysis score of less than 3 indicates minimal risk for preterm delivery (and high probability of tocolytic success) while increasingly higher scores are associated with greater risk for preterm delivery (and lower probability of successful tocolytic intervention) .
- the tocolysis index is a modestly accurate method for assessing crude risk, it is neither reproducible between physicians (inter-observer error) nor a consistent predictor among individuals.
- Kanayama and co-workers evaluated the effect of four therapeutic strategies on preterm delivery rate as well as cervical expression of granulocyte elastase, a putative mediator of the labor process.
- the four therapeutic regimens evaluated included ritodrine infusion only (Group A) , daily urinastatin vaginal suppositories (Group B) , combination of ritodrine infusion and vaginal urinastatin suppositories (Group C) , and combination of ritodrine infusion, vaginal urinastatin suppositories, and systemic antibiotic therapy (Group D) .
- Fuzishiro et al. reported that a patient with history of habitual abortion was observed to have a protruding amniotic sac at 20 weeks of gestation. She was treated with vaginal antibiotics and urinastatin, tocolytics and bed rest. Her pregnancy was maintained up to 36 weeks. Japan. J. Obstet. Gynecol. Neonatal. Hematol. 2.-107-10, 1992.
- Urinastatin whose use is described above, is purified from human urine. It has been reported to suppress IL-l / 8-induced reduction of proteoglycan synthesis, superoxide generation, and inhibit a variety of serine proteases, such as trypsin, ⁇ - chymotrypsin, plasmin, leukocyte elastase and leukocyte cathepsin G. Because urinastatin inhibits many chemical mediators in inflammation, urinastatin has been evaluated as an anti-inflammatory drug. Hence, urinastatin has been proposed for use in a variety of conditions, such as pancreatitis, septic shock, operative stress, arthritis, thrombosis and preterm delivery.
- the present invention provides a method of diagnosing and treating pregnant females at risk for impending preterm delivery.
- the method includes first testing for the presence of a significant amount of fetal fibronectin in the subject's vaginal or cervical secretions, which indicates that the pregnant subject is at risk for impending preterm delivery. If a significant amount of fetal fibronectin is present, the subject is administered effective amounts of a tocolytic agent, at least one urinastatin-like compound and at least one antibiotic.
- the method of diagnosing and treating a pregnant female at risk for impending preterm delivery includes diagnosing by testing for the presence of a significant amount of fetal fibronectin in the female's vaginal or cervical secretions.
- Females in whom a significant amount of fetal fibronectin is found are administered an effective amount of a tocolytic agent for less than about one week, an effective amount of at least one urinastatin-like compound daily until 35 weeks and an effective amount of an antibiotic until the subject gives birth.
- the method of diagnosing and treating pregnant subjects at risk for preterm delivery includes diagnosing imminent preterm delivery by means of a diagnostic test with specificity greater than 80% and sensitivity in excess of 80%.
- Subjects in whom the diagnostic test indicates imminent preterm delivery are given effective amounts of a tocolytic agent, at least one urinastatin-like compound and at least one antibiotic.
- a method of increasing the interval a pregnant woman carries the fetus after having been diagnosed as being at risk for imminent premature delivery comprises the steps of administering an effective amount of a tocolytic agent, administering an effective amount of at least one urinastatin-like compound, and administering an effective amount of at least one antibiotic.
- the method of diagnosing and treating a pregnant female at imminent risk for preterm delivery calls for determining the concentration of elastase in the cervical and/or vaginal fluids. If the female has an abnormally high level of elastase, the female is administered a tocolytic agent, at least one urinastatin-like compound and at least one antibiotic.
- the pharmaceutical composition comprising MGMTSRYFYNGTSMA, RAFIQLWAFDAVKGK and an antibiotic.
- BRIEF DESCRIPTION OF DRAWING Figure 1 shows a tabular summary of the data for pregnant women undergoing treatment according to Example 2.
- the present invention is a method for diagnosing and treating a pregnant female with impending premature delivery.
- Urinastatin-like compound includes but is not limited to urinastatin, analogs and fragments thereof.
- Urinastatin is a glycoprotein having an approximate molecular weight of less than about 67kD in purified form. Urinastatin inhibits trypsin, elastase, granulocyte elastase, chymotrypsin, plasmin, hyaluronidase, amylase and creatine phosphokinase. In addition, urinastatin inhibits cytokine action and stabilizes lysosomal surfaces.
- Urinastatin has been sequenced and described in EP publication No. 0 100 985, published 1 August 1983, which is hereby incorporated by reference.
- "Analogs of urinastatin” include polypeptides with conservative substitutions or deletions of amino acids which do not change the configuration, enzymatic activity, or activity in subjects.
- the urinastatin analogs include glycosylated and nonglycosylated polypeptides, as well as polypeptides with other post- translational changes, such as glycosylation with different sugars, acetylation, etc.
- fragment of urinastatin includes urinastatin analogs which are oligopeptide portions of the glycoprotein and which are active for the intended use.
- Active oligopeptides include at least two peptides: the elastase inhibitor, comprising urinastatin amino acids 36-50, or MGMTSRYFYNGTSMA, and the plasmin/cytokine inhibitor, comprising urinastatin amino acids 92-106, or RAFIQLWAFDAVKGK.
- the elastase inhibitor comprising urinastatin amino acids 36-50, or MGMTSRYFYNGTSMA
- the plasmin/cytokine inhibitor comprising urinastatin amino acids 92-106, or RAFIQLWAFDAVKGK.
- An effective amount of urinastatin means an amount which significantly delays impending preterm delivery. An effective amount is sufficient by itself to diminish the rate of uterine contractions to about 1 in 30 minutes, within about 6 hours. An effective amount also is sufficient to depress the level of elastase in vaginal or cervical secretions significantly or to the level seen in females with normal pregnancies.
- the effective amount of urinastatin is preferably between about 500 and 10,000 Units per day. Preferably, the amount of urinastatin administered is about 750 to 5,000 Units per day. Even more preferably, the amount of urinastatin administered is about 1,000 U/day.
- a tocolytic agent is defined as a drug which is capable of suppressing uterine contractions.
- tocolytic agents include but are not limited to ritodrine, terbutaline, salbutamol (albuterol) , nifedipine and indomethacin.
- An effective amount of a tocolytic agent means that quantity sufficient to reduce the number of uterine contractions (UC) to about 1-2 in 30 minutes within not more than 3 hours.
- an antibiotic includes a compound capable of killing and/or stopping multiplication of microorganisms.
- the microorganisms which are of greatest concern in pregnant females are the natural flora of the vagina.
- the microorganisms which cause very serious infections in pregnant females include anaerobes.
- the present invention calls for the administration of a broad spectrum antibiotic.
- broad spectrum antibiotics include amoxicillin, ampicillin, erythromycin, azithromycin, and cephalosporins.
- Administration of more than one antibiotic and combinations of antibiotics are contemplated in the present invention.
- One such combination is UNASYN® ampicillin sodium/sulbactam sodium. Clindamycin is preferred as it is effective against anaerobes.
- an effective amount of an antibiotic is that amount normally used to treat an infection.
- the recommended dosage of UNASYN is 1.5 to 3.0 grams every six hours.
- Preterm delivery means childbirth before the fetus has reached about 36 completed ( ⁇ 37.0) weeks of gestation, as determined by patient history, ultrasound sizing, last menstrual period or other accepted methods.
- Impending or imminent preterm delivery includes delivery of a fetus with a gestational age between 24 and 34 completed weeks which occurs within 7 to 10 days of the time of diagnosis of threatened preterm delivery or preterm labor. Impending preterm delivery needs to be identified, so that appropriate intervention can be undertaken to prevent premature delivery of a child whose immaturity contributes to mortality and morbidity. Impending preterm delivery is often associated with premature separation of the placenta and fetal membranes and/or premature uterine contractions. Testing for a specific marker for impending preterm pregnancy includes all the usual methods for testing substances, including solid state chemistry, chromatography and specific antibody recognition techniques. Antibody recognition techniques include various sandwich antibody assays, using radio-, fluorescent- and enzyme-linked antibodies.
- Fetal fibronectin is a unique fibronectin, found in amniotic fluid, placental tissue extracts and malignant cell lines. Fetal fibronectin is distinguished by an epitope termed the "oncofetal domain.” This oncofetal domain is recognizable by a specific monoclonal antibody, which is used in a highly specific and sensitive test for fetal fibronectin.
- “Significant amounts of fetal fibronectin” are levels which are above the concentrations commonly observed in the cervical or vaginal secretions of females with normal pregnancies between 24 and 34 completed weeks of pregnancy. In general, fetal fibronectin concentrations greater than about 50 ng/ml, as determined by a sensitive enzyme-linked immunoassay, are considered significantly elevated. Low levels of fetal fibronectin, i.e., concentrations of less than about 50 ng/ml, are present in the cervical and vaginal secretions of females with normal, uncomplicated pregnancies between 24 and 34 completed weeks.
- fetal fibronectin may be elevated before 24 weeks of pregnancy, this elevation is due to the normal development and growth of the placenta and does not necessarily reflect poor pregnancy outcome, e.g., preterm delivery, etc. Between 24 and 34 completed weeks, concentrations of fetal fibronectin greater than about 50 ng/ml in cervical or vaginal secretions are associated with preterm delivery.
- “Analytical sensitivity” refers to the least amount of analyte that can be statistically distinguished from zero.
- “clinical sensitivity” refers to the proportion of women who deliver prematurely with elevated fetal fibronectin concentrations.
- the method for identifying female subjects with impending preterm delivery has a clinical sensitivity of at least 80%.
- “Analytical specificity” refers to the test's ability to report positive results due only to the presence of the desired analyte. Absence of "cross-reactivity” also refers to the same phenomena as “analytical specificity”.
- clinical specificity refers to the proportion of women with preterm deliveries in whom the fetal fibronectin concentration in cervical or vaginal secretions is greater than 50 ng/ml.
- the method for identifying female subjects with impending preterm delivery has a clinical specificity of at least 80%.
- Subjects are defined as humans and mammalian farm animals, sport animals and pets. Farm animals include, but are not limited to, cows, hogs and sheep. Sport animals include, but are not limited to, dogs and horses. The category pets includes, but is not limited to, cats and dogs.
- the present invention provides that the treatment and diagnosis of the patient at risk for preter delivery by a highly specific and sensitive method.
- the invention provides a treatment method for impending preterm delivery.
- this method is preceded by a suitable test for preterm delivery (i.e., one with both specificity and sensitivity greater than 80%) .
- the treatment step comprises administration of three drugs: a tocolytic agent, a urinastatin-like drug and an antibiotic.
- chorioamnionitis infection of the amniotic sac known as chorioamnionitis is a major contributor to preterm delivery.
- Clinical chorioamnionitis is diagnosed if the patient has leukocytosis (>10,000 white blood cells/mm 3 ) and the maternal temperature is above about 100.4°F and no other source of fever is found.
- a cervical culture may not be positive.
- the placental membranes can be seen to have polymorphonuclear leukocytes.
- chorioamnionitis the levels of a variety of inflammatory modulators are increased and are thought to contribute to uterine contractions and cervical dilatation.
- Urinastatin has the advantage of inhibiting a variety of mediators of inflammation. In view of its broad actions, urinastatin appears well suited to inhibiting the complex array of inflammatory mediators found in chorioamnionitis. Moreover, fetal urine and amniotic fluid contain large amounts of urinastatin (Terao and Kanayama. Sanfuiinka Jissai 37:158-68. 1988.) This suggests that the origin of the urinastatin is the fetus. Since urinastatin occurs naturally in fetuses and pregnant women, it would also appear to have the advantage of being a relatively safe drug for the fetus and pregnant woman.
- the tocolytic agent may be any known tocolytic agents.
- the particular tocolytic agent is not critical to the invention.
- Beta-mimetic agents have been popular as tocolytic agents. Such beta- mimetic agents include, but are not limited to, ritodrine, terbutaline, and albuterol (salbutamol) .
- Other tocolytic agents are believed to suppress uterine contractility by inhibiting the release of intracellular calcium, including for example, magnesium sulfate and nifedipine calcium antagonist/calcium channel blocker.
- Anti- prostaglandins, such as indomethacin and have also been suggested for use as tocolytic agents but are effective for only a short time and have significant maternal and fetal toxicity.
- the tocolytic agent generally is administered systemically.
- preferred routes include, but are not limited to, the intravenous and oral routes.
- the intravenous route may be preferred initially to develop high blood levels quickly; however, the oral route is often preferred, particularly if longer term maintenance therapy and drug administration are required.
- a urinastatin-like compound includes but is not limited to urinastatin, urinastatin analogs, and urinastatin fragments.
- Urinastatin is a glycoprotein having an approximate molecular weight less than about 67kD in a purified form. Urinastatin inhibits trypsin, elastase, granulocyte elastase, chymotrypsin, plasmin, hyaluronidase, amylase and creatine phosphokinase. Urinastatin has been described as inhibiting cytokine action and stabilizing lysosomal surfaces. At least a portion of the peptide urinastatin has been sequenced (EP publication No. 0 100 985, published 1 August 1983) .
- Urinastatin-like compounds include urinastatin which has been isolated from natural sources. Natural sources include, but are not limited to, the urine of human men (as used by Mochida Pharmaceutical Co., Ltd., Tokyo, Japan). Urinastatin from natural sources may be further processed to obtain active subunits or fragments. Urinastatin may also be synthesized by either chemical or recombinant nucleic acid methods. A urinastatin-like compound can be synthesized recombinantly in homologous and heterologous cells. A urinastatin-like compound can be synthesized in E. coli or Chinese hamster ovary
- urinastatin include substituted peptides which have the same active configuration as urinastatin itself.
- Analogs of urinastatin include polypeptides with conservative substitutions or deletions of amino acids which do not change the configuration, enzymatic activity, or activity in subject.
- Urinastatin analogs include glycosylated and nonglycosylated polypeptides, as well as polypeptides with other post-translational changes, such as glycosylation with different sugars, acetylation, etc.
- Analogs of urinastatin also include suitable fragments, such as those portions of the protein which are effective for the intended use.
- Active oligopeptides include, but are not limited to, the following two peptides: an elastase inhibitor. co prising amino acids 36-50, or MGMTSRYFYNGTSMA, and an inhibitor of plasmin, trypsin and cytokines, comprising amino acids 92-106, or RAFIQLWAFDAVKGK.
- a "fragment" of urinastatin includes peptides that are smaller in size than urinastatin and may be comprised of peptides of from about amino acid 36 to about amino acid 106 wherein the peptide is at least about 10 amino acids in length, preferably about 15 amino acids in length.
- chemical synthesis may be preferred over recombinant synthesis.
- the active oligopeptides may be administered individually or together. Further, fragments of urinastatin may be administered alone or with a tocolytic agent and/or an antibiotic. More preferred is their administration together. In a preferred embodiment both peptides are formulated in a vaginal suppository which also contains at least one antibiotic, preferably a cephalosporin. Another alternative is administration of one or both of the active oligopeptides conjugated to an antibiotic.
- One such example is the pharmaceutical conjugated compound MGMTSRYFYNGTSMA-RAFIQLWAFDAVKGK-antibiotic. Even more preferably, the antibiotic of the conjugated compound is a cephalosporin.
- the conjugation of the oligopeptides to the antibiotic can be performed by carboxyl and/or amide linkages using biochemical techniques well known in the art.
- a urinastatin-like compound may be administered systemically or locally. More preferred is local administration. Most preferred is intravaginal administration. Vaginal administration of the urinastatin-like compound can be performed in several other ways, including douche, suppository, foam and gel forms. In the form of a douche, an aqueous solution of the urinastatin-like compound is directed against the cervix. Preferably, the urinastatin-like compounds is administered in a solid or semi-solid form (foam, gel or suppository) which retains the urinastatin at the site of administration, preferably near the cervix.
- vaginal suppository which is a solid dosage form varying in weight and shape. After insertion, suppositories soften, melt or dissolve in the cavity fluids. Vaginal suppositories are usually globular or oviform and generally weigh about 5 grams.
- the usual suppository bases are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. Use of cocoa butter (also known as theobroma oil or cocoa oil) is preferred. Cocoa butter melts quickly at body temperature. Water-miscible suppository bases also may be used.
- Examples include polyethylene glycols or glycol-surfactant combinations.
- Polymers of ethylene glycol are available as polyethylene glycol polymers (Carbowax, polyglycols) of assorted molecular weights.
- Glycerinated gelatin is also often used as a vehicle for vaginal suppositories. Water-miscible suppository bases have the advantage of lack of dependence on a melting point approximating body temperature. Problems of handling, storage and shipping are simplified considerably.
- Suppositories are prepared by well known methods including rolling (hand-shaping) , molding (fusion) and cold compression.
- the urinastatin-like compound is preferably administered as a single daily dose. However, the urinastatin-like compound also may be administered in two or more divided doses.
- the preferred mode for preparing the urinastatin suppository is given in Example 1.
- the antibiotic or combination of antibiotics contemplated in the present invention are those indicated by either diagnosis or suspected presence of microorganisms and include, for example, broad spectrum antibiotics and preferably antibiotics which are known to be effective against anaerobic bacteria.
- the particular antibiotic is not critical.
- broad spectrum antibiotics include amoxicillin, ampicillin, erythromycin, azithromycin, and cephalosporin. Clindamycin is preferred because it is effective against anaerobes.
- Use of more than one antibiotic, including combination antibiotics, is also contemplated in the present invention.
- One such combination is UNASYN® ampicillin sodium/sulbactam sodium (Roerig, Pfizer, Inc.
- an effective amount of an antibiotic is that amount normally used to treat an infection.
- the recommended dosage of UNASYN is 1.5 to 3.0 grams every six hours.
- the antibiotic can be administered systemically or locally.
- oral administration is preferred; however, other methods, such as intravenous and intramuscular administration also can be used.
- the antibiotic can be inserted vaginally, in the form of a cream, suppository or other suitable dosage form.
- Various regimens for administering the antibiotic(s) can be utilized.
- mezlocillin may be given intravenously for 48 hours and followed by oral ampicillin until the delivery.
- Other dual antibiotic regimens comprise intravenous ampicillin/oral erythromycin and ampicillin/gentamicin.
- a preferred three-antibiotic regimen includes ampicillin, gentamicin and clindamycin.
- the tocolytic, urinastatin-like compound and antibiotic can be administered for various period of time.
- the subject is administered an effective amount of a tocolytic agent for less than about one week, an effective amount of at least one urinastatin like compound daily until 35 weeks, and an effective amount of an antibiotic until the subject gives birth.
- the dosage, timing and administration requirements for the tocolytic agent, urinastatin-like compounds and antibiotics may differ from subject to subject and are to be determined by the person responsible for treating the subject, without undue experimentation and using techniques known within the art.
- the above-described treatment steps are preceded by the diagnosis of impending preterm delivery.
- Diagnosis comprises testing for females who are at risk for preterm delivery with a method which is highly sensitive and specific for such a condition. Any suitable marker for preterm delivery can be used, so long as the test for the marker sufficiently distinguishes females at risk for preterm delivery from females who will not deliver early.
- a preferred test for impending preterm delivery has both specificity and sensitivity greater than about 80%.
- a particularly preferred method is a test for fetal fibronectin.
- Most preferred is an ELISA test for fetal fibronectin.
- An ELISA test of this type may be performed as follows. The ucosal sample to be tested is obtained from the cervix or the posterior fornix of the vagina on a swab. The swab is placed in buffer, in which the mucosal sample is diluted. Next, the concentration of fetal fibronectin is measured with an ELISA test (Fetal Fibronectin Immunoassay, Adeza Biomedical, Sunnyvale, CA) .
- This assay utilizes a monoclonal antibody specific for the oncofetal antigen, followed by a goat .anti-human plasma fibronectin IgG conjugated to alkaline phosphatase and a phenolphthalein monophosphate substrate.
- the absorbance of each standard and sample was determined at a wavelength of 550 nm with an automated microtiter-plate reader, and fetal-fibronectin concentrations were derived from the SoftMax software program (Molecular Devices, Menlo Park, CA) . Values greater than about 50 ng/ml, determined during weeks 21-37 of pregnancy, are significant amounts and considered predictive of impending preterm delivery.
- the invention has been disclosed by direct description. The following are examples showing the efficacy of the method in diagnosing and preventing premature births in female subjects. The examples are only examples and should not be taken in any way as limiting to the scope of the method.
- This powder was prepared from the fresh urine of healthy men, generally according to the method of Proksch and Routh (J. Clin. Lab. Med. 2i:491, 1972) .
- the dose of urinastatin was expressed in units; one unit of urinastatin inhibits 2 ⁇ g of trypsin (3200 NFU/mg, Canada Packers, Toronto, Ontario, Canada) by 50% according to the method of Kassel (Methods Enzvmol. 19:844. 1970).
- a batch of urinastatin suppositories was prepared as follows: 300,000 units of UTI powder
- Uretebsol W 35 sorbent for suppositories (Mochida Co., Tokyo, Japan) at 55°C.
- the main ingredient of Uretebsol W 35 is cocoa butter.
- 1 ml aliquots of the UTI solution were poured.
- the trays were stored at 4°C for about 2 hours.
- the suppositories had set, were firm and were ready to use.
- the completed suppositories are preferably stored at room temperature (20-25° C) .
- 168 patients in their 24th to 35 week of pregnancy were diagnosed with imminent premature delivery.
- the diagnosis of imminent premature delivery was based on a tocolysis index of 2 or greater. Factors of cervical dilation, ruptured membranes, uterine activity and vaginal bleeding were considered for the tocolysis index.
- the tocolysis index was determined by evaluating these factors and assigning points as shown in the following table. The index is the sum of these points.
- Group 1 received ritodrine intravenous infusion at 50-300 ⁇ g per day.
- Groups 2 and 3 were given daily urinastatin suppositories containing 5000 units and 1000 units, respectively.
- Group 4 received IV ritodrine at 50-300 ⁇ g per day and one 1000 unit urinastatin suppository per day.
- Group 5 received IV ritodrine at 50-300 ⁇ g per day, one 1000 unit urinastatin suppository per day, and cephalosporin. The patients were treated until they delivered. A number of parameters were tracked and are reported in Figure 1. The tocolysis index immediately before the start of treatment varied from 2-8.
- Example 3 Patients are diagnosed as having risk of imminent preterm delivery by means of the fetal fibronectin immunoassay are treated with a combination of ritodrine (a tocolytic) , urinastatin (UTI) and cephalosporin antibiotic.
- Mucous samples are obtained from women whose gestation period is less than about 34 weeks and who have signs and symptoms indicative of preterm delivery.
- the fetal fibronectin level is determined by a method which has both specificity and sensitivity greater than 80%.
- the mucous sample to be tested is obtained from the cervix or the posterior fornix of the vagina on a swab. The swab is placed in buffer, which dilutes the mucous sample.
- fetal fibronectin is measured with an ELISA test (Fetal Fibronectin Immunoassay, Adeza Biomedical) .
- This assay utilizes a monoclonal antibody specific for the oncofetal antigen, followed by a goat anti-human plasma fibronectin IgG conjugated to alkaline phosphatase and a phenolphthalein monophosphate substrate. The absorbance of each standard and sample was determined at a wavelength of 550 nm with an automated microtiter-plate reader. Fetal-fibronectin concentrations were derived from the SoftMax software program (Molecular Devices) .
- Patient with fetal fibronectin values greater than about 0.05 ⁇ g/ml, determined during weeks 21-37 of pregnancy, are considered to be at highest risk for impending preterm delivery (at risk of delivering within about seven days) and are entered into one of the following treatment groups.
- Group A patients are given ritodrine drip infusion therapy;
- Group B patients are given daily UTI suppository therapy (about 1000 units/suppository) ;
- Group C patients are given a combination of daily UTI suppository and ritodrine drip infusion therapy;
- Group D patients are given a combination of ritodrine infusion, UTI suppository and oral cephalosporin therapy.
- the times to depress uterine contractions are monitored after four days of therapy. After four days of therapy, treatments are stopped but UC are monitored by a belt apparatus.
- Females whose fetal fibronectin values exceed 0.05 ⁇ g/ml during weeks 21-37 of pregnancy are randomly assigned to treatment groups to receive ritodrine alone, UTI alone or combination therapy of ritodrine, UTI and antibiotic as described in Example 3.
- patients' fetal fibronectin values before the start of therapy are plotted against the rate of premature births to determine the effect of therapy on more or less risk- prone patients.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95901153A EP0732932A1 (en) | 1993-11-04 | 1994-11-04 | Use of urinastatin-like compounds to prevent premature delivery |
AU10504/95A AU1050495A (en) | 1993-11-04 | 1994-11-04 | Use of urinastatin-like compounds to prevent premature delivery |
JP7513445A JPH09505568A (en) | 1993-11-04 | 1994-11-04 | Use of ulinastatin-like compounds to prevent preterm birth |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/148,160 US5650394A (en) | 1993-11-04 | 1993-11-04 | Use of urinastatin-like compounds to prevent premature delivery |
US08/148,160 | 1993-11-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1995012406A1 true WO1995012406A1 (en) | 1995-05-11 |
WO1995012406A9 WO1995012406A9 (en) | 1996-06-13 |
Family
ID=22524560
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/012751 WO1995012406A1 (en) | 1993-11-04 | 1994-11-04 | Use of urinastatin-like compounds to prevent premature delivery |
Country Status (6)
Country | Link |
---|---|
US (1) | US5650394A (en) |
EP (1) | EP0732932A1 (en) |
JP (1) | JPH09505568A (en) |
AU (1) | AU1050495A (en) |
CA (1) | CA2175328A1 (en) |
WO (1) | WO1995012406A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996026273A1 (en) * | 1995-02-23 | 1996-08-29 | Adeza Biomedical Corporation | Polypeptides derived from urinastatin having calcium channel blocking activity and their use to delay premature delivery |
US5650394A (en) * | 1993-11-04 | 1997-07-22 | Adeza Biomedical | Use of urinastatin-like compounds to prevent premature delivery |
US5783555A (en) * | 1994-12-29 | 1998-07-21 | Mochida Pharmaceutical Co., Ltd. | Ulinastatin-containing suppository |
US6475992B2 (en) | 1996-01-25 | 2002-11-05 | Pharmacy And Therapeutic Advisory Consultancy Pty Ltd | Methods of and compositions for potentiating the action of agents active on cell wall sites of the susceptible bacteria |
US7228295B2 (en) | 1997-08-14 | 2007-06-05 | Adeza Biomedical Corporation | Methods for selecting, developing and improving diagnostic tests for pregnancy-related conditions |
EP1936376A3 (en) * | 2003-02-06 | 2009-04-01 | Adeza Biomedical Corporation | Screening and treatment methods for prevention of preterm delivery |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US20020031513A1 (en) * | 1997-11-24 | 2002-03-14 | Shamir Leibovitz | Method and pharmaceutical composition for inhibiting premature rapture of fetal membranes, ripening of uterine cervix and preterm labor in mammals |
IL122278A (en) * | 1997-11-24 | 2007-10-31 | Shamir Leibovitz | Pharmaceutical composition for inhibiting premature rupture of fetal membranes, ripening of uterine cervix and preterm labor in mammals |
US20060024725A1 (en) * | 2004-07-30 | 2006-02-02 | Robert Hussa | Oncofetal fibronectin as a marker for pregnancy-related indications |
US20080254479A1 (en) * | 2004-08-30 | 2008-10-16 | Cervimark, Llc | Methods and Kits For Predicting Risk For Preterm Labor |
US20080090759A1 (en) | 2004-08-30 | 2008-04-17 | Robert Kokenyesi | Methods and kits for predicting risk for preterm labor |
AU2010313447A1 (en) * | 2009-10-29 | 2012-05-31 | The Trustees Of The University Of Pennsylvania | Method of predicting risk of preterm birth |
GB201203217D0 (en) * | 2012-02-23 | 2012-04-11 | King S College London | Marker for preterm labour |
US9797903B2 (en) | 2012-10-24 | 2017-10-24 | Winthrop-University Hospital | Non-invasive biomarker to identify subject at risk of preterm delivery |
CN105854008B (en) * | 2016-05-30 | 2019-10-08 | 广东天普生化医药股份有限公司 | Purposes of the composition containing ulinastatin in preparation treatment oral cavity cancer drug |
JP2020533595A (en) | 2017-09-13 | 2020-11-19 | プロジェニティ, インコーポレイテッド | Pre-eclampsia biomarkers and related systems and methods |
EP4070113A4 (en) | 2019-12-04 | 2023-12-20 | Biora Therapeutics, Inc. | Assessment of preeclampsia using assays for free and dissociated placental growth factor |
BR112022017718A2 (en) | 2020-03-05 | 2022-11-16 | Diamedica Usa Inc | ULINASTATIN POLYPEPTIDES |
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JPS57144224A (en) * | 1981-03-02 | 1982-09-06 | Mochida Pharmaceut Co Ltd | Remedy for respiratory dieseases |
DE3230275A1 (en) * | 1982-08-14 | 1984-02-16 | Bayer Ag, 5090 Leverkusen | ELASTAS INHIBITORS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
JPS6427473A (en) * | 1987-07-23 | 1989-01-30 | Mochida Pharm Co Ltd | Human pancreas-secreting trypsin inhibitor and production thereof |
GB2208511A (en) * | 1987-08-07 | 1989-04-05 | Bayer Ag | Variants of bovine pancreatic trypsin inhibitor produced by recombinant dna technology |
EP0401508B1 (en) * | 1989-05-13 | 1994-11-23 | Bayer Ag | Proteinaseinhibitors, method for their preparation and pharmaceutical compositions containing them |
JPH0584083A (en) * | 1990-11-13 | 1993-04-06 | Mochida Pharmaceut Co Ltd | New polypeptide, new dna coding the same polypeptide, production of new polypeptide, new medicine composition and new enzyme inhibiting method |
CA2082226A1 (en) * | 1991-11-08 | 1993-05-09 | Hideaki Morishita | Polypeptide, dna fragment encoding the same, drug composition containing the same and process for producing the same |
JPH05308988A (en) * | 1992-05-12 | 1993-11-22 | Mochida Pharmaceut Co Ltd | New polypeptide, new dna, new vector, new transformant, new medicinal composition and production of the new polypeptide |
JP2769083B2 (en) * | 1993-02-22 | 1998-06-25 | 日清食品株式会社 | Novel peptide having elastase inhibitory activity and method for producing the same |
JP3570558B2 (en) * | 1993-05-01 | 2004-09-29 | 持田製薬株式会社 | DNA fragment, vector containing the same, transformant transformed with the vector, and method for producing protein using the vector |
US5650394A (en) * | 1993-11-04 | 1997-07-22 | Adeza Biomedical | Use of urinastatin-like compounds to prevent premature delivery |
-
1993
- 1993-11-04 US US08/148,160 patent/US5650394A/en not_active Expired - Fee Related
-
1994
- 1994-11-04 CA CA002175328A patent/CA2175328A1/en not_active Abandoned
- 1994-11-04 AU AU10504/95A patent/AU1050495A/en not_active Abandoned
- 1994-11-04 WO PCT/US1994/012751 patent/WO1995012406A1/en not_active Application Discontinuation
- 1994-11-04 JP JP7513445A patent/JPH09505568A/en active Pending
- 1994-11-04 EP EP95901153A patent/EP0732932A1/en not_active Withdrawn
Non-Patent Citations (3)
Title |
---|
AM. J. OBSTET. GYNAECOL., Volume 168, No. 2, issued February 1993, J.C. MORRISON et al., "Oncofetal Fibronectin in Patients with False Labor as a Predictor of Preterm Delivery", pages 538-542. * |
BIOLOCICAL ABSTRACTS, issued 1992, KANAYAMA et al., "The Effect of Granulocyte Elastase Inhibitor Urinastatin Vaginal Suppository on Patients with Imminent Premature Delivery"; & ACTA OBSTET. GYNAECOL. JPN., 44(4), pages 477-482. * |
NEW ENGLAND JOURNAL OF MEDICINE, Volume 325, No. 10, issued 05 September 1991, C.L. LOCKWOOD et al., "Fetal Fibronectin in Cervial and Vaginal Secretions as a Predictor of Preterm Delivery", pages 669-674. * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5650394A (en) * | 1993-11-04 | 1997-07-22 | Adeza Biomedical | Use of urinastatin-like compounds to prevent premature delivery |
US5783555A (en) * | 1994-12-29 | 1998-07-21 | Mochida Pharmaceutical Co., Ltd. | Ulinastatin-containing suppository |
WO1996026273A1 (en) * | 1995-02-23 | 1996-08-29 | Adeza Biomedical Corporation | Polypeptides derived from urinastatin having calcium channel blocking activity and their use to delay premature delivery |
US6475992B2 (en) | 1996-01-25 | 2002-11-05 | Pharmacy And Therapeutic Advisory Consultancy Pty Ltd | Methods of and compositions for potentiating the action of agents active on cell wall sites of the susceptible bacteria |
US7228295B2 (en) | 1997-08-14 | 2007-06-05 | Adeza Biomedical Corporation | Methods for selecting, developing and improving diagnostic tests for pregnancy-related conditions |
EP1936376A3 (en) * | 2003-02-06 | 2009-04-01 | Adeza Biomedical Corporation | Screening and treatment methods for prevention of preterm delivery |
Also Published As
Publication number | Publication date |
---|---|
AU1050495A (en) | 1995-05-23 |
JPH09505568A (en) | 1997-06-03 |
US5650394A (en) | 1997-07-22 |
CA2175328A1 (en) | 1995-05-11 |
EP0732932A1 (en) | 1996-09-25 |
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