Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-01-25
2001-12-25
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S727000, C514S565000
Reexamination Certificate
active
06333350
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the regulation of cervical dilatation and extensibility by the use of nitric oxide donors and/or substrates or nitric oxide inhibitors.
2. Description of the Related Art
Parturition (expulsion of the fetus from the uterus), requires both contractions of the myometrium, the smooth muscle of the uterus, and a softening of the connective tissue of the cervix, so that it will stretch and dilate sufficiently to allow the fetus to be expelled. This softening is known as “ripening”.
The current preferred method of cervical ripening is by the use of prostaglandin B
2
. This is used as a vaginal gel or tablet or as a gel placed in the cervix. One worry about the use of prostaglandin E
2
is that there is a possibility of hyperstimulation of the uterus, leading to excessively strong myometrial contractions before the cervix is ripened and therefore before a comfortable or safe birth is possible.
The ideal preparation would soften and efface the cervix without causing myometrial contractions. This would allow the subsequent contractions (induceable if necessary with a small dose of prostaglandin) to deliver the baby with a minimum of resistance. There is good evidence from animal experiments that the antiprogestins such as RU486 would meet these requirements, but the problem with this drug is that it has associated antiglucocorticoid activity which might be detrimental to the fetus.
One of the most exciting recent advances in biology and medicine is the discovery that nitric oxide is produced by endothelial cells and that it is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and immune activation (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991; Ignarro, 1991). Nitric oxide is an important mediator of relaxation of the muscular smooth muscle (Montada, Palmer and Higgs, 1991) and was formerly known as EDRF (endothelin-derived relaxing factor) (Furchgott und Zawadzki, 1980; Moncada, Palmer and Higgs, 1991).
Nitric oxide is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least different isoforms of a flavin-containing enzyme, nitric oxide synthase (Montada, Palmer and Higgs, 1991).
Nitric oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1, isosorbid mononitrate, isosorbid di nitrate, etc.
Synthesis of nitric oxide has been shown to be competitively inhibited by analogies of L-arginine; NG-nitro-Larginine methyl ester (L-NAME), NG-monoethyl-L-arginine (LMMA), N-iminoethyl-L-amithine (L-NIO), L-monomethyl-Larginine (L-NNMA), L-NG-methylarginine (LNMA), Nw-nitro-L-arginine (L-NA) and Aminaguanidine. Treatment of nonpregnant guinea pigs with L-NAME results in increased uterine contractility. Thus, inhibition of nitric oxide synthase-stimulated uterine contractility indicates that the tonic release of nitric oxide maintains the uterus in a quiescent state. Similarly, treatment of pregnant guinea pigs with L-NAME induced preterm labor. On the other hand, treatment of rat uterine strips in vitro with L-arginine inhibited contractions. These studies show that nitric oxide production by the uterus inhibits uterine contractility and a blockade of this synthesis results in increased muscle contractility both in pregnant and nonpregnant animals. Thus, nitric oxide substrates or donors are useful therapeutically to prevent uterine contractility and nitric oxide inhibitors are effective in stimulating uterine contractions.
Based on preliminary studies using rhesus monkees, Jennings et al. (The Journal of Maternal-Fetal Medicine 2:170-175 (1993)) have suggested that nitric oxide may be important in uterine quisence during pregnancy, and exogenous nitric oxide may be useful in controlling preterm labour.
Nitric oxide synthase (NOS) activity was demonstrated in multiple structures within the gravid rat uterus by Natuzzi et al. (Biochem. and Biophys. Res. Commun., 194, No.1, 1-8, (1993)) and they conclude NOS to be present within multiple structures of the gravid rat uterus. Reduction in NOS activity at parturition suggests NO may contribute to the maintenance of uterine contractile quisence during gestation.
Also, morphological studies have already shown the occurence of NOS (NADPH-diaphorase, a histochemical method detecting all NOS isoforms) and NO metabolizing enzymes such as superoxide dismutase in the cervix (Papka et al., Neuroscience Letters 147 (1992); Shiotani et al., Acta Histochem. Cytochem. 26:57-64 (1993)).
It has now been found that L-NAME treatment s.c. in pregnant guinea pigs on days 48-49 p.c. (term day 67+3 days) surprisingly led to a reduction in the cervical extensibility and a reduction in the cervical dilatation.
In pregnant rats, an increased production of nitric oxide (parameter, nitrite and nitrate release in vitro) from the uterine cervix has been found at the time of delivery in comparison with day 18 of pregnancy. In contrast there was a reduction in the uterine (myometrial) NO production in the course of rat pregnancy. The antiprogestins onapristone increased the nitric oxide production in the uterine cervix in pregnant rats still further, but had an inhibitory effect on the NO production in the uterus (myometrium). Treatment with the same dose of onapristone induced cervical ripening in rats.
These findings show that
treatment with a nitric oxide inhibitor such as L-NAME inhibits cervical ripening but stimulates uterine contractions in pregnant guinea pigs;
the NO production, which has a relaxing effect on the myometrium, decreases in the pregnant uterus (myometrium) during the course of pregnancy, but it increases in the uterine cervix during normal and antiprogestin-induced parturition in rats;
the divergent effects of a nitric oxide inhibitor such as L-NAME on uterine contractility and uterine cervix are due either to different actions of the NO-system or to the presence of different enzyme isoforms in the myometrium and cervix and
the NO-system plays an important role in the control of uterine cervix, the NO production being increased during the ripening process of the cervix.
It is, therefore, concluded that:
(a) a local application of nitric oxide donors and/or substrates can be used to induce cervical ripening or
(b) a local application of a nitric oxide-inhibitor can be used to prevent or inhibit cervical ripening, e.g. for the treatment of cervical insufficiency (too early cervical ripening) or preterm labour.
Thus the present invention is directed to the use of nitric oxide donors and/or substrates or nitric oxide inhibitors for manufacture of a medicament for regulating cervical dilatation and/or extensibility.
The present invention involves the use of either
(a) at least one nitric oxide donor and/or substrate for manufacture of a medicament to be administered locally (e. g. intracervically or intravaginally) for induction of cervical ripening or
(b) at least one nitric oxide inhibitor for manufacture of a medicament to be administered locally (e. g. intracervically or intravaginally) for inhibition of cervical rirening for treatment of cervical insufficiency or preterm labor.
Suitable for the purposes of this invention as (a) nitric oxide donor and/or substrate or (b) nitric oxide inhibitor are all the compounds known to the persons skilled in the art as having the required properties; the compounds mentioned under “Description of related art” are preferred.
The nitric oxide donor and/or substrate (a) can further be used in combination with (i) at least one of an antiprogestin, a prostaglandin and/or a cytokine.
Examples for antiprogestins are
onapristone (11&bgr;-[4(Dimethylamino)phenyl]-17&agr;-hydroxy-17&bgr;-(3-hydroxypropyl)-13&agr;-estra-4,9-diene-3-one), RU 486 (11&bgr;-[4-(Dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(1-propinyl)estra-4,9-diene-3-one), (Z)-11&bgr;-[4-(Dimethylamino)phenyl]-17&bgr;-hydroxy-17&agr;-(3-hydroxy-1-propenyl)estr-4-ene-3-one (EP-
Chwalisz Kristof
Garfield Robert E.
Criares Theodore J.
Kim Jennifer
Millen White Zelano & Branigan P.C.
Schering AG
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