Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-24
2003-08-26
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S227200
Reexamination Certificate
active
06610720
ABSTRACT:
BACKGROUND OF THE INVENTION
The adrenergic receptors were first divided into &agr; and &bgr; classes by Ahlquist in 1948. This division was based on a pharmacological characterisation. Both the &agr;-receptors and the &bgr;-adrenoceptors have since been subdivided into &agr;
1
and &agr;
2
and &bgr;
1
and &bgr;
2
.
There are three known sub-types of the &agr;
2
-adrenergic receptor population, designated &agr;
2A
, &agr;
2B
and &agr;
2C
. All &agr;
2
-adrenergic receptor subtypes affect the same effector systems, i.e., inhibition of adenylate cyclase, activation of receptor-operated K
+
channels, and inhibition of voltage-sensitive Ca
2+
channels.
Alpha-2 adrenergic agonists are useful for treating a variety of disorders including: respiratory disorders (e.g., asthma, nasal congestion, congestive obstructive pulmonary disease (COPD), cough, cystic fibrosis), gastrointestinal disorders (e.g., diarrhoea, irritable bowel syndrome), ocular disorders (e.g., glaucoma), cardiovascular disorders (e.g., myocardial ischemia, shock, arrhythmias, angina, congestive heart failure), benign prostatic hypertrophy and migraine. Many compounds disclosed in the art as alpha-2 adrenoceptor agonists are not alpha-2 adrenoceptor selective (e.g., they interact with other alpha receptors such as alpha-1 adrenoceptors). Alpha-2 adrenoceptor selectivity is desirable when treating alpha-2 associated or alpha-2 mediated disorders. For example, alpha-2 adrenergic agonists that possess significant alpha-1 adrenergic effects are known to cause cardiovascular side effects such as hypertension.
Alpha-2 adrenoceptor agonists such as clonidine or xylazine are known to cause emesis in cats and dogs (Hikasa et al,
J. Pharmacol. Exp. Ther.
(1989) 261, 746-754; Hikasa et al,
Eur. J. Pharmacol.
(1992) 229, 241-251; Hikasa et al,
Am. J. Vet. Res.
(1992) 50, 1348-1351; and Japundzic-Zigon et al,
Pharmacol. Res.
(1997) 35, 287-297. In both species, clonidine has been shown to be the most potent emetic alpha-2 adrenoceptor agonist with an ED
50
of 25 &mgr;g/kg (i.m.) in dogs and 0.075 &mgr;g/kg (i.c.v.) in cats (Hikasa et al, 1992, supra). This effect is thought to be mediated predominantly through the activation of alpha-2 adrenoceptors, since drugs with alpha-2 adrenoceptor antagonistic activity, such as yohimbine, were reported to abolish clonidine-induced emesis in these species (Hikasa et al, 1989, and 1992; and Japundzic-Zigon et al, 1997, supra).
Surprisingly, however, the inventors have found that these previously reported observations in the cat and dog are inconsistent with the effects of alpha-2 adrenoceptor agonists and antagonists in the ferret. It is widely recognized that the ferret is an excellent model for studying the emetic response with considerable predictability of the effects of anti-emetic agents in man. The inventors have found that administration of yohimbine alone to ferrets caused unexpected retching and vomiting. Moreover, in contrast to what has been reported in cats and dogs, clonidine did not trigger emesis in ferrets even at doses of 250 &mgr;g/kg (i.e. 10 times the ED
50
reported in dogs). It is of interest to note that pigeons have been reported to respond similarly to the administration of yohimbine or clonidine (Khandker et al,
Pharmacol. Res.
(1994) 29, 383-387) but there is no literature precedent for emesis in pigeons as a predictor for the effects of anti-emetic agents in man. In humans, nausea and vomiting has been reported following parenteral administration of yohimbine (Weiner at page 190 in Goodman & Gilman's “The Pharmacological Basis of Therapeutics, MacMillan Publishing Company, New York 1985).
The mechanism by which yohimbine activates the emetic reflex is not clear. In the studies described herein, the emetic action of yohimbine in the ferret can not be explained by an unspecific effect of yohimbine since similar responses were noted with two other potent and selective alpha-2 adrenoceptor antagonists, namely MK-912 and MK-467 (Pettibone et al, 1987, supra; Clineschmidt et al, 1988, supra). It also appears that both a peripheral and a central locus of action are involved. Inhibition of the alpha-2 adrenoceptor either with a peripherally active antagonist, MK-467, (Clineschmidt et al, 1988, supra) or a brain-penetrant antagonist, MK-912, (Pettibone et al, 1987, supra) was associated with emesis in the ferret. In addition, yohimbine was able to trigger the emetic reflex whether or not the route of administration was bypassing the lumen of the gastrointestinal tract.
In the ferret, clonidine was found to prevent emesis induced by PDE4 inhibitors. Consistent with the antagonists studies, it appears that the anti-emetic action of clonidine also involves a peripheral and a central locus of action. Emesis induced by PDE4 inhibitors having a mixed peripheral-central site of action (e.g. RS14203, R-rolipram) as well as that induced by PDE4 inhibitors acting predominantly via a peripheral site of action (e.g. CT-2450) was prevented by clonidine (Robichaud et al, 1999, supra). In apparently contradictory reports, clonidine has been noted to lower the incidence and frequency of vomiting following strabismus surgery in children (3-12 yr) (Mikawa et al,
Can. J. Anaesth.
(1995) 42, 977-981, whereas Kumar et al,
Anaesthesiol. Scand.
(1992) 36, 159-164 reported that, in elderly patients undergoing intraocular surgery, clonidine had no effect on emesis despite the fact that it induced sedation (an alpha-2 adrenoceptor agonist-mediated response).
There remains a need in the art for an effective therapy for the treatment or prevention of emesis. In accordance with the present invention, alpha-2 adrenoceptor agonists may be employed to treat and/or prevent emesis, as evidenced by the disclosure herein. Surprisingly, an alpha-2 adrenoreceptor agonist provide an effective therapy for the treatment or prevention of emesis. Such compounds exhibit unexpected and advantageous results, for example, by minimizing the side effects in the prevention or treatment emesis.
Accordingly, the present invention provides a method for the treatment and/or prevention of emesis which comprises administering to a patient in need of such treatment an effective amount of an alpha-2 adrenoceptor agonist. Although the present invention is not limited to a specific mechanism of action, the inventors postulate that the activity of an alpha-2 adrenoreceptor agonist provides efficacy in treatment or prevention of emesis.
SUMMARY OF THE INVENTION
The present invention is directed to the use of a class of adrenergic receptor agonists in therapy. More particularly, this invention is concerned with methods for using an alpha-2 adrenoceptor agonist alone or in combination with other antiemetic agents for the treatment and/or prevention of emesis.
DESCRIPTION OF THE INVENTION
The present invention relates to methods for the treatment or prevention of emesis by administering an alpha-2 adrenoreceptor agonist. The present invention further relates to methods for the treatment or prevention of emesis in a patient which comprises administering an alpha-2 adrenoreceptor agonist.
The present invention further relates to a method for the treatment or prevention of emesis in a patient which comprises administering an alpha-2 adrenoreceptor agonist, wherein the alpha-2 adrenoreceptor agonist minimize the side effects of nausea and/or emesis associated with other pharmacological agents.
The present invention accordingly provides the use of an alpha-2 adrenoreceptor agonist for the manufacture of a medicament for the treatment or prevention of emesis.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of emesis comprising an alpha-2 adrenoreceptor agonist, together with at least one pharmaceutically acceptable carrier or excipient.
As used herein, the term “emesis” will be understood to include nausea and vomiting. The alpha-2 adrenoceptor agonists of use in the present invention are beneficial in the therapy of acute, delayed
Delacroix-Muirheid C.
Jones Dwayne C.
Merck Frosst Canada & Co.
Thies J. Eric
Winokur Melvin
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