Microdose therapy

Details Microdose therapy Microdose therapy

2000-07-11

2002-07-23

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S192000, C514S231200, C514S470000, C514S565000, C514S668000

Reexamination Certificate

active

06423683

ABSTRACT:

FIELD OF THE INVENTION
The field of invention is the treatment of conditions concerned with peripheral vasoconstriction. More particularly, the invention is concerned with methods for establishing normal vascular tone in regions of the circulation which demonstrate pathophysiology. In particular, the invention concerns a method of treating erectile dysfunction by provision of nitric oxide, nitric oxide producing agents, or activators of guanyl cyclase in small doses or microdoses, i.e., doses that do not induce undesirable side effects, such as systemic vasodilation, under normal conditions.
BACKGROUND OF THE INVENTION
It is widely known that administration of nitric oxide (NO), or compounds which deliver NO (i.e., NO donors, NO producing agents) to a subject, can provoke powerful vasodilator responses. Such administration is often accompanied by a number of undesirable side effects which include headache, flushing, and hypotension.
The physiological role of NO has been described as that of a powerful chronic vasodilator agent based on there being a marked increase in vascular tone following NO synthase (NOS) blockade (Johnson et al.,
Am. J. Hypertens
. 5:919, 1992; Tolins et al.,
Hypertens
. 17:909, 1991). The role of NO as a chronic vasodilator has only been inferred by indirect means, i.e., by removal of NOS activity. Endogenously, much more multiplicity and overlap in the control of vasodilation can be inferred from the scientific literature. For example, vasodilation can be induced by acetylcholine, bradykinin, adenosine, adenosine triphosphate (ATP), histamine, vasoactive intestinal polypeptide (VIP), and leukotrienes, amongst others. The actions of these endogenous modulators have been shown to be dependent, at least in part, on the presence of the endothelium, an effect likely mediated by endothelial derived relaxing factor/NO (EDRF/NO) (Garg, U. C. et al.,
J. Biol. Chem
. 266:9, 1991; Garg, U. C. et al.,
J. Clin. Invest
. 83:1774, 1989; Palmer, R. M. J. et al,
Nature
327:524, 1987). Other vasodilator mechanisms exist which are not endothelium dependent, such as &bgr;
2
-adrenergic receptor activation, atrial natriuretic peptide (ANP) and certain prostaglandins. The actions of NO have been suggested to be mostly cGMP-mediated via guanylate cyclase activation, although other mechanisms have been suggested. For example, Garg et al. (
J. Biol. Chem
. 266:9, 1991
; J. Clin. Invest
. 83:1774, 1989) and others (Assender, J. W. et al.,
J. Cardiovasc. Pharmacol
. 17(Suppl.3):S104, 1991; O'Conner, K. J. et al,
J. Cardiovasc. Pharmacol
. 17(Suppl.3):S100-S103, 1991) demonstrated a difference in the effects of NO-generating vasodilator agents in inhibiting vascular smooth muscle cell growth in culture; however, it is clear that NO can act not only as a vasodilator but also to inhibit vascular growth responses in a number of conditions (Farhy, R. D. et al.,
Circ. Res
. 72:1202, 1993).
It has been believed and widely practised that NO, in humans and animals, produced via sodium nitroprusside (SNP) infusion, causes vasodilation in peripheral vasculature at doses greater than 10 &mgr;g/kg per min. It has recently been determined that NO also performs a function through interaction with endothelin (ET) (Banting et al,
J. Hypertens
. 14:975, 1996; Richard et al.,
Circulation
91:771,1995). Prior to this time, ET had been believed to play a minimal role in maintaining tone in the peripheral microvasculature and to have little impact on the state of contraction of smooth muscle in those vessels. Recent studies have indicated (Banting et al,
J. Hypertens
. 14:975, 1996) that ET is under the inhibitory control of NO and that administration of NOS inhibitors results in elevated levels of ET.
Endothelins were first described in 1988 and have been shown to be powerful vasoconstrictors, predominantly found in vascular endothelium and, since that time, numerous ET antagonists and their pharmaceutically acceptable salts have been identified and can be obtained commercially (e.g., Sigma, American Peptides). Detailed descriptions of the chemical structures of various ET antagonists may be found in U.S. Pats. No. 5,284,828 issued 8 February 1994 to Hemmi et al, No. 5,378,715 issued Jan. 3, 1995 to Stein et al., and No. 5,382,569 issued Jan. 17, 1995 to Cody et al. In addition, U.S. Pat. No. 5,338,726 issued Aug. 16, 1994 to Shinosaki et al. describes the chemical structure of ET converting enzyme inhibitors, To date, however, antagonists of ET have not been approved for therapeutic use, although a number of investigators have postulated that ET antagonists could be used for conditions ranging from renal failure, endotoxic shock, asthma, angina, or diabetes to pulmonary hypertension and possibly other indications.
Under normal physiological conditions, ET can be found in almost all parts of circulation at very low levels. In general, in the normal rodent circulation ET is not found in elevated quantities and appears to have little detectable role in the normal regulation of vascular tone, i.e., there is no appreciable decrease in blood pressure when an ET antagonist is administered by injection in normal circulation. Further, at present there does not appear to be any evidence suggesting that ET plays a physiological role even in a small portion of the circulation under normal circulatory conditions in experimental models. However, it is likely that the systemic circulation may appear to be normal when, in fact, specific regions of the circulation are undergoing pathophysiological changes such as occurs in conditions such as erectile dysfunction (ED) (Adams et al.,
Int. J. Impot. Res
. 9:85-91, 1997).
Consequently, there are cardiovascular conditions which are traditionally treated in human beings by significant doses of NO or NO donors, such as glyceryl trinitrate (GTN) (0.2 mg/h and greater). However, these doses are known to induce systemic vasodilation and provoke considerable overall systemic side effects (The, L. S. et al.,
Brit. J. Rheum
. 34:636, 1995). This is particularly so where a pathological condition exists only in certain major organs (e.g., heart, kidney, liver). As a result, a satisfactory method for promoting recovery of normal perfusion pressure in organs with certain pathologies without producing overall systemic hypotension has not been discovered.
Based on the understanding that a significant portion of underlying problems in clinical erectile dysfunction relates to “vascular” mechanisms, much of the current state-of-the-art research involves determining the contribution that the different vascular effector control systems make in normal and pathophysiological states. There is substantial understanding of hemodynamic events that lead to an erection, and yet the quantitative roles of each of the neuroeffector, humoral and local systems in these events remain poorly described. Since 1990, NO has been considered the primary non-adrenergic non-cholinergic neurotransmitter in the penis and has been presumed to be the primary mediator of corporal relaxation during erection (Ignarro L. J. et al.,
Biochem. Biophys. Res. Comm
., 170:843, 1990).
It is well established that, for an erection to occur, neurally mediated (autonomic) vasodilation of the penile arterial blood vessel and the trabecular meshwork takes place (Lue, T. F. et al.,
J. Urol
. 137(5):829, 1987) permitting increased blood flow into the cavernous bodies of the penis. The expanding intra corporal volume compresses the effluent veins that lie between the erectile tissue and the surrounding fibrous, relatively inelastic, tunica albuginea. The outflow capacity is thereby decreased and entrapment of blood ensues, resulting in the transformation of the flaccid penis into its erect state (Lue, T. F. et al.,
J. Urol
. 137(5):829, 1987; Juenemann, K. P. et al.,
J. Urol
. 136(1):158, 1986; Lue, T. F. et al.,
J. Urol
. 130:1237, 1983; Weiss, H. et al.,
Ann Intern. Med
. 76:793, 1980). The level of arterial vascular tone (i.e., blood pressure) is one of critical importance in this process, although adequat

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