Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-10
2002-08-20
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S275000, C514S312000, C514S349000, C514S353000, C514S355000
Reexamination Certificate
active
06436944
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of impotence comprising co-administering (1) a potassium channel opener and (2) a compound which elevates cyclic guanosine 3′,5′-monophosphate (cGMP) levels. The combination is particularly suitable for the treatment of patients suffering from impotence or erectile dysfunction.
BACKGROUND OF THE INVENTION
Impotence is the inability to obtain and/or sustain an erection sufficient for penetration of the vagina and/or intercourse. Thus, impotence is also referred to as “erectile insufficiency” or “erectile dysfunction”. It has been estimated that 10-12 million American men between the ages of 18 and 75 suffer from chronic impotence, with the great majority being over age 55.
The penis normally becomes erect when certain tissues, in particular the corpora cavernosa in the central portion of the penis, become engorged with blood, thereby causing them to become less flaccid, and in turn causing an erection. Impotence can result from psychologic disturbances (psychogenic), from physiologic abnormalities (organic) or from a combination of both. Thus, in some males erectile dysfunction may be due to anxiety or depression, with no apparent somatic or organic impairment. In other cases, erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis. In still other cases, the dysfunction may be due to venous leakage or abnormal drainage in which there is leakage from veins in the penis such that sufficient pressure for an erection can be neither obtained nor maintained. In still other cases, the dysfunction is associated with a neuropathy or due to nerve damage arising from, for example, surgery or a pelvic injury. Typically, multiple factors are responsible for impotence.
Pharmacological, biophysical and molecular studies have revealed multiple subtypes for membrane ion channels that form potassium selective pores in the plasma membrane of many mammalian cells. One can classify the family of K channels simply by their respective gating properties. In other words, a comparison of the pharmacological and electrophysiological properties of potassium channels has given rise to an operational definition for grouping the various subtypes based largely on their gating properties. At present, potassium channels of known amino acid sequence comprise two distantly related protein families. One of these channel families is termed, “voltage-gated,” the other channel family is termed “inward rectifying.”
The structure of the voltage-gated channel protein is known to be comprised of six membrane spanning domains in each subunit, each of which is regulated by changes in membrane potential. B. Hille, “Ionic Channels of Excitable Membranes” (Sinauer, Sunderland, Mass., 1992). Voltage-gated potassium channels sense changes in membrane potential and move potassium ions in response to this alteration in the cell membrane potential. Molecular cloning studies on potassium channel proteins has yielded information primarily for members of the voltage-gated family of potassium channels. Various genes encoding these voltage-gated family of potassium channel proteins have been cloned using Drosophila genes derived from both the Shaker, Shaw and Shab loci; Wei, A. et. al., Science (1990) Vol. 248 pp. 599-603.
Unlike the voltage-gated channel proteins with six membrane spanning regions,the inward rectifier channels have only two membrane spanning domains, each sensitive to changes in the net potassium concentration. Within this class of channels are the ATP-sensitive potassium channels. These channels are classified by their sensitivity to concentration fluxes in ATP. The ATP-sensitive, or ATP-gated, potassium channel is an important class of channels that links the bioenergetic situation of the cell to changes in cell function. These channels are blocked by high intracellular ATP concentrations and are open when ATP decreases. Lazdunski (1992); M. Lazdunski et al., “ATP-Sensitive K<+> Channels”, Renal Physiol. Biochem. Vol. 17: pp. 118-120 (1994).
Although ATP-gated potassium channels were originally described in cardiac tissue, Noma, A. Nature (1983) Vol. 305 pp. 147-148, they have subsequently been described in pancreatic beta-cells, Cook et. al., Nature (1984) Vol. 311 pp. 271-273, vascular smooth muscle, Nelson, M. T. et. al., Am. J. Physiol. (1990) Vol. 259 pp. C3-C18 and in the thick ascending limb of the kidney, Wang, W. et. al. Am. J. Physiol. (1990) Vol. 258, pp. F244-F-253.
The ATP-sensitive or ATP-gated potassium channels play an important role in human physiology. The ATP-sensitive potassium channel, like other potassium channels, selectively regulate the cell's permeability to potassium ions. These channels function to regulate the contraction and relaxation of the smooth muscle by opening or closing the channels in response to the modulation of receptors or potentials on the cell membrane. When ATP-sensitive potassium channels are opened, the increased permeability of the cell membrane allows more potassium ions to migrate outwardly so that the membrane potential shifts toward more negative values. When the membrane potential shifts toward more negative values the opening of the voltage-dependent calcium channels is reduced, this reduces the influx of calcium ions into the cell because the calcium channels become “increasingly less open” as the membrane potential becomes more negative. Consequently, drugs having ATP-sensitive potassium channel opening activity, drugs known as potassium channel openers, can relax vascular smooth muscle and are useful as hypotensive and coronary vasodilating agents.
A relatively large number of compounds are now known which open cell membrane ATP-sensitive potassium channels, particularly in smooth muscle: minoxidil sulfate, diazoxide and nicorandil are well known potassium channel openers. The target site for these agents is presumably on the potassium channel itself, but may also be on an associated regulatory protein.
Potassium channel openers represent a widely diverse series of compounds which all have the reported effect of opening only a subset of channels described as sensitive to ATP. As explained above, these compounds cause physiological responses by increasing membrane permeability to potassium, this leads to hyperpolarization of the cell membrane and temporal desensitization to electrical and chemical stimuli.
Openers which target these channels have been synthesized as possible drugs in hypertension, angina pectoris, coronary heart disease, asthma, and urinary incontinence. There are various references which describe potassium channel openers:
Cook et al., “Potassium Channels: Structure, Classification, Function and TherapeuticPotential”, ed. N. S. Cook, Ellis Horwood, Chichester (1990), p.p. 181-255;
David W. Robertson et al. , Journal of Medicinal Chemistry, “Potassium Channel Modulators: Scientific Applications and Therapeutic Promise,” vol. 33, No. 6, June 1990, pp. 1529-1541;
Gillian Edwards et al., “Structure-Activity Relationships of K+Channel Openers,” vol. 11, No. 10, October 1990, pp. 417-422;
Valerie A. Ashwood et al., “Synthesis and Antihypertensive Activity of Pyran Oxygen and Amide Nitrogen Replacement Anal oges of the Potassium Channel Activator Cromakalim,” Journal of Medicinal Chemistry, vol. 34, No. 11, November 1991, pp. 3261-3267;
Susan D. Longman et al., “Potassium Channel Activator Drugs: Mechanism of Action, Pharmacological Properties, and Therapeutic Potential,” Medicinal Research Reviews, vol. 12, No. 2, Mar. 1, 1992, pp. 73-148; and
Karnail S. Atwal, “Modulation of Potassium Channels by Organic Molecules,” Medicinal Research Reviews, vol. 12, No. 6, November 1992, pp. 569-591.
Agents which elevate cGMP levels are also well known and can work through any of several mechanisms. Agents which selectively inhibit an enzyme predominantly involved in cGMP breakdown, for example a cGMP phosphodiesterase (cGMP PDE), constitute one example. Other phosphodiesterases can also hydrolyze cGMP, and inhibitors of
Benson Gregg C.
Musser Arlene K.
Pfizer Inc.
Richardson Peter C.
Rose Shep K.
LandOfFree
Combination effective for the treatment of impotence does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Combination effective for the treatment of impotence, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Combination effective for the treatment of impotence will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2958327