Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-15
2002-04-30
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06380183
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns the treatment of diseases involving cyst formation, such as polycystic kidney disease. The present invention also concerns various endogenous and exogenous ligands of peripheral-type benzodiazepine receptors, and in particular, their use in the prevention or treatment of cyst formation.
BACKGROUND OF THE INVENTION
A. Diseases Involving Cyst Formation
There are several human diseases that result in the formation of cysts containing either semi-solid or fluid material. Benign cysts can occur, for example, in the ovary, spleen, lungs, kidney and liver, where they are often hereditary., Cysts can be acquired, as in diverticulosis of the intestines, or acquired as a secondary cause of an-inherited disease, as in cystic fibrosis, or can be directly inherited, as in polycystic disease of the kidney, which can also affect the liver and brain.
Renal cysts arise in the renal parenchyma, and begin as dilations or outpouchings from existing nephrons or collecting ducts or from the developmental counterparts of these structures. Renal cysts contain a fluid that presumably derives from their parent nephtron and/or is a local secretion. They may be hereditary, developmental, or acquired, and may occur in the cortex, medulla or both, and may or may not be associated with other renal or systemic abnormalities. For further details see, for example, Brenner & Rector,
The Kidney
, Fourth Edition, 1991, Vol. II, pp. 1657-1659.
Polycystic kidney disease (PKD) is a subset of renal cystic disorders in which cysts are distributed throughout the cortex and medulla of both kidneys. PKD is usually the hallmark of a unique autosomal dominant (autosomal dominant polycystic kidney disease, ADPKD) or autosomal recessive (autosomal recessive polycystic kidney disease, ARPKD) disorder but may also be found in association with a variety of clinical conditions or acquired at some point of life by a patient with an underlying, noncystic renal disease. PKD is the most prevalent hereditary renal disorder, accounting for over 5 percent of patients on chronic hemodialysis.
ADPKD, the most common dominantly inherited kidney disease usually appears in midlife, and is characterized morphologically be massive cyst enlargement, moderate interstitial infiltration with mononuclear cells, and extensive fibrosis. Characteristic symptoms include proteinuria, abdominal pain and palpable kidneys, followed by hematuria, hypertension, pyuria, uremia and calculi. In about 15% of patients, death is due to cerebral aneurysm. ADPKD is caused by mutations in one of three genes: PKD1 on chromosome 16 accounts for approximately 85% of cases whereas PKD2 on chromosome 4 accounts for approximately 15%. Mutations in the so far unmapped PKD3 gene are rare. (Reeders et al.,
Nature
317:542-544 [1985]; Kimberling et al.,
Genomics
18:467-472 [1993]; Daoust et al.,
Genomics
25:733-736 [1995]; Koptides et al.,
Hum. Mol. Genet
. 8:509-513 [1999]).
ARPKD is a rare inherited disorder which usually becomes clinically manifest in early childhood, although presentation of ARPKD at later ages an survival into adulthood have also been observed in many cases. ARPKD was first studied in C57BL/6J mice in whom it arises spontaneously (Preminger et al.,
J. Urol
. 127:556-560 [1982]). The cpk mutation characteristic of this disease has been mapped to mouse chromosome 12 (Davisson et al.,
Genomics
9:778-781 [1991]). The gene responsible for ARPKD in humans has been mapped to chromosome 6 p. More recently, fine mapping of the autosomal recessive polycystic kidney disease locus (PKHD1) has been reported (Mucher et al.,
Genomics
48:40-45 [1998]).
It has been reported that taxol and taxol derivatives inhibit the progression of PKD and prolongs the survival of polycystic cpk mice (Woo et al.,
Nature
368:750-753 [1994]; PCT publication WO 94/08041; U.S. Pat. No. 5,882,881). Since taxol specifically induces the expression of TNF-&agr; in macrophages and lymphocytes, it has also been suggested that TNF-&agr; is useful in the treatment of PKD (U.S. Pat. No. 5,750,495).
In APKD, the renal cysts remain small for 30-40 years. They then start to expand, progressively replacing normally functioning renal parenchyma. Factors involved in cyst expansion include loss of epithelial differentiation, increased proliferation and apoptosis, secretion of chloride and other ions into the cyst fluid and the development of inflammation around the outer circumference of the cyst wall (Grantham, J.
Am J.Kid.Dis
. 28:788-803 [1996]).
There is a need for the identification of endogenous and exogenous factors that are suitable for the prevention and treatment of diseases involving cyst formation and cyst expansion. In view of the severity and frequency of occurrence of PKD, there is a particular need for finding therapeutic agents useful in the prevention and treatment of this disease.
B. Ligands of Peripheral-Type Benzodiazepine Receptors (PTBR)
Ligands of PTBR's have been known for many years and anti-anxiety CNS effects of PTBR agonists (e.g. Valium) are widely known. With respect to benzodiazepine receptors outside the CNS (PTBR) most of what is known concerns the role of such receptors in mediating muscle relaxation, particularly smooth muscle relaxation. Vagal tone has been found to decrease following intravenous administration of diazepamn. (Adinoff et al., Psychiatry Research 41:89-97 [1992]). There is evidence for control of cardiac vagal tone by benzodiazepine receptors (DiMicco, Neuropharmnacology 26:553-559 [1987]). PTBR ligands Ro5-4864 and PK 11195, but not diazepam, have been described to depress cardiac function in an isolated working rat heart model (Edoute et al., Pharmacology 46:224-230 [1993]). Ro5-4864 has also been reported to increase coronary flow in an isolated perfused Langendorf rat heart without affecting heart rate and left ventricular contractility. PK 11195 did not antagonize this vasodilatory effect (Grupp et al., Eur. J. Pharm. 143:143-147 [1987]). In an isolated rat heart preparation, diazepain induced a transient negative inotropic effect followed by a positive inotropic response. The positive inotropy was antagonized by PK 11195. (Leeuwin et al., Eur. J. Pharm. 299:149-152 [1996]). Diazepam increased contractile force in Langendorf rat heart., (Leeuwin et al., Arch. Int. Pharmacodyn. 326:5-12 [1993]). Ro5-4864 has been shown to have a small (20%) depressant effect on the contraction amplitude (negative inotropic effect) of human atrial strips that was not antagonized by PK 11195 (Shany et al., Eur.J. Pharm. 253:231-236 [1994]). In a guinea pig heart preparation Ro5-4864 decreased the duration of intracellular action potential and contractility. Diazepam was less effective and clonazepam ineffective. The effects of Ro5-4864 were reversed by PK 11195 but not by a specific antagonist of the CNS BZR. (Mestre et al., Life Sciences 35:953-962 [1984]). The presence of PTBR binding sites in the hearts of dogs and humans was demonstrated in vivo by positron emission tomography using [
11
C]-PK 11195. (Charmonneau et al., Circulation 73:476-483 [1986]). It has also been reported that Ro5-4862 and dipyridamole can compete [
3
H]diazepam binding to heart tissue. Diazepam potentiates the actions of adenosine on isolated cardiac and smooth muscle and the coronary vasodilator action of adenosine in dogs. There is evidence that diazepam may be acting in a similar manner to dipyridamole by inhibiting adenosine uptake. (Davies and Huston, Eur. J. Pharm. 73:209-211 [1981]).
More recently, PTBR's have been shown to play a role in cell pathways underlying apoptosis. PTBR's expressed on mitochondria serve as docking receptors for Bcl
2
, a protein that inhibits apoptosis. The biological pathways in apoptosis modulated by PTBR ligand interactions are not specifically known.
SUMMARY OF THE I
Joly Alison
Schreiner George F.
Stanton Lawrence W.
White R. Tyler
Jones Dwayne C.
Knobbe Martens Olson & Bear LLP
Scios Inc.
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