Oral administration of adenosine analogs

Details Oral administration of adenosine analogs Oral administration of adenosine analogs

1998-11-04

2001-01-16

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S821000, C514S885000, C514S908000, C514S959000, C514S963000, C514S964000, C424S457000, C424S458000, C424S460000, C424S463000, C424S464000, C424S469000, C424S470000

Reexamination Certificate

active

06174873

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compositions comprising an adenosine analog. More particularly, the invention relates to compositions comprising an adenosine analog, wherein the composition comprises a dosage form suitable for oral (co)administration.
2. Description of Related Art
Certain adenosine analogs have been found to have very useful clinical pharmacological benefits. These include, but are not limited to, 2′-deoxycoformycin (also referred to as dCF, pentostatin, or NIPENT®), an inhibitor of adenosine deaminase; fludarabine monophosphate (FLU), a fluorinated analogue of adenine that is relatively resistant to adenosine-deaminase and 2-chloro-2′-deoxyadenosine (also known as cladribine or 2CDA) a drug also resistant to adenosine deaminase through introduction of a chlorine at the 2 carbon. Other adenosine analogs that have useful activity include deoxyadenosines generally, including 2′-deoxyadenosine, 3′-deoxyadenosine, and dideoxyadenosine.
In humans, these compounds are assumed to act through a number of adenosine related pathways, particularly the adenosine deaminase (ADA) pathway. A genetic deficiency of ADA may cause severe combined immunodeficiency. Dighiero, G., “Adverse and beneficial immunological effects of purine nucleoside analogues,”
Hematol Cell Ther
, 38:575-581 (1996). This document, and all others cited herein, are incorporated by reference as if reproduced fully herein.
While the exact nature of the ADA pathway intervention seems unclear, it may be that analogs of adenosine resistant to cellular deamination might mimic the ADA-deficient state. Lack of ADA seems to lead to a build up of deoxyadenosine and adenosine triphosphate in the cell, thus fatally accelerating DNA strand breaks in the cell. Under normal conditions, cells are continuously breaking and rejoining DNA. When this physiological process is accelerated by the effect of excess adenosine triphosphate, it leads to consumption of NAD for poly-ADP-ribose synthesis. This polymer is produced from nicotinamide adenosine dinucleotides (NAD) in a reaction catalyzed by the chromatin-associated poly(ADP-ribose) synthetase, leading to a depletion of the NAD content of the cell. This depletion induces a profound alteration of cellular reducing power, because of lethal ADP and ATP depletion.
The result is programmed cell death through activation of a Ca++, Mg++, dependent endonuclease. Hence, it appears that nucleoside analogs according to the invention can act on cells, with preferential lymphocytic activity, via an apoptotic process. The fact that supplementation of a cell medium with the NAD precursor of nicotinamide or 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase, prevented NAD depletion and reduces 2CDA toxicity, tends to support this hypothesis.
The various adenosine analogs affect the ADA pathway in different manners. DCF, for example, has been shown to be an quasi-irreversible inhibitor of ADA. By favoring the predominance of deoxycytidine kinase (DCK) over the dephosphorylating enzyme 5-nucleotidase in lymphocytes it induces a preferential accumulation of deoxyadenosine-5′-triphosphate (dATP). By comparison, FLU and 2CDA are rather resistant to the enzyme. Both drugs are initially phosphorylated by DCK and contribute to the accumulation of cellular adenosine triphosphate surrogates. As noted above, the accumulation of adenosine triphosphate, whether by the presumed DCF mechanism, or the FLU or 2CDA mechanism, promotes the apoptotic death of the cell.
Additional discussion of possible mechanisms of various adenosine analogs may be found in C. Dearden, et al., “Deoxycoformycin in the treatment of mature T-cell leukemias”,
Brit J. of Can
., 64(5):903-906 (November 1991); J. Seymour et al., “Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-&agr;-resistant hairy cell leukemia: 7-year follow-up”,
Leukemia
, 11, 42-47 (1997); J. Johnston et al., “Induction of Apoptosis in CD4+ Prolymphocytic Leukemia by Deoxyadenosine and 2′-Deoxycoformycin”,
Leukemia Research
, 16:8, 781-788 (1992); I. Fabian et al., “The Effect of Deoxycoformycin on Bone Marrow Cells Treated with Adenosine and Deoxyadenosine and Hemopoietic Growth Factors”,
Human Immunology
, 21, 81-87 (1988); E. Copelan et al., “Pharmacologic Marrow Purging in Murine T Cell Leukemia”,
Blood
, 71(6):1656-1661 (June 1988); W. Sheridan et al., “Preclinical studies on deoxycoformycin and deoxyadenosine as pharmacologic T cell purging tools”
Bone Marrow Trans
. 4:511-517 (1989); S. Sandhu et al., “Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart”, 265(4):1249-1256 (October 1993); D. Saito et al., “Effect of adenosine deaminase inhibitors on myocardial reactive hyperaemia following brief coronary occlusions”,
Cardiovascular Research
, 19, 578-583 (1985); G. Cristalli et al., “Adenosine Deaminase Inhibitors: Synthesis and Structure—Activity Relationships of Imidazole Analogues of erythro-9-(2-Hydroxy-3-nonyl)adenine”,
J. Med. Chem
. 34:1187-1192 (1991); G. Cristalli et al., “Adenosine Deaminase Inhibitors. Synthesis and Biological Activity of Deaza Analogues of erythro-9-(2-Hydroxy-3-nonyl)adenine”,
J. Med. Chem
., 31:390-393 (1988); R. Jackson et al., “The Biochemical Pharmacology of (2′-R)-Chloropentostatin, a Novel Inhibitor of Adenosine Deaminase”,
Advances in Enzyme Regulation
, 25:125-139; C. Vargeese, et al., “Adenosine Deaminase Inhibitors. Synthesis and Biological Evaluation of Putative Metabolites of (+)-erythro-9-(2S-Hydroxy-3R-nonyl)adenine”,
J. Med. Chem
. 37:3844-3849 (1994); G. Wolberg et al., “Effects of Adenosine Deaminase Inhibitors on Lymphocyte-mediated Cytolysis”,
Annals of the New York Academy of Sciences
, 451:215-226 (1985); G. Harriman et al., “Adenosine Deaminase Inhibitors. Synthesis and Biological Evaluation of 4-Amino-1-(2(S)-hydroxy-3(R)-nonyl)-1H-imidazo[4,5-c]pyridine (3-Deaza-(+)-EHNA) and Certain C1′ Derivatives”,
J. Med. Chem
. 37:305-308 (1994); I. Antonini et al., “Adenosine Deaminase Inhibitors. Synthesis of Deaza Analogues of erythro-9-(2-Hydroxy-3-nonyl)adenine”
J. Med. Chem
. 27:274-278 (1984); G. Cristalli et al., “Adenosine Deaminase Inhibitors: Synthesis and Structure—Activity Relationships of 2-Hydroxy-3-nonyl Derivatives of Azoles”,
J. Med. Chem
., 37:201-205 (1994); and H. Showalter et al., “Adenosine Deaminase Inhibitors. Synthesis and Biological Evaluation of (±)-3,6,7,8-Tetrahydro-3-[2-hydroxyethoxy)methyl]imidazo[4,5,-d][1,3]diazepin-8-ol and Some Selected C-5 Homologues of Pentostatin”,
J. Med. Chem
. 26:1478-1482 (1983).
A problem with administering these adenosine analogs is their dosage form. Currently, these analogs are available only in an intravenous (IV) dosage form. While this dosage form is customary, especially for use in oncology indications, it is limiting in a variety of ways. For example, IV dosing is expensive. It requires a highly trained medical professional to administer the IV dose. The dosing involves expensive equipment and materials. Additionally, IV dosing presents increased possibilities of infection, through use of contaminated equipment or accidental contamination, for example. This is a special concern in health care settings where increased incidences of antibiotic resistant bacteria are being noted.
A seemingly natural solution to the IV dosage problem is the development of an oral dosage form. Such a dosage form alleviates most, if not all, of the above-mentioned problems associated with IV or other parenteral dosage forms. However, the art recognized serious problems with the development of an oral dosage form. Chief among these is that adenosine analogs have been known for years to be susceptible to acid-catalyzed glycosidic cleavage. Therefore, one of skill in the art would expect that an orally administered adenosine analog would be cleaved in the sto

Affiliated with

Also associated with

Rating

Oral administration of adenosine analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Oral administration of adenosine analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oral administration of adenosine analogs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2484020