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(en)Propargylamine, propargylamine derivatives N-propargyl-1-aminoindan and analogs thereof, and pharmaceutically acceptable salts thereof, are useful for administration to a subject at high risk for or suffering from acute renal failure (ARF).
1.ApplicationNumber: US-24415005-A
1.PublishNumber: US-8263655-B2
2.Date Publish: 20120911
3.Inventor: BINAH OFER
ABASSI ZAID A.
YOUDIM MOUSSA B. H.
BARAC YARON
4.Inventor Harmonized: BINAH OFER(IL)
ABASSI ZAID A(IL)
YOUDIM MOUSSA B H(IL)
BARAC YARON(IL)
5.Country: US
6.Claims:
(en)Propargylamine, propargylamine derivatives N-propargyl-1-aminoindan and analogs thereof, and pharmaceutically acceptable salts thereof, are useful for administration to a subject at high risk for or suffering from acute renal failure (ARF).
7.Description:
(en)FIELD OF THE INVENTION
The present invention relates to methods and compositions for the treatment of renal failure and, more particularly, to propargylamine and derivatives thereof for use in said compositions and methods.
BACKGROUND OF THE INVENTION
Congestive Heart Failure
Congestive heart failure (CHF) is characterized by activation of neurohormonal systems such as the renin-angiotensin, sympathetic nervous system and vasopressin. It is commonly accepted that increased activity of these three vasoconstrictor systems plays a major role in the pathophysiology of CHF and may contribute to the clinical deterioration of patients with this syndrome. In particular, it has been documented that neurohormonal activation may have detrimental effects on the cardiovascular system and on the kidney. These include systemic vasoconstriction with increased afterload and the development of cardiac hypertrophy. In addition, neurohormonal activation may lead to deterioration in renal function, renal vasoconstriction, salt and water retention, and consequently edema formation (Dzau, 1987).
Cardiac hypertrophy is a major risk factor of cardiovascular mortality and morbidity (de Simone et al, 2001). It is a general adaptive response to states of hyperfunction (Meerson et al, 1996), and is observed in a wide variety of physiological and pathologic states, including pressure overload, volume overload, and excessive exposure to neurohumoral and metabolic stimuli. At its first stages, hypertrophy is a compensatory response. With the progression of the initial stimulus, a transition occurs in which an irreversible decompensation in cardiac function takes place, leading to heart failure, as well as to an increased tendency to develop arrhythmias (Chien, 1999; Swynghedauw and Baillard, 2000). The trigger for this transition from compensated hypertrophy to decompensation is unknown. Morphological and histological analyses reveal that decompensated hypertrophy and heart failure are usually characterized by ventricular dilation and collagen deposition, resulting in cardiac fibrosis and, subsequently, in myocardial stiffness.
Although of great importance, the mechanisms underlying the cardiac hypertrophy and fibrotic response remain poorly understood. It has been suggested that both the circulating and local myocardial neurohumoral systems such as renin-angiotensin-aldosterone system (RAAS) play a role in the development of ventricular hypertrophy and fibrosis (Dzau, 1987; Watkins et al, 1976). Similarly, activation of the sympathetic nervous system contributes to sodium retention, and to cardiac hypertrophy and fibrosis in clinical and experimental heart failure (Hostetter et al., 1983; Abassi et al. 1990; Brodsky et al., 1998).
Renal Failure
Acute renal failure (ARF) is a syndrome characterized by a sudden decrease in kidney function leading to a decrease or sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes and maintain fluid balance. It is a frequent clinical problem, particularly in the intensive care unit, where it is associated with a mortality of between 50% and 80% (Schrier et al, 2004). ARF may occur following exposure to various therapeutic agents such as cyclosporine, aminoglycosides, nonsteroidal antiinflammatory drugs, cisplatin, amphotericin B, or procedures, e.g., radiocontrast media, or exposure to heavy metal, which inflict toxic and ischemic damage to the renal tissue (Green et al, 2000).
The mechanisms underlying ARF involve both vascular and tubular factors (Kribben et al, 1999). An ischemic insult to the kidney due to hypoperfusion will, in general, be the cause of the ARF. While a decrease in renal blood flow with diminished oxygen and substrate delivery to the tubule cells is an important ischemic factor, it must be remembered that a relative increase in oxygen demand by the tubule is also a factor in renal ischemia. Renal ischemia leads to a series of cellular events which might culminate in organ failure, depending on the cell type and the duration of ischemia. It was assumed that reperfusion, instituted before irreversible damage to the tissue occurred, would limit the insult to the organ. Contrary to such expectations, it was reported that reperfusion enhances renal damage (Canavese et al., 1988). Several suggestions for the basis of this ‘reperfusion injury’ have been proposed. It has been linked to an attenuated restoration in renal blood flow which returns only to 60% of its preischemic value (Arendshorst et al., 1975; Cristol et al., 1993). Others have suggested that reactive oxygen species (ROS) generated during ischemia and reperfusion in the mitochondria, cause the damage (Canavese et al., 1988; Greene et al., 1991).
Chronic renal failure (CRF) is the progressive loss of kidney function. The kidneys attempt to compensate for renal damage by hyperfiltration (excessive straining of the blood) within the remaining functional nephrons (filtering units that consist of a glomerulus and corresponding tubule). Over time, hyperfiltration causes further loss of function.
Chronic loss of function causes generalized wasting (shrinking in size) and progressive scarring within all parts of the kidneys. In time, overall scarring obscures the site of the initial damage. Yet, it is not until over 70% of the normal combined function of both kidneys is lost that most patients begin to experience symptoms of kidney failure.
Propargylamine and Propargylamine Derivatives
Rasagiline, R(+)-N-propargyl-1-aminoindan, a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor, has been shown to exhibit neuroprotective activity and antiapoptotic effects against a variety of insults in cell cultures and in vivo.
Rasagiline is being developed for Parkinson's disease as monotherapy or as an adjunct to L-dopa therapy (Youdim et al., 2001; Parkinson Study Group, 2002; Finberg and Youdim, 2002; Gassen et al., 2003). Phase III controlled studies have shown that rasagiline is effective with a dose of as low as 1 mg/kg in monotherapy (Parkinson Study group, 2002) and as an adjunct to L-dopa, comparable in its effect to the anti-Parkinson catechol-O-methyltranferase (COMT) inhibitor, entacapone (Brooks and Sagar, 2003). Rasagiline has recently finished the phase III clinical trials and has been approved for Parkinson's disease.
Rasagiline exhibits neuroprotective activities both in vitro and in vivo (for review see Mandel et al., 2003; Youdim et al., 2003) which may contribute to its possible disease modifying activity. It is metabolized to its major two metabolites: aminoindan (TVP-136) and S(−)-N-propargyl-1-aminoindan (TVP-1022) (Youdim et al., 2001), which also have neuroprotective activity against serum deprivation and 1-methamphetamine-induced neurotoxicity in partially differentiated PC-12 cells (Am et al., 2004).
By contrast, selegiline (1-deprenyl), a selective MAO-B inhibitor which is a useful anti-Parkinson drug both in monotherapy (Parkinson Study Group, 1989) and as an adjunct to L-DOPA therapy, and has L-DOPA sparing action (Birkmayer et al., 1977; Riederer and Rihne, 1992; Parkinson Study Group, 1989), is a propargyl derivative of 1-methamphetamine. Thus, the major metabolite of selegiline, 1-methamphetamine (Szoko et al., 1999; Kraemer and Maurer, 2002; Shin, 1997), is neurotoxic (Abu-Raya et al., 2003; Am et al., 2004). In contrast to aminoindan, L-methamphetamine prevents the neuroprotective activities of rasagiline and selegiline in partially differentiated cultured PC-12 cells (Am et al., 2004).
Selegiline and methamphetamine, unlike rasagiline and aminoindan, have sympathomimetic activity (Simpson, 1978) that increases heart rate and blood pressure (Finberg et al., 1990; Finberg et al., 1999). Recent studies (Glezer and Finberg, 2003) have indicated that the sympathomimetic action of selegiline can be attributed to its 1-methamphetamine and amphetamine metabolites. These properties are absent in rasagiline and in its metabolite aminoindan. Parkinsonian patients receiving combined treatments with selegiline plus levodopa have been reported to have a higher mortality rate than those treated with levodopa alone (Lees, 1995). This is not related to its MAO-B inhibitory activity, but rather attributed to its sympathomimetic action and methamphetamine metabolites (Reynolds et al., 1978; Lavian et al., 1993).
Several propargylamine derivatives have been shown to selectively inhibit MAO-B and/or MAO-A activity and, thus to be suitable for treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In addition, these compounds have been further shown to protect against neurodegeneration by preventing apoptosis.
R(+)-N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof were first disclosed in U.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 as useful for the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer type, depression, and the hyperactive syndrome. The 4-fluoro-, 5-fluoro- and 6-fluoro-N-propargyl-1-aminoindan derivatives were disclosed in U.S. Pat. No. 5,486,541 for the same purposes.
U.S. Pat. Nos. 5,519,061, 5,532,415, 5,599,991, 5,744,500, 6,277,886, 6,316,504, 133, U.S. Pat. Nos. 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 disclose R(+)-N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof as useful for treatment of additional indications, namely, an affective illness, a neurological hypoxia or anoxia, neurodegenerative diseases, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
U.S. Pat. No. 6,251,938 describes N-propargyl-phenylethylamine compounds, and U.S. Pat. Nos. 6,303,650, 6,462,222 and 6,538,025 describe N-propargyl-1-aminoindan and N-propargyl-1-aminotetralin compounds, said to be useful for treatment of depression, attention deficit disorder, attention deficit and hyperactivity disorder, Tourette's syndrome, Alzheimer's disease and other dementia such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
The first compound found to selectively inhibit MAO-B was R-(−)-N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(−)-deprenyl, R-(−)-deprenyl, or selegiline. In addition to Parkinson's disease, other diseases and conditions for which selegiline is disclosed as being useful include: drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers. WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (e.g., see Tatton, et al., 1991 and 1993). U.S. Pat. No. 6,562,365 discloses the use of desmethylselegiline for selegiline-responsive diseases and conditions.
U.S. Pat. Nos. 5,169,868, 5,840,979 and 6,251,950 disclose aliphatic propargylamines as selective MAO-B inhibitors, neuroprotective and cellular rescue agents. The lead compound, (R)-N-(2-heptyl)methyl-propargylamine (R-2HMP), has been shown to be a potent MAO-B inhibitor and anti-apoptotic agent (Durden et al., 2000).
Propargylamine was reported many years ago to be a mechanism-based inhibitor of the copper-containing bovine plasma amine oxidase (BPAO), though the potency was modest. U.S. Pat. No. 6,395,780 discloses propargylamine as a weak glycine-cleavage system inhibitor. Copending U.S. patent application Ser. No. 10/952,379 discloses that propargylamine exhibits neuroprotective and anti-apoptotic activities and can, therefore, be used for all known uses of rasagiline and similar drugs containing the propargylamine moiety.
Copending U.S. patent application Ser. No. 10/952,367 of the present applicants discloses and claims a method for treatment of a cardiovascular disorder or disease which comprises administering to the subject an amount of an active agent selected from the group consisting of propargylamine, a propargylamine derivative, and a pharmaceutically acceptable salt thereof.
All and each of the above-mentioned US patents and patent applications are herewith incorporated by reference in their entirety as if fully disclosed herein.
To the best of our knowledge, the renal effects of rasagiline and its metabolites were not disclosed nor examined.
SUMMARY OF THE INVENTION
Since rasagiline is a new anti-Parkinson drug with neuroprotective activity and promising clinical value, our aims were to examine for the first time the acute and chronic effects of rasagiline and its metabolites on: (i) renal clearance and excretory function in rats with renal ischemia, and (ii) on renal functions in rats with experimental heart failure. We have then found that rasagiline and its S-enantiomer S(−)-N-propargyl-1-aminoindan produced significant diuretic and natriuretic responses in association with glomerular filtration rate (GFR) in rats with congestive heart failure, and induced diuretic and natriuretic responses accompanied by improved GFR in the ischemic kidney.
The present invention thus relates to a method for treatment of a subject susceptible to or suffering from renal failure, which comprises administering to the subject an amount of an agent selected from the group consisting of propargylamine, a propargylamine derivative and a pharmaceutically acceptable salt thereof, effective to treat the subject.
The renal failure to be treated may be acute renal failure (ARF) or chronic renal failure (CRF).
In one preferred embodiment of the invention, the agent is a propargylamine derivative, preferably N-propargyl-1-aminoindan or an enantiomer thereof such as R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and, more preferably, its enantiomer S-(−)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE FIGURES
FIGS. 1A-1B show the effects of pretreatment with rasagiline or S-(−)-N-propargyl-1-aminoindan (TVP-1022) (1 mg/kg), 30 minutes prior to the induction of renal ischemia in rats, on the glomerular filtration rate (GFR) of the normal ( 1 A) and ischemic ( 1 B) kidney.
FIGS. 2A-2B show the effects of pretreatment with rasagiline or S-(−)-N-propargyl-1-aminoindan (1 mg/kg), 30 minutes prior to the induction of renal ischemia in rats, on the fractional excretion of sodium (FENa) of the normal ( 2 A) and ischemic ( 2 B) kidney.
FIGS. 3A-3B show the effect of chronic treatment with rasagiline ( 3 A) or S-(−)-N-propargyl-1-aminoindan ( 3 B) on daily urine volume in rats with CHF and in sham operated animals.
FIGS. 4A-4B show the effects of chronic treatment with rasagiline ( 4 A) or S-(−)-N-propargyl-1-aminoindan ( 4 B) at doses of 1 or 7.5 mg/kg/day on the daily sodium excretion in rats with CHF and in sham operated animals.
FIGS. 5A-5B show the effects of chronic treatment with rasagiline ( 5 A) or S-(−)-N-propargyl-1-aminoindan ( 5 B) at doses of 1 or 7.5 mg/kg/day on the cumulative sodium excretion in rats with CHF and in sham operated animals.
FIGS. 6A-6B show the effects of chronic treatment with rasagiline or S-(−)-N-propargyl-1-aminoindan on blood urea nitrogen (BUN) ( 6 A) and on creatinine clearance test (CCT=GFR) ( 6 B) in rats with CHF. These drugs were given chronically to rats with A-V fistula via gavage, at doses of 1 or 7.5 mg/kg/day for 2 weeks.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for treatment of a subject susceptible to or suffering from renal failure which comprises administering to the subject an amount of an active agent selected from the group consisting of propargylamine, a propargylamine derivative, and a pharmaceutically acceptable salt thereof, effective to treat the subject.
In one embodiment, the method of the invention may be used for the treatment of acute renal failure (ARF), independently of its cause and of its type.
In another embodiment, the method of the invention may be used for the treatment of chronic renal failure (CRF), independently of its cause and of its type.
Depending on the localization or the nature of the renal insult, ARF and RCF may be classified as prerenal, renal or postrenal ARF or CRF.
ARF is a syndrome characterized by a sudden decrease of the glomerular filtration rate (GFR) and consequently an increase in blood nitrogen products (blood urea nitrogen and creatinine). Prerenal ARF may be caused, for example, by myocarditis, myocardial infarction, congestive heart failure, arrhythmia, pericardial tamponade, pulmonary embolism, decreased extracellular fluid volume, excessive diuresis, hemorrhage, vomiting, diarrhea, sepsis, peritonitis, pancreatitis, burns, etc. The condition is reversible if the underlying disease is resolved. Parenchymatous or renal ARF are caused, for example, by acute tubular necrosis or injury resulting from cardiovascular surgery, sepsis, exposure to toxic substances and nephrotoxic drugs, accumulation of endogenous nephrotoxins, hemoglobinuria, or intrarenal precipitation (hypercalcemia, urates, sulfonamides, acyclovir, myeloma protein), or by acute glomerulonephritis. Obstructive or postrenal ARF may be caused by congenital abnomalies, acquired uropathies, malignant diseases, some drugs, infections, and others.
CRF is the progressive loss of kidney function. The cause(s) of CRF may be difficult if not impossible to be determined. Prerenal conditions such as poor cardiac function, chronic liver failure, and atherosclerosis (“hardening”) of the renal artery may induce ischemic nephropathy. Interference with the normal flow of urine can produce backpressure within the kidneys, can damage nephrons, and lead to obstructive uropathy, a disease of the urinary tract. Abnormalities that may hamper urine flow and cause post-renal CRF include bladder outlet obstruction, kidney stones, and obstruction of the tubules. Renal CFR is caused by changes within the kidneys and include diabetic nephropathy, chronic glomerular nephritis, chronic interstitial nephritis, vasculitis, renal vascular CRF
In one preferred embodiment, the active agent used in the present invention is N-propargyl-1-aminoindan, either in its racemic form (described, for example, in U.S. Pat. No. 6,630,514) or as the R-enantiomer R(+)-N-propargyl-1-aminoindan (described, for example, in U.S. Pat. No. 5,387,612) or as the S-enantiomer S-(−)-N-propargyl-1-aminoindan (described, for example, in U.S. Pat. No. 6,277,886). In more preferred embodiments of the invention, the active agent is rasagiline, the R(+)-N-propargyl-1-aminoindan, or its enantiomer S(−)-N-propargyl-1-aminoindan.
In another preferred embodiment, the active agent is a pharmaceutically acceptable salt of N-propargyl-1-aminoindan or of an enantiomer thereof including, but not limited to, the mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts. In preferred embodiments, the salt is a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan such as, but not limited to, the mesylate salt (described, for example, in U.S. Pat. No. 5,532,415), the esylate and the sulfate salts (both described, for example, in U.S. Pat. No. 5,599,991), and the hydrochloride salt (described, for example, in U.S. Pat. No. 6,630,514) of R(+)-N-propargyl-1-aminoindan or S(−)-N-propargyl-1-aminoindan.
In a further embodiment, the active agent is an analog of N-propargyl-1-aminoindan, an enantiomer or a pharmaceutically acceptable salt thereof. In one embodiment, the analogs are the compounds described in U.S. Pat. No. 5,486,541 such as, but not limited to, the compounds 4-fluoro-N-propargyl-1-aminoindan, 5-fluoro-N-propargyl-1-aminoindan, 6-fluoro-N-propargyl-1-aminoindan, an enantiomer thereof and pharmaceutically acceptable addition salts thereof. In another embodiment, the analogs are the compounds described in U.S. Pat. No. 6,251,938 such as, but not limited to, the compounds (rac)-3-(N-methyl,N-propyl-carbamyloxy)-α-methyl-N′-propargyl phenethylamine HCl; (rac)-3-(N,N-dimethyl-carbamyloxy)-α-methyl-N′-methyl, N′-propargyl phenethylamine HCl; (rac)-3-(N-methyl,N-hexyl-carbamyloxy)-α-methyl-N′-methyl, N′-propargyl phenethylamine mesylate; (rac)-3-(N-methyl,N-cyclohexyl-carbamyloxy)-α-methyl-N′-methyl,N′-propargylphenethyl HCl; and (S)-3-(N-methyl,N-hexyl-carbamyloxy)-α-methyl-N′-methyl,N′-propargyl phenethylamine ethane-sulfonate. In a further embodiment, the analogs are the compounds described in U.S. Pat. No. 6,303,650 such as, but not limited to, the compounds (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (rac) 6-(N,N-dimethyl, carbamyloxy)-N′-methyl-N′-propargyl-1-aminoindan HCl; (rac) 6-(N-methyl, N-ethyl-carbamyloxy-N′-propargyl-1-aminotetralin HCl; (rac) 6-(N,N-dimethyl-thiocarbamyloxy)-1-aminoindan HCl; (rac) 6-(N-propyl-carbamyloxy-N′-propargyl-1-aminoindan HCl; (rac) 5-chloro-6-(N-methyl,N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (S)-6-(N-methyl), N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; and (R)-6-(N-methyl,N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan hemi-(L)-tartrate, and 6-(N-methyl,N-ethyl-carbamyloxy)-N′-methyl,N′-propargyl-1-aminoindan described in U.S. Pat. No. 6,462,222.
In a still further embodiment, the active agent is an aliphatic propargylamine described in U.S. Pat. Nos. 5,169,868, 5,840,979 and 6,251,950 such as, but not limited to, the compounds N-(1-heptyl)propargylamine; N-(1-octyl)propargylamine; N-(1-nonyl)propargylamine; N-(1-decyl)propargylamine; N-(1-undecyl)propargylamine: N-(1-dodecyl)propargylamine; R—N-(2-butyl)propargylamine; R—N-(2-pentyl)propargylamine; R—N-(2-hexyl)propargylamine; R—N-(2-heptyl)propargylamine; R—N-(2-octyl)propargylamine; R—N-(2-nonyl)propargylamine; R—N-(2-decyl)propargylamine, R—N-(2-undecyl)propargylamine; R—N-(2-dodecyl)propargylamine: N-(1-butyl)-N-methylpropargylamine; N-(2-butyl)-N-methylpropargylamine; N-(2-pentyl)-N-methylpropargylamine; N-(1-pentyl)-N-methylpropargylamine; N-(2-hexyl)-N-methylpropargylamine; N-(2-heptyl)-N-methylpropargylamine; N-(2-decyl)-N-methylpropargylamine; N-(2-dodecyl)-N-methylpropargylamine; R(−)-N-(2-butyl)-N-methylpropargylamine; or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the active agent is selegiline, desmethylselegiline or norprenyl, pargyline or chlorgyline.
In still another embodiment, the active agent is the compound (N-methyl-N-propargyl-10-aminomethyl-dibenzo[b,f]oxepin (known as CGP 3466, described in Zimmermann et al., 1999).
All the US patents and other publications mentioned hereinabove are hereby incorporated by reference in their entirety as if fully disclosed herein.
For use in the method of the present invention, a pharmaceutical composition is provided for prevention and/or treatment of renal failure comprising a pharmaceutically acceptable carrier and an agent selected from the group consisting of propargylamine, a propargylamine derivative, or a pharmaceutically acceptable salt thereof as described above.
The pharmaceutical composition provided by the present invention may be in solid, semisolid or liquid form and may further include pharmaceutically acceptable fillers, carriers or diluents, and other inert ingredients and excipients. The composition can be administered by any suitable route, e.g. intravenously, orally, parenterally, rectally, or transdermally. The dosage will depend on the state of the patient and severity of the disease and will be determined as deemed appropriate by the practitioner.
In one embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical composition is in a suitable form for oral administration including tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, and sublingual tablets. In a more preferred embodiment, the pharmaceutical composition is a tablet containing an amount of the active agent in the range of about 0.1-100 mg, preferably from about 1 mg to about 10 mg.
In another embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is an injectable solution. The amount of the active agent in the injectable solution is in the range of from about 0.1 mg to about 100 mg per injection, more preferably 1 mg to about 10 mg per injection.
For parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion. For rectal administration there are provided suppositories with hydrophilic or hydrophobic (gel) vehicles.
The dosage and frequency of administration of the drug will depend from the age and condition of the patient, type of disorder and its severity, and will be determined according to the physician's judgment.
In one embodiment of the invention, the active agent is administered alone. In other embodiments of the invention, the active agent is administered in combination with another known drug for treatment of renal failure, either before, simultaneously or after said other drug.
The following examples illustrate certain features of the present invention but are not intended to limit the scope of the present invention.
The invention will now be illustrated by the following non-limiting Examples.
EXAMPLES
Material and Methods
(i) Materials. Rasagiline and its enantiomer S(−)-N-propargyl-1-aminoindan were kindly donated by Teva Pharmaceutical Industries Ltd. (Petach Tikva, Israel).
(ii) Animals. Studies were conducted on Sprague Dawley rats (Harlan Laboratories Ltd., Jerusalem, Israel), weighing 290˜330 g. The animals were kept in a temperature-controlled room, and were fed standard rat chow containing 0.5% NaCl and tap water ad libitum. All experiments were performed according to the guidelines of the Technion Committee for Supervision of Animal Experiments (Haifa, Israel). Rats were subjected to one of the experimental protocols, described in Examples 1 and 2 hereinafter.
(iii) Chemical analysis. Sodium concentration in plasma and urine was determined by flame photometry (model IL 943, Instrumentation Laboratory). Inulin and creatinine concentrations were determined by the colorimetric anthrone method. Glomerular filtration rate (GFR) was equated with the clearance of inulin or creatinine.
(iv) Statistical analysis. Statistical significance was assessed by one-way analysis of variance (ANOVA), ANOVA for repeated measures, or two-way ANOVA, as appropriate. The Dunnett test and Tukey's multiple comparisons test were used for data point comparisons of each group. P<0.05 was considered statistically significant. Data are presented as means±S.E.M.
In the following experiments, our aim was to examine the efficacy of rasagiline and its S-isomer, S(−)-N-propargyl-1-aminoindan, in two different experimental protocols: (i) Renoprotective efficacy in renal ischemia; and (ii) Renal function in rats with experimental heart failure.
Example 1
Acute Studies—Effects of Rasagiline or S-(−)-N-propargyl-1-aminoindan on Renal Clearance Parameters in Rats with Renal Ischemia
This protocol was designed to assess the reno-protective effects of rasagiline and S-(−)-N-propargyl-1-aminoindan in a rat renal ischemia-reperfusion injury (IRI) model of acute renal failure (ARF). For this purpose, the effects of either rasagiline or S-(−)-N-propargyl-1-aminoindan on renal clearance parameters, i.e., glomerular filtration rate (GFR), absolute and fractional sodium excretion rates (U Na V and FE Na , respectively), and urinary flow (V) were studied in rats that underwent renal ischemia. Rats that underwent the same procedure, but were treated with vehicle, served as controls.
The surgical procedure for the induction of renal ischemia has been previously described (Sela et al., 1992). Briefly, the animals were anesthetized with Inactin (100 mg/kg, i.p.), placed on a thermo-regulated (37° C.) surgical table and prepared for hemodynamic and clearance studies (Brodsky et al., 1998). After tracheotomy, polyethylene tubes (PE 50 ) were inserted into the carotid artery, jugular vein and urinary bladder for blood pressure monitoring, infusion of various solutions and urine collections, respectively. A solution of 2% inulin in 0.9% saline was infused throughout the experiment at a rate of 1.0% of body weight per hour. After surgery and a 60-minute equilibration period, two baseline clearance periods of 30 minutes each were obtained. Then, the left kidney was exposed and the renal artery was clamped for forty-five minutes of ischemia, followed by 60 min of reperfusion. The right kidney served as the control, for each animal. Thirty minutes prior to the induction of the renal ischemia, animals were treated with either rasagiline or S-(−)-N-propargyl-1-aminoindan administered as a bolus injection (1.0 mg/kg, I.V.), followed by a sustained infusion of the drugs at a dose of 2 mg/kg/h throughout the whole experiment. Animals treated with saline served as controls. Then, two additional clearance periods were obtained under the influence of the drug. Urine volume was determined gravimetrically. Blood samples were obtained in the midst of every 2 nd clearance period.
As shown in FIGS. 1A-1B , it seems that S-(−)-N-propargyl-1-aminoindan, and to a lesser extent rasagiline, improved the function of the ischemic kidney as well as the function of the control normal kidney. FIG. 2A shows that S-(−)-N-propargyl-1-aminoindan, and to a greater extent rasagiline, increased the fractional excretion of Na + (FENa) by normal kidney. In contrast, S-(−)-N-propargyl-1-aminoindan enhanced FENa by ischemic kidney more than rasagiline ( FIG. 2B ).
Example 2
Chronic Studies—Effects of Chronic Administration of Rasagiline or S-(−)-N-propargyl-1-aminoindan on Sodium Excretion in Rats with Heart Failure
This protocol was designed to evaluate the effects of long-term administration (14 days) of rasagiline or S-(−)-N-propargyl-1-aminoindan on renal clearance and excretory parameters in rats with experimental congestive heart failure induced by the placement of an arterio-venous fistula between the abdominal aorta and the inferior vena-cava as described previously (Abassi et al., 1990).
In short, the abdominal aorta and inferior vena-cava were exposed through a mid-abdominal incision under pentobarbital anesthesia (60 mg/kg, I.P.), and an arterio-venous shunt was surgically created in the common wall of the two vessels (side to side, 1.2 mm O.D.). Following surgery, the rats were allowed to recover and housed in individual metabolic cages for measurements of daily urine volume and urinary sodium/potassium excretion.
Rasagiline or S-(−)-N-propargyl-1-aminoindan were dissolved in drinking water and given orally at a dose of 1 or 7.5 mg/kg/day for 5 days to normal rats. Following this period, the animals were subjected either to sham operation (n=6) or to creation of aortocaval fistula (ACF) (n=6) as described above. These experimental groups were treated daily by gavage with 1 or 7.5 mg/kg of rasagiline or S-(−)-N-propargyl-1-aminoindan for additional 14 days, and their daily urine volume, sodium and potassium excretion were measured. Rats treated with vehicle (water) served as controls. After completion of the treatment period, animals from the different experimental groups were killed by decapitation and their blood was collected in pre-cooled tubes. Rats with sham operation or animals with arterio-venous fistula treated with vehicle served as controls.
As shown in FIGS. 3A-3B , chronic administration of S-(−)-N-propargyl-1-aminoindan, but not of rasagiline, to rats with CHF increased the urinary flow rate. Similarly, the absolute and cumulative urinary sodium excretions ( FIGS. 4 and 5 , respectively) were markedly enhanced by S-(−)-N-propargyl-1-aminoindan and, to a lesser extent, by rasagiline. As shown in FIG. 6 , these effects were associated with enhanced GFR, suggesting that S-(−)-N-propargyl-1-aminoindan can improve kidney function in heart failure disease state.
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1.PublishNumber: US-8263655-B2
2.Date Publish: 20120911
3.Inventor: BINAH OFER
ABASSI ZAID A.
YOUDIM MOUSSA B. H.
BARAC YARON
4.Inventor Harmonized: BINAH OFER(IL)
ABASSI ZAID A(IL)
YOUDIM MOUSSA B H(IL)
BARAC YARON(IL)
5.Country: US
6.Claims:
(en)Propargylamine, propargylamine derivatives N-propargyl-1-aminoindan and analogs thereof, and pharmaceutically acceptable salts thereof, are useful for administration to a subject at high risk for or suffering from acute renal failure (ARF).
7.Description:
(en)FIELD OF THE INVENTION
The present invention relates to methods and compositions for the treatment of renal failure and, more particularly, to propargylamine and derivatives thereof for use in said compositions and methods.
BACKGROUND OF THE INVENTION
Congestive Heart Failure
Congestive heart failure (CHF) is characterized by activation of neurohormonal systems such as the renin-angiotensin, sympathetic nervous system and vasopressin. It is commonly accepted that increased activity of these three vasoconstrictor systems plays a major role in the pathophysiology of CHF and may contribute to the clinical deterioration of patients with this syndrome. In particular, it has been documented that neurohormonal activation may have detrimental effects on the cardiovascular system and on the kidney. These include systemic vasoconstriction with increased afterload and the development of cardiac hypertrophy. In addition, neurohormonal activation may lead to deterioration in renal function, renal vasoconstriction, salt and water retention, and consequently edema formation (Dzau, 1987).
Cardiac hypertrophy is a major risk factor of cardiovascular mortality and morbidity (de Simone et al, 2001). It is a general adaptive response to states of hyperfunction (Meerson et al, 1996), and is observed in a wide variety of physiological and pathologic states, including pressure overload, volume overload, and excessive exposure to neurohumoral and metabolic stimuli. At its first stages, hypertrophy is a compensatory response. With the progression of the initial stimulus, a transition occurs in which an irreversible decompensation in cardiac function takes place, leading to heart failure, as well as to an increased tendency to develop arrhythmias (Chien, 1999; Swynghedauw and Baillard, 2000). The trigger for this transition from compensated hypertrophy to decompensation is unknown. Morphological and histological analyses reveal that decompensated hypertrophy and heart failure are usually characterized by ventricular dilation and collagen deposition, resulting in cardiac fibrosis and, subsequently, in myocardial stiffness.
Although of great importance, the mechanisms underlying the cardiac hypertrophy and fibrotic response remain poorly understood. It has been suggested that both the circulating and local myocardial neurohumoral systems such as renin-angiotensin-aldosterone system (RAAS) play a role in the development of ventricular hypertrophy and fibrosis (Dzau, 1987; Watkins et al, 1976). Similarly, activation of the sympathetic nervous system contributes to sodium retention, and to cardiac hypertrophy and fibrosis in clinical and experimental heart failure (Hostetter et al., 1983; Abassi et al. 1990; Brodsky et al., 1998).
Renal Failure
Acute renal failure (ARF) is a syndrome characterized by a sudden decrease in kidney function leading to a decrease or sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes and maintain fluid balance. It is a frequent clinical problem, particularly in the intensive care unit, where it is associated with a mortality of between 50% and 80% (Schrier et al, 2004). ARF may occur following exposure to various therapeutic agents such as cyclosporine, aminoglycosides, nonsteroidal antiinflammatory drugs, cisplatin, amphotericin B, or procedures, e.g., radiocontrast media, or exposure to heavy metal, which inflict toxic and ischemic damage to the renal tissue (Green et al, 2000).
The mechanisms underlying ARF involve both vascular and tubular factors (Kribben et al, 1999). An ischemic insult to the kidney due to hypoperfusion will, in general, be the cause of the ARF. While a decrease in renal blood flow with diminished oxygen and substrate delivery to the tubule cells is an important ischemic factor, it must be remembered that a relative increase in oxygen demand by the tubule is also a factor in renal ischemia. Renal ischemia leads to a series of cellular events which might culminate in organ failure, depending on the cell type and the duration of ischemia. It was assumed that reperfusion, instituted before irreversible damage to the tissue occurred, would limit the insult to the organ. Contrary to such expectations, it was reported that reperfusion enhances renal damage (Canavese et al., 1988). Several suggestions for the basis of this ‘reperfusion injury’ have been proposed. It has been linked to an attenuated restoration in renal blood flow which returns only to 60% of its preischemic value (Arendshorst et al., 1975; Cristol et al., 1993). Others have suggested that reactive oxygen species (ROS) generated during ischemia and reperfusion in the mitochondria, cause the damage (Canavese et al., 1988; Greene et al., 1991).
Chronic renal failure (CRF) is the progressive loss of kidney function. The kidneys attempt to compensate for renal damage by hyperfiltration (excessive straining of the blood) within the remaining functional nephrons (filtering units that consist of a glomerulus and corresponding tubule). Over time, hyperfiltration causes further loss of function.
Chronic loss of function causes generalized wasting (shrinking in size) and progressive scarring within all parts of the kidneys. In time, overall scarring obscures the site of the initial damage. Yet, it is not until over 70% of the normal combined function of both kidneys is lost that most patients begin to experience symptoms of kidney failure.
Propargylamine and Propargylamine Derivatives
Rasagiline, R(+)-N-propargyl-1-aminoindan, a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor, has been shown to exhibit neuroprotective activity and antiapoptotic effects against a variety of insults in cell cultures and in vivo.
Rasagiline is being developed for Parkinson's disease as monotherapy or as an adjunct to L-dopa therapy (Youdim et al., 2001; Parkinson Study Group, 2002; Finberg and Youdim, 2002; Gassen et al., 2003). Phase III controlled studies have shown that rasagiline is effective with a dose of as low as 1 mg/kg in monotherapy (Parkinson Study group, 2002) and as an adjunct to L-dopa, comparable in its effect to the anti-Parkinson catechol-O-methyltranferase (COMT) inhibitor, entacapone (Brooks and Sagar, 2003). Rasagiline has recently finished the phase III clinical trials and has been approved for Parkinson's disease.
Rasagiline exhibits neuroprotective activities both in vitro and in vivo (for review see Mandel et al., 2003; Youdim et al., 2003) which may contribute to its possible disease modifying activity. It is metabolized to its major two metabolites: aminoindan (TVP-136) and S(−)-N-propargyl-1-aminoindan (TVP-1022) (Youdim et al., 2001), which also have neuroprotective activity against serum deprivation and 1-methamphetamine-induced neurotoxicity in partially differentiated PC-12 cells (Am et al., 2004).
By contrast, selegiline (1-deprenyl), a selective MAO-B inhibitor which is a useful anti-Parkinson drug both in monotherapy (Parkinson Study Group, 1989) and as an adjunct to L-DOPA therapy, and has L-DOPA sparing action (Birkmayer et al., 1977; Riederer and Rihne, 1992; Parkinson Study Group, 1989), is a propargyl derivative of 1-methamphetamine. Thus, the major metabolite of selegiline, 1-methamphetamine (Szoko et al., 1999; Kraemer and Maurer, 2002; Shin, 1997), is neurotoxic (Abu-Raya et al., 2003; Am et al., 2004). In contrast to aminoindan, L-methamphetamine prevents the neuroprotective activities of rasagiline and selegiline in partially differentiated cultured PC-12 cells (Am et al., 2004).
Selegiline and methamphetamine, unlike rasagiline and aminoindan, have sympathomimetic activity (Simpson, 1978) that increases heart rate and blood pressure (Finberg et al., 1990; Finberg et al., 1999). Recent studies (Glezer and Finberg, 2003) have indicated that the sympathomimetic action of selegiline can be attributed to its 1-methamphetamine and amphetamine metabolites. These properties are absent in rasagiline and in its metabolite aminoindan. Parkinsonian patients receiving combined treatments with selegiline plus levodopa have been reported to have a higher mortality rate than those treated with levodopa alone (Lees, 1995). This is not related to its MAO-B inhibitory activity, but rather attributed to its sympathomimetic action and methamphetamine metabolites (Reynolds et al., 1978; Lavian et al., 1993).
Several propargylamine derivatives have been shown to selectively inhibit MAO-B and/or MAO-A activity and, thus to be suitable for treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In addition, these compounds have been further shown to protect against neurodegeneration by preventing apoptosis.
R(+)-N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof were first disclosed in U.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 as useful for the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer type, depression, and the hyperactive syndrome. The 4-fluoro-, 5-fluoro- and 6-fluoro-N-propargyl-1-aminoindan derivatives were disclosed in U.S. Pat. No. 5,486,541 for the same purposes.
U.S. Pat. Nos. 5,519,061, 5,532,415, 5,599,991, 5,744,500, 6,277,886, 6,316,504, 133, U.S. Pat. Nos. 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 disclose R(+)-N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof as useful for treatment of additional indications, namely, an affective illness, a neurological hypoxia or anoxia, neurodegenerative diseases, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
U.S. Pat. No. 6,251,938 describes N-propargyl-phenylethylamine compounds, and U.S. Pat. Nos. 6,303,650, 6,462,222 and 6,538,025 describe N-propargyl-1-aminoindan and N-propargyl-1-aminotetralin compounds, said to be useful for treatment of depression, attention deficit disorder, attention deficit and hyperactivity disorder, Tourette's syndrome, Alzheimer's disease and other dementia such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
The first compound found to selectively inhibit MAO-B was R-(−)-N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(−)-deprenyl, R-(−)-deprenyl, or selegiline. In addition to Parkinson's disease, other diseases and conditions for which selegiline is disclosed as being useful include: drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers. WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (e.g., see Tatton, et al., 1991 and 1993). U.S. Pat. No. 6,562,365 discloses the use of desmethylselegiline for selegiline-responsive diseases and conditions.
U.S. Pat. Nos. 5,169,868, 5,840,979 and 6,251,950 disclose aliphatic propargylamines as selective MAO-B inhibitors, neuroprotective and cellular rescue agents. The lead compound, (R)-N-(2-heptyl)methyl-propargylamine (R-2HMP), has been shown to be a potent MAO-B inhibitor and anti-apoptotic agent (Durden et al., 2000).
Propargylamine was reported many years ago to be a mechanism-based inhibitor of the copper-containing bovine plasma amine oxidase (BPAO), though the potency was modest. U.S. Pat. No. 6,395,780 discloses propargylamine as a weak glycine-cleavage system inhibitor. Copending U.S. patent application Ser. No. 10/952,379 discloses that propargylamine exhibits neuroprotective and anti-apoptotic activities and can, therefore, be used for all known uses of rasagiline and similar drugs containing the propargylamine moiety.
Copending U.S. patent application Ser. No. 10/952,367 of the present applicants discloses and claims a method for treatment of a cardiovascular disorder or disease which comprises administering to the subject an amount of an active agent selected from the group consisting of propargylamine, a propargylamine derivative, and a pharmaceutically acceptable salt thereof.
All and each of the above-mentioned US patents and patent applications are herewith incorporated by reference in their entirety as if fully disclosed herein.
To the best of our knowledge, the renal effects of rasagiline and its metabolites were not disclosed nor examined.
SUMMARY OF THE INVENTION
Since rasagiline is a new anti-Parkinson drug with neuroprotective activity and promising clinical value, our aims were to examine for the first time the acute and chronic effects of rasagiline and its metabolites on: (i) renal clearance and excretory function in rats with renal ischemia, and (ii) on renal functions in rats with experimental heart failure. We have then found that rasagiline and its S-enantiomer S(−)-N-propargyl-1-aminoindan produced significant diuretic and natriuretic responses in association with glomerular filtration rate (GFR) in rats with congestive heart failure, and induced diuretic and natriuretic responses accompanied by improved GFR in the ischemic kidney.
The present invention thus relates to a method for treatment of a subject susceptible to or suffering from renal failure, which comprises administering to the subject an amount of an agent selected from the group consisting of propargylamine, a propargylamine derivative and a pharmaceutically acceptable salt thereof, effective to treat the subject.
The renal failure to be treated may be acute renal failure (ARF) or chronic renal failure (CRF).
In one preferred embodiment of the invention, the agent is a propargylamine derivative, preferably N-propargyl-1-aminoindan or an enantiomer thereof such as R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof and, more preferably, its enantiomer S-(−)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE FIGURES
FIGS. 1A-1B show the effects of pretreatment with rasagiline or S-(−)-N-propargyl-1-aminoindan (TVP-1022) (1 mg/kg), 30 minutes prior to the induction of renal ischemia in rats, on the glomerular filtration rate (GFR) of the normal ( 1 A) and ischemic ( 1 B) kidney.
FIGS. 2A-2B show the effects of pretreatment with rasagiline or S-(−)-N-propargyl-1-aminoindan (1 mg/kg), 30 minutes prior to the induction of renal ischemia in rats, on the fractional excretion of sodium (FENa) of the normal ( 2 A) and ischemic ( 2 B) kidney.
FIGS. 3A-3B show the effect of chronic treatment with rasagiline ( 3 A) or S-(−)-N-propargyl-1-aminoindan ( 3 B) on daily urine volume in rats with CHF and in sham operated animals.
FIGS. 4A-4B show the effects of chronic treatment with rasagiline ( 4 A) or S-(−)-N-propargyl-1-aminoindan ( 4 B) at doses of 1 or 7.5 mg/kg/day on the daily sodium excretion in rats with CHF and in sham operated animals.
FIGS. 5A-5B show the effects of chronic treatment with rasagiline ( 5 A) or S-(−)-N-propargyl-1-aminoindan ( 5 B) at doses of 1 or 7.5 mg/kg/day on the cumulative sodium excretion in rats with CHF and in sham operated animals.
FIGS. 6A-6B show the effects of chronic treatment with rasagiline or S-(−)-N-propargyl-1-aminoindan on blood urea nitrogen (BUN) ( 6 A) and on creatinine clearance test (CCT=GFR) ( 6 B) in rats with CHF. These drugs were given chronically to rats with A-V fistula via gavage, at doses of 1 or 7.5 mg/kg/day for 2 weeks.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for treatment of a subject susceptible to or suffering from renal failure which comprises administering to the subject an amount of an active agent selected from the group consisting of propargylamine, a propargylamine derivative, and a pharmaceutically acceptable salt thereof, effective to treat the subject.
In one embodiment, the method of the invention may be used for the treatment of acute renal failure (ARF), independently of its cause and of its type.
In another embodiment, the method of the invention may be used for the treatment of chronic renal failure (CRF), independently of its cause and of its type.
Depending on the localization or the nature of the renal insult, ARF and RCF may be classified as prerenal, renal or postrenal ARF or CRF.
ARF is a syndrome characterized by a sudden decrease of the glomerular filtration rate (GFR) and consequently an increase in blood nitrogen products (blood urea nitrogen and creatinine). Prerenal ARF may be caused, for example, by myocarditis, myocardial infarction, congestive heart failure, arrhythmia, pericardial tamponade, pulmonary embolism, decreased extracellular fluid volume, excessive diuresis, hemorrhage, vomiting, diarrhea, sepsis, peritonitis, pancreatitis, burns, etc. The condition is reversible if the underlying disease is resolved. Parenchymatous or renal ARF are caused, for example, by acute tubular necrosis or injury resulting from cardiovascular surgery, sepsis, exposure to toxic substances and nephrotoxic drugs, accumulation of endogenous nephrotoxins, hemoglobinuria, or intrarenal precipitation (hypercalcemia, urates, sulfonamides, acyclovir, myeloma protein), or by acute glomerulonephritis. Obstructive or postrenal ARF may be caused by congenital abnomalies, acquired uropathies, malignant diseases, some drugs, infections, and others.
CRF is the progressive loss of kidney function. The cause(s) of CRF may be difficult if not impossible to be determined. Prerenal conditions such as poor cardiac function, chronic liver failure, and atherosclerosis (“hardening”) of the renal artery may induce ischemic nephropathy. Interference with the normal flow of urine can produce backpressure within the kidneys, can damage nephrons, and lead to obstructive uropathy, a disease of the urinary tract. Abnormalities that may hamper urine flow and cause post-renal CRF include bladder outlet obstruction, kidney stones, and obstruction of the tubules. Renal CFR is caused by changes within the kidneys and include diabetic nephropathy, chronic glomerular nephritis, chronic interstitial nephritis, vasculitis, renal vascular CRF
In one preferred embodiment, the active agent used in the present invention is N-propargyl-1-aminoindan, either in its racemic form (described, for example, in U.S. Pat. No. 6,630,514) or as the R-enantiomer R(+)-N-propargyl-1-aminoindan (described, for example, in U.S. Pat. No. 5,387,612) or as the S-enantiomer S-(−)-N-propargyl-1-aminoindan (described, for example, in U.S. Pat. No. 6,277,886). In more preferred embodiments of the invention, the active agent is rasagiline, the R(+)-N-propargyl-1-aminoindan, or its enantiomer S(−)-N-propargyl-1-aminoindan.
In another preferred embodiment, the active agent is a pharmaceutically acceptable salt of N-propargyl-1-aminoindan or of an enantiomer thereof including, but not limited to, the mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts. In preferred embodiments, the salt is a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan such as, but not limited to, the mesylate salt (described, for example, in U.S. Pat. No. 5,532,415), the esylate and the sulfate salts (both described, for example, in U.S. Pat. No. 5,599,991), and the hydrochloride salt (described, for example, in U.S. Pat. No. 6,630,514) of R(+)-N-propargyl-1-aminoindan or S(−)-N-propargyl-1-aminoindan.
In a further embodiment, the active agent is an analog of N-propargyl-1-aminoindan, an enantiomer or a pharmaceutically acceptable salt thereof. In one embodiment, the analogs are the compounds described in U.S. Pat. No. 5,486,541 such as, but not limited to, the compounds 4-fluoro-N-propargyl-1-aminoindan, 5-fluoro-N-propargyl-1-aminoindan, 6-fluoro-N-propargyl-1-aminoindan, an enantiomer thereof and pharmaceutically acceptable addition salts thereof. In another embodiment, the analogs are the compounds described in U.S. Pat. No. 6,251,938 such as, but not limited to, the compounds (rac)-3-(N-methyl,N-propyl-carbamyloxy)-α-methyl-N′-propargyl phenethylamine HCl; (rac)-3-(N,N-dimethyl-carbamyloxy)-α-methyl-N′-methyl, N′-propargyl phenethylamine HCl; (rac)-3-(N-methyl,N-hexyl-carbamyloxy)-α-methyl-N′-methyl, N′-propargyl phenethylamine mesylate; (rac)-3-(N-methyl,N-cyclohexyl-carbamyloxy)-α-methyl-N′-methyl,N′-propargylphenethyl HCl; and (S)-3-(N-methyl,N-hexyl-carbamyloxy)-α-methyl-N′-methyl,N′-propargyl phenethylamine ethane-sulfonate. In a further embodiment, the analogs are the compounds described in U.S. Pat. No. 6,303,650 such as, but not limited to, the compounds (rac) 6-(N-methyl, N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (rac) 6-(N,N-dimethyl, carbamyloxy)-N′-methyl-N′-propargyl-1-aminoindan HCl; (rac) 6-(N-methyl, N-ethyl-carbamyloxy-N′-propargyl-1-aminotetralin HCl; (rac) 6-(N,N-dimethyl-thiocarbamyloxy)-1-aminoindan HCl; (rac) 6-(N-propyl-carbamyloxy-N′-propargyl-1-aminoindan HCl; (rac) 5-chloro-6-(N-methyl,N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; (S)-6-(N-methyl), N-propyl-carbamyloxy)-N′-propargyl-1-aminoindan HCl; and (R)-6-(N-methyl,N-ethyl-carbamyloxy)-N′-propargyl-1-aminoindan hemi-(L)-tartrate, and 6-(N-methyl,N-ethyl-carbamyloxy)-N′-methyl,N′-propargyl-1-aminoindan described in U.S. Pat. No. 6,462,222.
In a still further embodiment, the active agent is an aliphatic propargylamine described in U.S. Pat. Nos. 5,169,868, 5,840,979 and 6,251,950 such as, but not limited to, the compounds N-(1-heptyl)propargylamine; N-(1-octyl)propargylamine; N-(1-nonyl)propargylamine; N-(1-decyl)propargylamine; N-(1-undecyl)propargylamine: N-(1-dodecyl)propargylamine; R—N-(2-butyl)propargylamine; R—N-(2-pentyl)propargylamine; R—N-(2-hexyl)propargylamine; R—N-(2-heptyl)propargylamine; R—N-(2-octyl)propargylamine; R—N-(2-nonyl)propargylamine; R—N-(2-decyl)propargylamine, R—N-(2-undecyl)propargylamine; R—N-(2-dodecyl)propargylamine: N-(1-butyl)-N-methylpropargylamine; N-(2-butyl)-N-methylpropargylamine; N-(2-pentyl)-N-methylpropargylamine; N-(1-pentyl)-N-methylpropargylamine; N-(2-hexyl)-N-methylpropargylamine; N-(2-heptyl)-N-methylpropargylamine; N-(2-decyl)-N-methylpropargylamine; N-(2-dodecyl)-N-methylpropargylamine; R(−)-N-(2-butyl)-N-methylpropargylamine; or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the active agent is selegiline, desmethylselegiline or norprenyl, pargyline or chlorgyline.
In still another embodiment, the active agent is the compound (N-methyl-N-propargyl-10-aminomethyl-dibenzo[b,f]oxepin (known as CGP 3466, described in Zimmermann et al., 1999).
All the US patents and other publications mentioned hereinabove are hereby incorporated by reference in their entirety as if fully disclosed herein.
For use in the method of the present invention, a pharmaceutical composition is provided for prevention and/or treatment of renal failure comprising a pharmaceutically acceptable carrier and an agent selected from the group consisting of propargylamine, a propargylamine derivative, or a pharmaceutically acceptable salt thereof as described above.
The pharmaceutical composition provided by the present invention may be in solid, semisolid or liquid form and may further include pharmaceutically acceptable fillers, carriers or diluents, and other inert ingredients and excipients. The composition can be administered by any suitable route, e.g. intravenously, orally, parenterally, rectally, or transdermally. The dosage will depend on the state of the patient and severity of the disease and will be determined as deemed appropriate by the practitioner.
In one embodiment, the pharmaceutically acceptable carrier is a solid and the pharmaceutical composition is in a suitable form for oral administration including tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, and sublingual tablets. In a more preferred embodiment, the pharmaceutical composition is a tablet containing an amount of the active agent in the range of about 0.1-100 mg, preferably from about 1 mg to about 10 mg.
In another embodiment, the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is an injectable solution. The amount of the active agent in the injectable solution is in the range of from about 0.1 mg to about 100 mg per injection, more preferably 1 mg to about 10 mg per injection.
For parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion. For rectal administration there are provided suppositories with hydrophilic or hydrophobic (gel) vehicles.
The dosage and frequency of administration of the drug will depend from the age and condition of the patient, type of disorder and its severity, and will be determined according to the physician's judgment.
In one embodiment of the invention, the active agent is administered alone. In other embodiments of the invention, the active agent is administered in combination with another known drug for treatment of renal failure, either before, simultaneously or after said other drug.
The following examples illustrate certain features of the present invention but are not intended to limit the scope of the present invention.
The invention will now be illustrated by the following non-limiting Examples.
EXAMPLES
Material and Methods
(i) Materials. Rasagiline and its enantiomer S(−)-N-propargyl-1-aminoindan were kindly donated by Teva Pharmaceutical Industries Ltd. (Petach Tikva, Israel).
(ii) Animals. Studies were conducted on Sprague Dawley rats (Harlan Laboratories Ltd., Jerusalem, Israel), weighing 290˜330 g. The animals were kept in a temperature-controlled room, and were fed standard rat chow containing 0.5% NaCl and tap water ad libitum. All experiments were performed according to the guidelines of the Technion Committee for Supervision of Animal Experiments (Haifa, Israel). Rats were subjected to one of the experimental protocols, described in Examples 1 and 2 hereinafter.
(iii) Chemical analysis. Sodium concentration in plasma and urine was determined by flame photometry (model IL 943, Instrumentation Laboratory). Inulin and creatinine concentrations were determined by the colorimetric anthrone method. Glomerular filtration rate (GFR) was equated with the clearance of inulin or creatinine.
(iv) Statistical analysis. Statistical significance was assessed by one-way analysis of variance (ANOVA), ANOVA for repeated measures, or two-way ANOVA, as appropriate. The Dunnett test and Tukey's multiple comparisons test were used for data point comparisons of each group. P<0.05 was considered statistically significant. Data are presented as means±S.E.M.
In the following experiments, our aim was to examine the efficacy of rasagiline and its S-isomer, S(−)-N-propargyl-1-aminoindan, in two different experimental protocols: (i) Renoprotective efficacy in renal ischemia; and (ii) Renal function in rats with experimental heart failure.
Example 1
Acute Studies—Effects of Rasagiline or S-(−)-N-propargyl-1-aminoindan on Renal Clearance Parameters in Rats with Renal Ischemia
This protocol was designed to assess the reno-protective effects of rasagiline and S-(−)-N-propargyl-1-aminoindan in a rat renal ischemia-reperfusion injury (IRI) model of acute renal failure (ARF). For this purpose, the effects of either rasagiline or S-(−)-N-propargyl-1-aminoindan on renal clearance parameters, i.e., glomerular filtration rate (GFR), absolute and fractional sodium excretion rates (U Na V and FE Na , respectively), and urinary flow (V) were studied in rats that underwent renal ischemia. Rats that underwent the same procedure, but were treated with vehicle, served as controls.
The surgical procedure for the induction of renal ischemia has been previously described (Sela et al., 1992). Briefly, the animals were anesthetized with Inactin (100 mg/kg, i.p.), placed on a thermo-regulated (37° C.) surgical table and prepared for hemodynamic and clearance studies (Brodsky et al., 1998). After tracheotomy, polyethylene tubes (PE 50 ) were inserted into the carotid artery, jugular vein and urinary bladder for blood pressure monitoring, infusion of various solutions and urine collections, respectively. A solution of 2% inulin in 0.9% saline was infused throughout the experiment at a rate of 1.0% of body weight per hour. After surgery and a 60-minute equilibration period, two baseline clearance periods of 30 minutes each were obtained. Then, the left kidney was exposed and the renal artery was clamped for forty-five minutes of ischemia, followed by 60 min of reperfusion. The right kidney served as the control, for each animal. Thirty minutes prior to the induction of the renal ischemia, animals were treated with either rasagiline or S-(−)-N-propargyl-1-aminoindan administered as a bolus injection (1.0 mg/kg, I.V.), followed by a sustained infusion of the drugs at a dose of 2 mg/kg/h throughout the whole experiment. Animals treated with saline served as controls. Then, two additional clearance periods were obtained under the influence of the drug. Urine volume was determined gravimetrically. Blood samples were obtained in the midst of every 2 nd clearance period.
As shown in FIGS. 1A-1B , it seems that S-(−)-N-propargyl-1-aminoindan, and to a lesser extent rasagiline, improved the function of the ischemic kidney as well as the function of the control normal kidney. FIG. 2A shows that S-(−)-N-propargyl-1-aminoindan, and to a greater extent rasagiline, increased the fractional excretion of Na + (FENa) by normal kidney. In contrast, S-(−)-N-propargyl-1-aminoindan enhanced FENa by ischemic kidney more than rasagiline ( FIG. 2B ).
Example 2
Chronic Studies—Effects of Chronic Administration of Rasagiline or S-(−)-N-propargyl-1-aminoindan on Sodium Excretion in Rats with Heart Failure
This protocol was designed to evaluate the effects of long-term administration (14 days) of rasagiline or S-(−)-N-propargyl-1-aminoindan on renal clearance and excretory parameters in rats with experimental congestive heart failure induced by the placement of an arterio-venous fistula between the abdominal aorta and the inferior vena-cava as described previously (Abassi et al., 1990).
In short, the abdominal aorta and inferior vena-cava were exposed through a mid-abdominal incision under pentobarbital anesthesia (60 mg/kg, I.P.), and an arterio-venous shunt was surgically created in the common wall of the two vessels (side to side, 1.2 mm O.D.). Following surgery, the rats were allowed to recover and housed in individual metabolic cages for measurements of daily urine volume and urinary sodium/potassium excretion.
Rasagiline or S-(−)-N-propargyl-1-aminoindan were dissolved in drinking water and given orally at a dose of 1 or 7.5 mg/kg/day for 5 days to normal rats. Following this period, the animals were subjected either to sham operation (n=6) or to creation of aortocaval fistula (ACF) (n=6) as described above. These experimental groups were treated daily by gavage with 1 or 7.5 mg/kg of rasagiline or S-(−)-N-propargyl-1-aminoindan for additional 14 days, and their daily urine volume, sodium and potassium excretion were measured. Rats treated with vehicle (water) served as controls. After completion of the treatment period, animals from the different experimental groups were killed by decapitation and their blood was collected in pre-cooled tubes. Rats with sham operation or animals with arterio-venous fistula treated with vehicle served as controls.
As shown in FIGS. 3A-3B , chronic administration of S-(−)-N-propargyl-1-aminoindan, but not of rasagiline, to rats with CHF increased the urinary flow rate. Similarly, the absolute and cumulative urinary sodium excretions ( FIGS. 4 and 5 , respectively) were markedly enhanced by S-(−)-N-propargyl-1-aminoindan and, to a lesser extent, by rasagiline. As shown in FIG. 6 , these effects were associated with enhanced GFR, suggesting that S-(−)-N-propargyl-1-aminoindan can improve kidney function in heart failure disease state.
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