This invention provides compositions and methods for increasing cellular respiration of melanized catecholamine neurons, and methods for alleviating symptoms or stopping appearance and/or progression of symptoms of Parkinson""s Disease, and methods for preventing symptoms of on-off syndrome associated with treatment with dopamine or a dopamine agonist of a patient suffering symptoms of a disease selected from the group consisting of idiopathic and atypical Parkinson""s disease, conditions characterized by nigrostriatal degeneration and multiple system atrophy, said methods comprising administering to said patient an effective amount of a neuromelanin-binding composition having a quinoline ring in a suitable pharmaceutical carrier. Preferably the composition comprises (xe2x88x92)-chloroquine.

Idiopathic Parkinson""s Disease (IPD) is a progressive neurodegenerative disorder. The onset of IPD symptoms begin to manifest when a threshold reduction of 60%-70% nigral neurons accompanied by an 80%-90% attenuation in striatal dopamine efflux, has been reached (Koller, W. C., xe2x80x9cWhen does Parkinson""s disease begin?xe2x80x9d, (1992) Neurology 42(S4):27-31). Symptoms include tremor, postural imbalance, rigidity, bradykinesia and akinesia (Diagnostic Clinical Neuropsychology, Bigler, E. and Clement, P., Eds., 3rd Ed. 1997). These symptoms intensify as the disease progresses. In severe stages of IPD, following the onset of akinesia, even the simplest movements require a monumental degree of concentration and mental effort, often to the point of anguish (Textbook of Medical Physiology, Guyton, A. C. and Hall, J. E., Eds., 9th Ed., W. B. Saunders Company, Philadelphia, Pa., 1996). IPD is also characterized by a number of autonomic (Vainshtok, A. B., xe2x80x9cTreatment of Parkinsonism with delagil,xe2x80x9d (1972) Klin. Med (Mosk) 50(9):51-56) and non-motor symptoms including depression (Cummings, J. L., xe2x80x9cDepression and Parkinson""s Disease: A Review,xe2x80x9d (1992) Am. J. Psychiatry 149(4):443-454) and frontal lobe dysfunction (Gotham, A. M. et al., xe2x80x9cLevodopa treatment may benefit or impair xe2x80x98frontalxe2x80x99 function in Parkinson""s disease,xe2x80x9d (1986) Lancet 25;2(8513):970-971).
In the United States, it is estimated that 5-24 in every 100,000 people suffer from IPD, with the majority of low income cases going undiagnosed (Chrischilles, E. A. et al., xe2x80x9cThe health burdens of Parkinson""s disease,xe2x80x9d (1998) Movement Disorders 13(3):406-413 ). In 1995, the World Health Organization conducted a global epidemiological evaluation of the incidence of IPD, showing a worldwide incidence of 5.32 per 100,000 people with an astounding incidence rate of 49.33 per 100,000 people over the age of 65 (M. Privett, WHO). Although more recent epidemiological figures are unavailable, in 1996 with the world population being approximately 5.7 billion, an estimated 2.8 million people had a confirmed diagnosis of IPD.
Current pharmacological treatments for IPD and other Parkinsonian-like motor disorders include anticholinergic agents, catechol-o-methyltransferase inhibitors and dopaminergic agents (Physicians"" Desk Reference, 2000, 54th Ed., Medical Economics Company, Inc., Montvale, N.J.). Since the late sixties, dopamine precursor L-DOPA, has been employed for the symptomatic relief of IPD motor dysfunction (Mena, M. A. et al., xe2x80x9cPharmacokinetics of L-DOPA in patients with Parkinson""s disease,xe2x80x9d (1986) Advances in Neurology 45:481-486). However, following long term use of L-DOPA (generally 5-8 years), diminished therapeutic efficacy is observed in approximately 50% of IPD patients (Roos, R. A. et al., xe2x80x9cResponse fluctuations in Parkinson""s disease,xe2x80x9d (1990) Neurology 40(9): 1344-1346). A wearing off of L-DOPA efficacy precedes the development of serious motor side effects such as on/off motor oscillations and dyskinesias (Carlsson, Arvid, xe2x80x9cDevelopment of new pharmacological approaches in Parkinson""s disease,xe2x80x9d (1986) Advances in Neurology 45:513-518). Further, when medications are increased to compensate for the development of these new motor dysfunctions, more serious side effects are generally observed, including psychiatric complications, while producing only minimal therapeutic benefit (Stoof, J. C. et al., xe2x80x9cLeads for the development of neuroprotective treatment in Parkinson""s disease and imaging methods for estimating treatment efficacy,xe2x80x9d (1999) Eur. J. Pharmacol. 375(1-3):75-86).
Deprenyl, a monoamine oxidase (MAO) B inhibitor, was the first drug suggested to provide causal treatment of Parkinson""s Disease by alleviating symptoms and attenuating the progression of the illness (Mytilineou, C. et al., xe2x80x9cL-(xe2x88x92)-desmethylselegiline, a metabolite of selegiline [L-(xe2x88x92)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro,xe2x80x9d (1997) J. Neurochemistry 68(1):434-436). However, there remains much controversy regarding the therapeutic efficacy of Deprenyl. While some physicians prefer to prescribe Deprenyl when patients first present with symptoms of Parkinson""s Disease (Goldstein, M. and Lieberman, A., xe2x80x9cThe role of the regulatory enzymes of catecholamine synthesis in Parkinson""s disease,xe2x80x9d (1992) Neurology 42(S4):8-12), other physicians dispute claims of neural protection (Olanow, C. W. and Calne, D., xe2x80x9cDoes selegiline monotherapy in Parkinson""s disease act by symptomatic or protective mechanisms?xe2x80x9d (1992) Neurology 42(S4):13-26).
Poewe and Wenning (Poewe, W. H. and Wenning, G. K., xe2x80x9cThe natural history of Parkinson""s disease,xe2x80x9d (1998) Annals of Neurology 44(S1):S1-S9) reviewed several longitudinal studies which evaluated Parkinson""s Disease medications. The Parkinson""s Research Group of the United Kingdom found that when Deprenyl was co-administered with L-DOPA, a 60% increase in patient mortality was observed, compared to the group being treated with L-DOPA only. Deprenyl is now rarely prescribed by European physicians for the treatment of IPD. In contrast, American researchers determined that Deprenyl is capable of delaying the need to commence L-DOPA treatment for a period of up to nine months. However, no neural protection was found in two-year patient follow-up examinations (Poewe and Wenning, 1998, supra). In Parkinson""s Disease the average lifespan is 9.4 years following an initial diagnosis. Further, the onset of gait disorders is closely associated with mortality rate. To be superior to current causal treatments (i.exe2x80x94Deprenyl), a pharmacological treatment must: a) prolong the need to commence L-DOPA for more than nine months; b) retain efficacy beyond a two-year period; and, c) prevent, delay, or otherwise alleviate gait disorders.
Up to 20% of the people initially diagnosed with IPD, actually suffer from atypical IPD (APD), striatonigral degeneration (SND), or multiple symptom atrophy (MSA) (Antonini, A. et al., xe2x80x9cDifferential diagnosis of Parkinsonism with [18F]Fluorodeoxyglucose and PET,xe2x80x9d (1998) Movement Disorders 13(2):268-274). Little or no response to conventional Parkinson""s Disease drug therapy is usually the differentiating factor between a diagnosis of APD, SND and MSA as opposed to IPD (Dethy, S. et al., xe2x80x9cAsymmetry of basal ganglia glucose metabolism and dopa responsiveness in Parkinsonism,xe2x80x9d (1998) Movement Disorders 13(2):275-280). Often, little can be done for people suffering these atypical afflictions. Therefore, it would be of great benefit if a pharmacological means were identified that could alleviate symptoms of atypical Parkinson""s Disease, as well as IPD.
The exact cause or causes of IPD are still unknown. Nonetheless, scientists have discovered a multitude of pathological abnormalities in the Parkinsonian brain. These findings include but are not limited to: a) toxic metabolite formation during neuromelanin (NM) synthesis (Graham, D. G., xe2x80x9cAutoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitroxe2x80x9d (1978) Molecular Pharmacology 14:644-653); b) heightened affinity of endogenous and exogenous toxins for NM (Tipton, K. F. and Singer, T. P., xe2x80x9cAdvances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds,xe2x80x9d (1993) J. Neurochem. 61(4):1191-1206); c) mitochondrial impairment (Mizuno, Y. et al., xe2x80x9cMitochondrial dysfunction in Parkinson""s disease,xe2x80x9d (1998) Annals of Neurology 44(S1):S99-S109); d) increased oxidative stress potentiated by reduced levels of antioxidants (Merad-Boudia, M. et al., xe2x80x9cMitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson""s disease,xe2x80x9d (1998) Biochem. Pharmacology 56:645-655); e) protein oxidation and lipid peroxidation (Jenner, P. et al., xe2x80x9cUnderstanding cell death in Parkinson""s disease,xe2x80x9d (1998) Annals of Neurology 44(1):S72-S84); f) augmented iron content and abnormal Fe(II)/Fe(III) ratios (Riederer, P. et al., xe2x80x9cTransition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains,xe2x80x9d (1989) J. Neurochemistry 52(2):515-520); and g) the accumulation of extracellular protein peptide fragments (Loo, D. T. et al., xe2x80x9cApoptosis is induced by xcex2-amyloid in cultured central nervous system neurons,xe2x80x9d (1993) Proc. Natl. Acad. Sci. USA 90:7951-7955). An example of these extracellular amyloid peptide fragments are the non-Axcex2 components in Lewy bodies (Culvenor, J. G. et al., xe2x80x9cNon-Axcex2 component of Alzheimer""s disease amyloid (NAC) revisited,xe2x80x9d (1999) Am. J. Pathology 155:1173-1181) which trigger an apoptotic cascade. Taken individually, these pathological findings would not pose a tremendous cellular threat. Collectively and occurring simultaneously, they serve to progressively annihilate the melanized catecholamine neurons residing in the mesencephalon, ultimately producing the classic signs of Parkinson""s Disease.
Chloroquine Compounds
Chloroquine [7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline] (The Merck Index, p. 2220, 1996) is a synthetically manufactured anti-malarial containing the quinoline nucleus. Chloroquine was developed over fifty years ago. It continues to be the most widely employed drug for the treatment of the asexual erythrocytic form of P. falciparum (Deepalakshmi, P. D. et al., xe2x80x9cEffect of chloroquine on rat liver mitochondria,xe2x80x9d (1994) Indian J. Exp. Biology 32(11):797-799). Unfortunately, due to widespread use of chloroquine, treatment resistant stains of malaria, first reported in 1961, continue to emerge globally, making the use of chloroquine obsolete in many regions (Bitonti, A. J. et al., xe2x80x9cReversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine,xe2x80x9d (1988) Science 241:1301-1303). A number of chloroquine derivates have been identified for antimalarial and other use. See U.S. Pat. Nos. 5,948,791, 5,834,505, 5,736,557, 5,639,737, 5,624,938, 5,596,002 and 4,421,920.
Due to the widespread use of chloroquine, a number of beneficial therapeutic properties and medicinal applications, outside of conventional malarial treatment, have been identified. Most of the following studies employed chloroquine phosphate.
Chloroquine phosphate is a potent inhibitor of acid chondromucoprotease present in cartilage and of cathepsin B1, a protease especially important in the initiation of proteolysis (De Duve, C. et al., xe2x80x9cLysosomotropic agents,xe2x80x9d (1974) Biochem. Pharm. 23:2495-2531). These properties have rendered chloroquine phosphate useful in the treatment of rheumatoid arthritis (Clinical Toxicology, supra, Section III, pp. 355-362). Further, chloroquine phosphate is known to reduce hypertension (Physician""s Desk Reference, pp. 2301-2302, 1996). Chloroquine phosphate and other 4-aminoquinoline compounds have been prescribed for the treatment of cardiac arrhythmia (Clinical Toxicology, supra, Section III, pp. 355-362). A version of antimalarial drug called Cardioquin(copyright) is produced by the Purdue Fredrick Company for the maintenance of sinus rhythm after conversions from atrial fibrillation (Physician""s Desk Reference, pp. 2521-2522, 2000). Chloroquine phosphate also targets malignant metastatic melanomas that generally bear an accumulation of melanin. The utilization of chloroquine phosphate for the treatment of these tumors is limited by the lack of accumulation in the amelanotic forms that readily manifest (Lindquist, N. G., xe2x80x9cAccumulation of drugs on melanin,xe2x80x9d (1973) Acta Radiol. Diag. (Stockholm) 325:1-92). A more recent application of chloroquine phosphate is to suppress the human immunodeficiency virus type 1 (HIV-1) replication in vivo within T-cells and monocytes (Sperber, K. et al., xe2x80x9cHydroxychloroquine treatment of patients with human immunodeficiency virus type 1,xe2x80x9d (1995) Clinical Therapeutics 17(4):622-636; Ornstein, M. H. and Sperber, K., xe2x80x9cThe anti-inflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis,xe2x80x9d (1996) Arthritis Rheum. 39(1):157-161).
The above medicinal applications of chloroquine phosphate are generally known to those practicing medicine in the USA. The following applications of chloroquine phosphate have been discovered and successfully employed by doctors throughout the world. Chloroquine phosphate has been used to treat renal disorders such as glomerulonephritis and amyloidosis, with observed improvement in renal function and attainment of various lengths of remission (Makarenko, I. E. and Levitsky, E. P., xe2x80x9cResoquin in the clinic of internal illnesses, and the possible side effects of its use,xe2x80x9d (1950). A randomized trial of the prolonged use of chloroquine phosphate to treat advanced pulmonary sarcoidosis, suggests that patients responded better to chloroquine phosphate and withstood medication side effects better than with conventional corticosteroids (Baltzan, M. et al., xe2x80x9cRandomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis,xe2x80x9d (1999) Am. J. Respir. Crit. Care Med. 160:192-197). Conditions of acute hypertension can benefit from the administration of chloroquine phosphate, which acts as a vasodilator without depressing cardiac contractibility (Abiose, A. K. et al., xe2x80x9cChloroquine-induced venodilation in human hand veins,xe2x80x9d (1997) Clin. Pharm. and Therapeutics 61(6):677-683). Chloroquine phosphate inhibits lysosomal proteolysis in vitro, and has been suggested to be a useful agent in counteracting protein wasting observed in several catabolic diseases (De Feo, P. et al., xe2x80x9cChloroquine reduces whole body proteolysis in humans,xe2x80x9d (1994) Am. J. Physiology 267:E183-E186). Chloroquine phosphate inhibits the biological availability of iron and has been suggested as advantageous for the treatment of iron-loading disorders (Legssyer, R. et al., xe2x80x9cEffect of chronic chloroquine administration on iron loading in the liver and reticuloendothelial system and on oxidative responses by the alveolar macrophages,xe2x80x9d (1999) Biochem. Pharmacology 57(8):907-91 1). Several case histories have been published regarding the efficacy in administering chloroquine phosphate to infants suffering from desquamative interstitial pneumonitis who presented with failure to thrive, tachypnea and hypoxia (Springer, C. et al., xe2x80x9cChloroquine treatment in desquamative interstitial pneumonia,xe2x80x9d (1987) Archives of Disease in Childhood 62:7677), and were non-respondent to steroids (Leahy, F. et al., xe2x80x9cDesquamative interstitial pneumonia responsive to chloroquine,xe2x80x9d (1985) Clinical Pediatrics 24(4):230-232).
Further recognized, but non-FDA approved, uses of chloroquine phosphate include treatments for: cholera, idiopathic pulmonary hemosiderosis, lupus erythematosus, lymphoid interstitial pneumonitis, onchocerca volvulus, porphyria cutanea tarda, m. sarcoidosis, and ulcerative colitis (MICROMEXEX(copyright), 2000, available: http//phamtom.uchsc.edu/mdxcgi/di). U.S. Pat. No. 5,430,039 suggests the use of chloroquine to inhibit neuronal cell death resulting from a calcium-related disorder of the central or peripheral nervous system, erroneously characterizing Parkinson""s Disease as such a disorder. Vainshtok, A. B., xe2x80x9cTreatment of Parkinsonism with delagil,xe2x80x9d (1972) Klin. Med (Mosk) 50(9):51-56, reports administration of Delagil, a chloroquine compound or analog (exact compound unknown) to a group of medication-free patients (dosage unknown) suffering symptoms related to Parkinson""s disease with moderate to dramatic response.
Enantiomers of Chloroquine
Chloroquine and hydroxychloroquine are racemic mixtures of (xe2x88x92)- and (+)-enantiomers. The (xe2x88x92)-enantiomers are also known as (R)-enantiomers (physical rotation) and 1-enantiomers (optical rotation). The (+)-enantiomers are also known as (S)-enantiomers (physical rotation) and r-enantiomers (optical rotation). The (+)-enantiomer metabolizes peripherally about eight times more rapidly than the (xe2x88x92)-enantiomer, producing toxic metabolites including de-ethyl chloroquine (Augustijins, P. and Verbeke, N. [1993] xe2x80x9cStereoselective pharmacokinetic properties of chloroquine and de-ethyl chloroquine in humans,xe2x80x9d Clinical Pharmacokinetics 24(3):259-69; Augustijins, P. et al. [1999], xe2x80x9cStereoselective de-ethylation of chloroquine in rat liver microsomes,xe2x80x9d Eur. J. Drug Metabolism and Pharmacokinetics 24(1):105-8; DuCharme, J. and Farinotti R. [1996], xe2x80x9cClinical pharmacokinetics and metabolism of chloroquine,xe2x80x9d Clinical Pharmacokinetics 31(4):257-74). Administering (+)-chloroquine may cause cardiac side effects due to toxic metabolite formation. The (xe2x88x92)-enantiomer has a longer half-life and lower clearance than the (+)-enantiomer (Ducharme, J. et al. (1995), xe2x80x9cEnantio-selective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects,xe2x80x9d British J. Clinical Pharmacology 40(2):127-33). The enantiomers of chloroquine and hydroxychloroquine may be prepared by procedures known to the art.
All publications referred to herein are incorporated by reference to the extent not inconsistent herewith.
This invention provides compositions and methods for increasing cellular respiration of melanized catecholamine neurons such as dopamine neurons in the substantia nigra, epinephrine and norepinephrine neurons, of protecting such neurons against oxidative degradation, and for treatment of Parkinson""s Disease, including both alleviation of symptoms and preventing onset or progression of symptoms. The compositions of this invention may be administered long-term. The compositions of this invention are also useful for preventing on-off syndrome, a condition in which L-Dopa and other dopamine agonists temporarily or permanently lose their ability to ameliorate the symptoms of Parkinson""s Disease after an initial period of effectiveness.
The term xe2x80x9cCQxe2x80x9d includes chloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline), chloroquine phosphate (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline phosphate, and hydroxychloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline), and mixtures thereof. Similarly, the terms (xe2x88x92)-chloroquine and (+)-chloroquine include (xe2x88x92)- and (+)-chloroquine phosphate and (xe2x88x92)- and (+)-hydroxychloroquine respectively.
Compositions useful for increasing cellular respiration of melanized catecholamine neurons, and/or alleviating, preventing or halting progress of Parkinson""s symptoms comprise neuromelanin-binding chloroquine analogs and derivatives containing a quinoline nucleus, preferably selected from the group consisting of:
7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline (chloroquine);
7-hydroxy-4-(4-diethylamino-1-methylbutylamino)quinoline; chloroquine phosphate;
7-chloro-4-(4-diethylamino-1-butylamino)quinoline (desmethylchloroquine);
7-hydroxy-4-(4-diethylamino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-diethylamino-1-butylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-diethylamino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-diethylamino-1-methylbutylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-diethylamino-1-methylbutylamino)quinoline;
7-chloro-4-(4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline (hydroxychloroquine);
7-hydroxy-4-(4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline; hydroxychloroquine phosphate;
7-chloro-4-(4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline (desmethylhydroxychloroquine);
7-hydroxy-4-(4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline;
8-[(4-aminopentyl)amino]-6-methoxydihydrochloride quinoline;
1-acetyl-1,2,3,4-tetrahydroquinoline; 8-[4-aminopentyl)amino]-6-methoxyquinoline dihydrochloride;
1-butyryl-1,2,3,4-tetrahydroquinoline; 7-chloro-2-(o-chlorostyryl)-4-[4-diethylamino-1-methylbutyl]aminoquiinoline phosphate;
3-chloro-4-(4-hydroxy-xcex1,xcex1xe2x80x2-bis(2-methyl-1-pyrrolidinyl)-2,5-xylidinoquinoline, 4-[(4-diethylamino)-1-methylbutyl)amino]-6-methoxyquinoline;
3,4-dihydro-1 (2H)-quinolinecarboxyaldehyde;
1,1xe2x80x2-pentamethylenediquinoleinium diiodide; and 8-quinolinol sulfate, enantiomers thereof, said compounds covalently linked or complexed or mixed with targeting agents, and mixtures thereof, as well as suitable pharmaceutical salts thereof. Chloroquine and hydroxychloroquine are preferred; (xe2x88x92)-enantiomers thereof are more preferred, and said compounds covalently linked or complexed or mixed with targeting agents are most preferred. Neuromelanin-binding compounds such as chlorpromazine and other antipsychotics which bind to dopamine receptors are not included within the scope of PD-effective neuromelanin-binding compounds of this invention. Any chloroquine analog or derivative known to the art and capable of binding neuromelanin may be useful in the methods of this invention.
Preferably the neuromelanin-binding compound is selected from the group consisting of compounds capable of crossing the blood-brain barrier in effective amounts. Such compounds include those which are more lipophilic, are capable of changing to effective chirality after crossing the blood-brain barrier, have side chain substituents which enhance compound transport via blood-brain barrier transporter mechanisms, or are complexed or covalently linked with antibodies or other targeting moieties, or administered in combination with other compounds facilitating their crossing the blood-brain barrier, as known to the art. The (xe2x88x92)-enantiomer of chloroquine (referred to herein as the active enantiomer) is preferred.
In a preferred embodiment, the compositions useful for increasing cellular respiration of melanized catecholamine neurons comprise an effective amount of a composition comprising (xe2x88x92)-CQ or (xe2x88x92)-CQ mixed, complexed or covalently linked with a targeting agent; an amount of (+)-CQ less than that of said (xe2x88x92)-CQ or (xe2x88x92)-CQ complexed or covalently linked with a targeting agent; and a suitable pharmaceutical carrier.
A targeting agent is a substance that when complexed with the CQ helps carry it across the blood brain barrier. Preferred targeting agents are lipophilic moieties known to the art which are attached to the active molecule at a position which does not interfere with the ability of the quinoline ring to bind to neuromelanin, and antibodies such as an antibody capable of binding to the transferrin receptor on brain capillary cells, e.g., as described in U.S. Pat. No. 6,015,555, incorporated herein by reference to the extent not inconsistent herewith.
Such compositions containing (xe2x88x92)-chloroquine may include anywhere from no (+)-CQ to about 49% (+)-CQ. An amount of (+)-CQ sufficient to bind to enzymes causing peripheral breakdown of CQ is preferred, leaving more of the (xe2x88x92)-CQ to cross the blood brain barrier where its therapeutic effect takes place. Preferably the compositions comprise between about 10% and about 20% (+)-CQ.
In one embodiment, a single adult dosage amount of said composition effective for increasing cellular respiration of melanized catecholamine neurons is provided, preferably less than an antimalarial single adult dosage amount, more preferably less than about 1 mM base equivalent, and most preferably less than about 0.5 mM base equivalents of CQ. As is known to the art, the term xe2x80x9cbase equivalentsxe2x80x9d refers to amount of active ingredient (e.g., in reference to chloroquine phosphate, refers to the chloroquine minus the phosphate and filler components). A single adult dosage amount with respect to use for alleviation, preventing or stopping progression of symptoms of Parkinson""s Disease or for other uses will be an amount effective when administered daily to provide the stated therapeutic effect.
Compositions of this invention may also comprise an effective amount of at least one adjuvant selected from the group consisting of antioxidants, retinal protective agents, other neural protective compounds, dopamine or dopamine agonists, and free radical deactivators. The antioxidant may be any antioxidant known to the art to prevent free radical formation and oxidative degradation of tissues and is preferably selected from the group consisting of probucol, pyncnogenol, Vitamin C, Vitamin E, superoxide dismutase, preferably synthetic, BHT, BHA, and melatonin. The retinal protective agent is preferably a composition administered locally to prevent binding of retinal melanin with the CQ, as is known to the art, e.g., alkanes and alcohols of C1-C4, and ginko biloba. The neural protective compound is any compound known to the art and preferably is selected from the group consisting of selegiline hydrochloride and other monoamine oxidase inhibitors. The dopamine agonist is any compound known to the art as an anti-Parkinson""s treatment and preferably is selected from the group consisting of L-DOPA, pramipexole, ropinerole, bromocriptine, tolcapone, and carbidopa. The free radical deactivator is any compound known to the art and preferably is selected from the group consisting of superoxide dismutase, selegiline, hydrochloride, and tolcapone.
This invention also provides kits comprising in close proximity, such as in a container or blister pack, effective dosage amounts and forms of the compositions of this invention for single doses, or doses per week, or other appropriate time period, preferably in combination with an adjuvant, such as an antioxidant, dopamine or dopamine agonist, or other adjuvant as discussed above suitable for co-administration with said composition, in effective dosage forms and amounts.
Suitable pharmaceutical carriers are known to the art and include carriers aiding in transport across the blood/brain barrier, such as nanoparticles onto which the compositions are absorbed, coated with a detergent, e.g., as described in Begley, D. J. (1996) xe2x80x9cThe blood-brain barrier: principles for targeting peptides and drugs to the central nervous system,xe2x80x9d J. Pharm. Pharmacol. 48(2):136-46, incorporated herein by reference to the extent not inconsistent herewith.
This invention also provides methods for increasing cellular respiration of melanized catecholamine neurons, and methods for alleviating symptoms or stopping appearance and/or progression of symptoms of Parkinson""s Disease, and methods for preventing symptoms of on-off syndrome associated with treatment with dopamine or a dopamine agonist of a patient suffering symptoms of a disease selected from the group consisting of idiopathic and atypical Parkinson""s disease, conditions characterized by nigrostriatal degeneration, multiple system atrophy, and vascular Parkinson""s Disease, said methods comprising administering to said patient an effective amount of the above composition of this invention. The methods are suitable for any mammal having such melanized neurons or symptoms of Parkinson""s Disease. Methods for treating or preventing symptoms of Parkinson""s Disease also comprise identifying patients having such symptoms or at risk of developing them.
Further provided are methods of making pharmaceutical compositions effective for increasing cellular respiration of melanized catecholamine neurons comprising: providing a compound or complex of this invention as described above, providing a suitable pharmaceutical carrier; and mixing said compound or complex and pharmaceutical carrier to form a composition effective to increase cellular respiration of melanized catecholamine neurons.
Instead of mixing (+)-CQ with (xe2x88x92)-CQ, the method of making the compositions of this invention comprising (xe2x88x92)-CQ may be practiced by starting with racemic chloroquine and removing an amount of (+)-CQ to leave a CQ composition effective to increase cellular respiration of melanized catecholamine neurons.
The term xe2x80x9cincreasing cellular respirationxe2x80x9d means measurably increasing oxygen consumption, increasing aerobic cellular respiration and reducing anaerobic cellular respiration, e.g., as measured by lactate in the cerebral spinal fluid.
The term xe2x80x9cdiminishing oxidative degradation of dopamine neurons in the substantia nigraxe2x80x9d means measurably diminishing such degradation as measured by assays known to the art, including measures of free iron ion availability and oxygenated radical formation.
The term xe2x80x9cParkinson""s Diseasexe2x80x9d as used herein includes idiopathic Parkinson""s Disease (IPD), atypical Parkinson""s Disease (APD), striatonigral degeneration (SND), multiple symptom atrophy (MSA), and vascular Parkinson""s Disease.
The term xe2x80x9calleviating symptoms of Parkinson""s Diseasexe2x80x9d means measurably reducing, inhibiting, attenuating and/or compensating for at least one symptom of Parkinson""s disease, such as tremor, postural imbalance, rigidity, bradykinesia, akinesia, gait disorders, and on/off fluctuations. These symptoms may result from toxic metabolite formation during neuromelanin (NM) synthesis, heightened affinity of endogenous and exogenous toxins for NM, mitochondrial impairment, increased oxidative stress potentiated by reduced levels of antioxidants, protein oxidation and lipid peroxidation, augmented iron content and abnormal Fe(II)/Fe(III) ratios, and the accumulation of extracellular protein peptide fragments, which conditions may also be alleviated by the compositions of this invention.
The compositions of this invention containing (xe2x88x92)-CQ should have more (xe2x88x92)-CQ or (xe2x88x92)-CQ mixed, complexed or covalently linked with a targeting agent than (+)-CQ because the toxic metabolites of (+)-CQ make it less suitable for long-term use, and the better melanin-binding properties of (xe2x88x92)-CQ, its longer half life, and lower clearance make it more effective for long-term administration (e.g. at least about six weeks, more preferably, about two years, and most preferably, at least about ten years or more).
An effective amount of the compositions of this invention is an amount necessary to produce a measurable effect. For example, an effective amount of the compositions of this invention to increase cellular respiration measurably increases cellular respiration by assays known to the art as discussed above. In compositions containing (xe2x88x92)-CQ, the effect may be produced by the (xe2x88x92)-CQ, or partially by the (xe2x88x92)CQ and partially by (+) CQ. Similarly, an effective amount of a composition of this invention to alleviate or stop the progression of symptoms of Parkinson""s Disease is an amount which does so based on art-known tests such as the Unified Parkinson""s Disease Rating Scale and the Tinetti Gait and Balance Assessment Tool, comparing symptoms of treated patients with symptoms of the same patients prior to and/or after treatment, or with symptoms of untreated patients at the same stage of Parkinson""s Disease.
Preventing symptoms of Parkinson""s Disease includes identifying patients at risk for developing such symptoms. Identification of patients susceptible to onset of Parkinson""s Disease may be done by genetic testing, prediction from family history or other means known to the art such as PET scans. When symptoms of Parkinson""s do not develop, or do not develop to the expected (average) degree, they are considered to have been prevented by the methods and compositions of this invention.
Preventing on-off symptoms in patients being treated with L-Dopa or like medications means measurably stopping or decreasing such symptoms as compared with patients at similar stages of Parkinson""s Disease being treated with such medications.
The compounds of this invention may formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular mixture employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily adult dosage of from about 0.5 to about 1000 mg, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Preferably a single daily adult dose comprises less than about 1 mM, and more preferably less than about 0.5 mM base equivalents, more preferably less than about 1 mM, and more preferably less than about 0.5 mM base equivalents.
The compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. In some cases it may be desirable to administer the compounds to the patient""s airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
xe2x80x9cSuitable pharmaceutical carriersxe2x80x9d as referred to herein include distilled and pharmaceutical grade water but do not include water or buffers unsuitable for administration to a human patient.
There are several mechanisms by which neuromelanin may contribute to symptoms of Parkinson""s disease by contributing to formation of toxic products including superoxide and hydroxy radicals, which catalyze lipid peroxidation, and oxidation of NADH resulting in disruption of the neuron""s respiration and reducing the amount of energy available to the neurons via aerobic respiration.
Neuromelanin can be considered a waste product of catecholamine degradation and gradually accumulates within the cytosol of catecholamine neurons throughout one""s lifetime. Dopamine is autoxidized to cytotoxic and reactive oxygenated species such as 6-hydroxydopamine (6-OHDA) and semiquinone radicals. Low glutathione levels contribute to oxidative stress in Parkinson""s disease, and allow available hydrogen peroxide to be further catalyzed by iron into highly toxic superoxide radicals and hydroxyl radical species as well as semiquinone radicals. Dopamine and L-DOPA interaction with superoxide radicals augments depletion of glutathione, leading to a downward spiral of detrimental reactions.
Monoamine oxidase forms toxic metabolites from a number of substances such as beta-carboline derivatives and tetrahydroisoquinoline which are present in excessive amounts in the cerebral spinal fluid of people with Parkinson""s Disease. These toxic metabolites have high affinity to neuromelanin, and once bound may cause almost complete arrest of ATP production, resulting in impaired respiration, loss of energy available to the neurons and massive melanized cell loss which leads to symptoms of Parkinson""s Disease. Inhibitors of monoamine oxidase B such as Deprenyl prevent formation of these toxic metabolites. Iron also tends to bind to neuromelanin, resulting in a cascade of pathogenic reactions leading to neuronal death. Increasing iron concentrations in basal ganglia are observed with normal aging, and in patients with Parkinson""s Disease, iron is pathologically elevated with high ferric/ferrous ion ratios. The ferric ions contribute, with 6-OHDA, to the formation of harmful superoxide and hydroxyl radicals leading to lipid peroxidation and cell breakdown.
Iron chelators have been shown to reverse impaired mitochondrial respiration caused by 6-OHDA inhibition of NADH dehydrogenase. 6-OHDA catalyzes the release of iron from intracellular ferritin stores which in turn catalyzes lipid peroxidation. This toxic chain of events can be inhibited by superoxide dismutase. Both iron chelators and chloroquine phosphate have been found to limit the availability of free iron, so that it is not available to catalyze these toxic reactions.
The iron transporter protein, diferric transferrin, which delivers iron throughout the body also contributes to loss of energy available to the neurons by interfering with availability of reduced NADH. Chloroquine phosphate has been found to inhibit intracellular oxidation of NADH by melanin.
Chloroquine phosphate binds to neuromelanin and does not inhibit enzymatic synthesis of iron into biologically essential compounds. It not only prevents incorporation of iron into neurons, but also inhibits and release of iron from intracellular iron pools. In addition chloroquine phosphate has been found to heighten an astrocytic immune response against accumulation of extracellular protein deposits in the brain contributing to Alzheimer""s Disease.
The (xe2x88x92) isomer of chloroquine is an even more effective neuromelanin binders than racemic chloroquine because it breaks down less peripherally, has a longer half-life and lower clearance, and so is more available to cross the blood brain barrier, as well as having a stabilizing effect on DNA. It is therefore preferred for use in this invention.

Chloroquine derivatives for the treatment of Parkinson""s disease


Methods and systems for accessing target sites in breast and other tissues comprising catheters having hooks or other anchoring means at their distal ends. The positions of the catheters and tissue are determined using a light source, optionally using both infrared and visible light sources. Once accessed, drugs may be delivered through the catheter, or the catheter may be used to facilitate surgical intervention.

1. Field of the Invention
The present invention relates to invasive methods and devices which position and anchor single or multiple lumen catheters proximate to breast lesions under radiographic guidance in order to provide a conduit or conduits for reversible placement of devices such as an optical fiber or allow the delivery of medicament or drug solutions such as anesthetic to sites in breast tissue along the length of the catheter.
2. Background of the Invention
There is an abundance of published literature surrounding wire needle localization (WNL) and its use in breast biopsy. Specifically, WNL is a surgical technique frequently invoked by surgeons to biopsy lesions in the breast discovered as a result of mammography or other breast screening methods. Patients undergoing WNL are placed on a radiographic table usually located in the radiology suite. The breast is placed between two compression plates, arranged moveably in relation to one another, for fixing the breast there between. The compression plates have holes which permit the introduction of a biopsy needle under radiographic guidance into the breast and proximate to the breast lesion to be biopsied. Once the needle is placed in the desired position in the breast, a thin, stiff wire with a distal retaining hook is inserted through the lumen of the needle. As the wire emerges from the distal aspect of the needle, the distal hook of the wire engages the breast tissue proximate to the breast lesion. The needle is withdrawn leaving the hook wire proximate to the lesion. The position of the wire relative to the lesion is verified radiographically. Radiographic views of the wire in the breast are taken and brought to the operating room so as to allow the surgeon to plan the surgical biopsy procedure.
The patient is transferred to the operating room. After physically examining the breast and placement of the wire in the breast as well as the radiographs of the wire placement, the surgeon plans the surgical approach for the removal of the desired breast tissue specimen. The wire serves as a marker which can be palpated by the surgeon during surgery. Using a typical syringe and needle, local anesthetic is administered in and around the proposed surgical area. An incision is made and the surgeon dissects around the wire. During the dissection, the surgeon continuously palpates the location of the wire in order to orient the dissection and determine that amount of tissue to be harvested or biopsied. The surgical objective of the biopsy is to remove an adequate tissue sample such that the wire and the lesion are at the center of the sample surrounded by an adequate margin thickness of normal breast tissue.
In U.S. Pat. No. 5,782,771 entitled xe2x80x9cDual, Fused, and Grooved Optical Localization Fibers,xe2x80x9d Hussman discloses the use of an optical fiber or bundle of optical fibers with a hook fixed to the distal aspect of the optical fiber or fiber bundle. The optical fiber-hook assembly can be passed through the lumen of a needle. As the optical fiber-hook assembly exits the needle and enters the breast tissue, the hook engages the tissue thus anchoring the optical fiber-hook assembly within the breast tissue. The other end of the optic fiber or fiber bundle can be connected to a light source. Light traverses the length of the optical fiber and transilluminates breast tissue and exits at the distal end of the optical fiber. The optical fiber enables the surgeon to identify the tip of the optical fiber by the light which originates from a light source such as a 15 mW 635 nm red laser diode. The tip of the optical fiber can be detected with the eye (since the eye is sensitive to 635 nm) if the tissue overlying permits ample light transmission for the eye to detect. If the tip of the optical fiber is buried deep in breast tissue and not visible to the eye, then a probe fabricated from optical fiber is invasively inserted into the breast. When the probe tip is maneuvered to a location near the fiber tip emitting light, the probe tip captures lights departing from the fiber tip. Light is transmitted along the length of the probe and exits the probe and incident upon the eye. The eye may detect light emanating from the distal end of the prove if sufficient light is emitted by the optical tip and transmitted to the eye via the probe. The operating room lights may have to be dimmed in order to improve performance of the Hussman technique.
Optically, all biological tissues are considered composite structures consisting of a scattering medium imbibed with various molecular components which collectively absorb or scatter light at specific wavelengths, i.e. the body is a spectral filter that selectively scatters or absorbs electromagnetic energy as a function of wavelength. In the range of 200 nm to 1,500 nm, the amount of light absorbed or scattered by different molecules is dependent on the chemical and physical properties of the molecule. In the visible part of the electromagnetic spectrum (400 nm to 700 nm), absorption due to tissues and tissue components coupled with light loss caused by scattering results in varying transmissivity of visible light through tissue. In the infrared spectrum above 1,300 nm, water present in tissue acts as an effective absorber of infrared, again limiting the transmission of infrared wavelengths longer than 1,300 nm. However, in the infrared range of 700 to 1,300 nm, infrared light has a relatively high transmissivity compared to visible light. This window of transmissivity (a measure of light transmission) is due to the lack of molecular components that strongly absorb infrared between 700 nm and 1,300 nm.
Fontenot, in U.S. Pat. No. 5,423,321 entitled xe2x80x9cDetection of Anatomic Passages Using Infrared Emitting Fiber,xe2x80x9d describes a method and devices which take advantage of the body""s inherently high light transmissivity in the near infrared range (700 nm to 1,300 nm). U.S. Pat. No. 5,423,321 describes intraluminal infrared transillumination of natural passages in the body such as the ureter which is a duct connecting the kidney to the bladder. A ureteral catheter enters the body through natural passages, specifically the vaginal orifice first, then the lumen of the urethra, bladder, and into the lumen of the ureter with the aid of a cystoscope. A plastic fiberoptic light guide is fitted into the lumen of the ureteral catheter and coupled to an infrared laser diode. Infrared laser light transilluminating the ureter and overlying tissues is detected with either a video system sensitive to near infrared or a detector probe coupled to a photodetector that is also sensitive to infrared.
As previously discussed, Hussman, in U.S. Pat. No. 5,782,771, describes a novel method and device for anchoring an optical fiber in breast tissue. However, fixing anchoring devices to the tip of optical fibers can weaken or embrittle the fibers causing the fiber to break in tissue while residing in the body. Also, in U.S. Pat. No. 5,782,771, Hussman uses visible light to transilluminate tissue overlying the tip of the optical fiber. Visible light is strongly attenuated by tissues. Thus, to detect the fiber tip emitting visible light in breast tissue and overlying skin, Hussman invasively introduces a probe consisting of a fiber or fiber bundle. The probe is directed towards the fiber tip which is emitting light. Subsequently, light captured by the distal end of the fiberoptic probe travels the length of the probe and exits the opposite end. The human eye may detect the emitted light from the probe if the room lights are dimmed and adequate light is transmitted from the tip of the optical fiber emitting light to the eye through the probe. Hussman does not discuss or present methods or devices that would allow the following: (1) the use of non-invasive methods and devices to detect the fiber tip such as the use of infrared emission-detection techniques, (2) the use of a conduit or catheter that could be fixed or anchor in tissue which would facilitate the reversible placement of a fiberoptic light guide into the lumen of a catheter.
Also, as previously discussed, Fontenot in U.S. Pat. No. 5,423,321, uses a non-anchoring catheter that enters the body through natural passages. For example, to enter the ureter in a female, a cystoscope is introduced into the vagina and into the lumen of the urethra, bladder, and into the lumen of the ureter. The ureteral catheter is then placed in the ureter and the cystoscope retracted. Fontenot transilluminates the natural passage using an emitting fiber and an infrared light source. Detection of the passage is facilitated with a detector probe or video system, both of which are sensitive to infrared light since the human eye cannot detect near infrared. Fontenot does not discuss or present methods or devices that would allow the following: (1) placement of a catheter that is fixed or anchored to the tissue using devices such as a hook wire at the distal aspect of the catheter, (2) placement of the catheter under radiographic guidance, (3) an over the wire method used to guide the catheter to a desired location, and (4) the invasive placement of catheter into tissue or an organ that is not through a natural passage.
It is an object of this invention to invasively insert a catheter under radiographic guidance into the breast and proximate to a breast lesion that forms a conduit for reversible placement of devices such as an emitting fiber or allow medicament or drug solutions such as anesthetic solutions to be delivered to sites in breast tissue along the length of the catheter.
It is another object of the present invention to invasively insert a catheter using an over the wire method, such wire that has been previously placed under radiographic guidance, thus forming a conduit for the reversible placement of devices such as an emitting fiber or allow medicament or drug solutions such as anesthetic solutions to be deliver to sites in breast tissue along the length of the catheter.
In accordance with another embodiment, a catheter with a wire hook or balloon can be fabricated or attached to the distal aspect of the catheter which functions to retain or anchor the catheter in breast tissue.
In yet another embodiment, an emission-detection is used to detect the tip of the catheter in breast tissue or track the course of the catheter in breast tissue.
The present invention relates to invasive placement of single or multi-lumen catheters in the breast tissue under radiographic guidance for the purposes of providing at least: (1) a landmark within the breast and adjacent to a target breast lesion, (2) a conduit for devices such as an optical fiber, (3) a conduit for the delivery of solutions containing medicaments or drugs to site in the breast along the length of the catheter, and (4) a means for anchoring such catheter in breast tissue. More specifically, the present invention consists of a catheter that can be fixed or anchored in breast tissue and provide a conduit for reversibly placing devices such as fiberoptic light guide into a desired position in the lumen of the catheter. The catheter has a means for anchoring the distal end of the catheter and such catheter can be placed proximate to a breast lesion under radiographic guidance. Exemplary means for anchoring catheters include mechanical devices, such as a hook wire or, an expansible anchor (e.g. a mallecott structure), an inflatable balloon formed at the distal end of the catheter. In one embodiment, an over the wire method is used to place a catheter proximate to a breast lesion. To aid in breast dissection and orientation, a visible or infrared light emission-detection scheme is used to detect the tip of the catheter or the course of the catheter as it tracks through breast tissue and exits the breast is also embodied in the invention.


A centering flange for use in mating shafts. The centering flange including a body. The body having a pole extending from one end thereof. The centering flange also including a plurality of lobes extending from the body equidistantly arrange around a perimeter of the body. The centering flange also including a circumferential recess on the side of the body opposite the pole. The integrated centering flange is used for mating a propshaft of an automotive vehicle to a driveline module.

1. Technical Field
The present invention relates generally to a driveline for a vehicle, and more particularly to the mounting and centering of a propshaft with an axle module.
2. Background Art
Drivetrain systems for vehicles have been known for many years. The drivetrain system generally includes an engine, a transmission, and a front and rear differential connected by a propshaft. Halfshafts connect the wheels to the differentials in the typical drivetrain system. The four general drive train systems are front wheel drive, rear wheel drive, all-wheel drive, and four wheel drive.
Drivetrain systems are generally distinguished by the delivery of power to a different combination of drive wheels, i.e. front drive wheels, rear drive wheels, or some combination of both. In addition to delivering power to a particular combination of drive wheels, most drivetrain systems permit the driven wheels to rotate at different speeds. This allows the outside wheels to rotate faster then the inside wheels on a turn and the front wheels to rotate faster than the rear drive wheels during straight line speed. An all wheel drive vehicle generally will deliver power to both the front and rear axles at all times. During a slip condition at one wheel more torque will be delivered to the axle in the non slip condition until the drivetrain returns to an equilibrium state. Some prior art all-wheel drive systems monitor each wheel separately and send power to each depending on its current state as determined by numerous sensors. A four wheel drive system generally is primarily rear or front wheel drive and only delivers power to the secondary or xe2x80x9chang-onxe2x80x9d axle when necessary.
Usually with the hang on or all wheel drive vehicle drive train systems a propeller shaft or driveshaft is needed between the front axle and the rear axle of the vehicle. This creates many packaging and installation constraints that are imposed upon the propshaft. The installation of the propshaft into the vehicle at the manufacturing facility must be done in limited space and in a very short time frame. Prior art systems have used a propshaft that has a centering device that included an appendage extending from a rear and or front axle module. The centering appendage had to be aligned with a receiving notch on the propshaft or driveshaft being installed to the axle module. However, with the above identified packaging difficulties found underneath the frame of the vehicle, the propshaft is difficult to install because of the angle needed to align the appendage with the notch between the propshaft and the axle module. Furthermore, reduction of the required time frame to install the propshaft to the rear axle module and greater emphasis on the installation of the propshaft to the rear axle module being done in an accurate and complete manner, adds pressure to the installation process. There have been attempts to readjust or redesign the centering appendage and the propshaft but still the angle needed to mount the propshaft to the rear axle module is too great and there has become a need in the art for a new method of centering the propshaft to the rear axle module.
Therefore, there is a need in the art for a modified mounting system for a flexible driveline coupling that allows centering and installation in a limited installation space and time.
One object of the present invention is to provide an improved driveline system for a vehicle.
Yet another object of the present invention is to provide a new mounting method for a driveline propshaft.
Still a further object of the present invention is to provide a flexible coupling to mount an integrated centering flange thereto for use in mounting a propshaft to a vehicle driveline module.
Still another object of the present invention is to provide a means to mount a propshaft to a driveline module that requires less angle of attachment then prior art systems.
Still a further object of the present invention is to provide an integrated centering flange for use in mounting a propshaft to a driveline module that will reduce the time and effort of manufacturing.
It is still a further object of the present invention to provide a way of connecting a propshaft to a driveline module that will eliminate packaging difficulties of the vehicle.
To achieve the foregoing objects a centering flange for use in mating a shaft to a driveline module is disclosed. The centering flange includes a body, and an appendage extending from one end of the body. The centering flange also includes a plurality of lobes extending from the body equidistantly arranged around the perimeter of the body. The centering flange also includes a circumferential recess on a side of the body opposite the appendage. The centering flange is connected to a flexible coupling on one end thereof while the other end is connected to a housing flange connected to the driveline module.
One advantage of the present invention is that it provides an improved driveline module for a vehicle.
Another advantage of the present invention is that it provides an integrated centering flange for use in connecting a propshaft to a driveline module.
Still another advantage of the present invention is that it provides a method of installing the propshaft to the driveline module with a reduced angle of attachment.
Still another advantage of the present invention is that the integrated centering flange allows for a quicker installation period thus increasing manufacturing productivity.
Yet another advantage of the present invention is that the integrated centering flange reduces the packaging necessary for the driveline module and the propshaft within the driveline space.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims, taken in conjunction with the accompany drawings.

Mounting system for a flexible driveline coupling


Breathing aid comprising a tube (4) which forms a main channel (5) and which is intended to be connected by its distal end (3) to a breathing tract of a patient so that the main channel (5) connects the breathing system of the patient to the outside. The breathing aid further comprising at least one auxiliary channel (8,8.1) for injecting a gas jet for ventilating the patient and opening into the main channel (5) close to the distal end (7) thereof. According to the invention this device is characterized in that at least the distal end of the auxiliary channel (8,8.1) opening into the main channel (5) is parallel thereto and in that, opposite the distal orifice (17) of the auxiliary channel (8,8.1), a face (14b) is provided for deflecting the breathable ventilation gas jet towards the inside of said main channel (5).

1. Field of the Invention
The present invention relates to a breathing aid which can be used on patients whose spontaneous respiration is absent or insufficient, whether they are under artificial respiration or not.
2. Description of Related Art
Different devices are known, such as masks, probes or oral, nasal, endotracheal, tracheotomic cannulae for providing the junction between the artificial respiration and/or anaesthetic appliance and the breathing system of a patient. Such devices, essentially in the form of tubes, depending on the case, may comprise immobilization means such as lugs or collars close to the proximal end for maintaining them on the mouth or nose of the patient, or else inflatable balloons close to the distal end for maintaining them in the trachea by friction.
Known devices have considerable drawbacks. Thus, for example, when a tube of known type is disconnected from the artificial breathing device and when the patient requires oxygen enriched air, it is necessary to introduce into said tube a probe connected to a source of oxygen. Furthermore, in the case of insufficient spontaneous respiration, the patient must necessarily remain connected to the breathing appliance until his spontaneous respiration is completely restored.
Thus, to overcome such drawbacks, breathing aids have already been proposed which, in addition to the main channel formed by the tube, comprise at least an auxiliary channel, formed for example in the wall of said tube, for injecting a breathable gas jet (oxygen, air or air-oxygen mixture) for ventilating the patient, this auxiliary channel opening into the main channel close to the distal end thereof.
However, such breathing aids with auxiliary breathable gas injection channels have the major drawback that said breathable gas jet strikes the mucous membrane directly, so that it is traumatized.


Separation directives for integrated circuit layout design data are formed based upon one or more printing feasibility analyses performed on the layout design data. At least one printing feasibility analysis is performed on layout design data to identify portions of the design that may not be correctly formed or “printed” during a photolithographic process. The geometric element edges involved in a potential printing defect are then identified as edges to be formed using separate masks. Further, separation directives may be created to specifically designate the identified edges as edges to be formed using separate masks in a photolithographic manufacturing process.

Electronic circuits, such as integrated microcircuits, are used in a variety of products, from automobiles to microwaves to personal computers. Designing and fabricating microcircuit devices typically involve many steps, known as a "design flow." The particular steps of a design flow often are dependent upon the type of microcircuit, its complexity, the design team, and the microcircuit fabricator or foundry that will manufacture the microcircuit. Typically, software and hardware "tools" verify the design at various stages of the design flow by running software simulators and/or hardware emulators, and errors in the design are corrected or the design is otherwise improved.
Several steps are common to most design flows. Initially, the specification for a new circuit is transformed into a logical design, sometimes referred to as a register transfer level (RTL) description of the circuit. With this logical design, the circuit is described in terms of both the exchange of signals between hardware registers and the logical operations that are performed on those signals. The logical design typically employs a Hardware Design Language (HDL), such as the Very high speed integrated circuit Hardware Design Language (VHDL). The logic of the circuit is then analyzed, to confirm that it will accurately perform the functions desired for the circuit. This analysis is sometimes referred to as "functional verification."
After the accuracy of the logical design is confirmed, it is converted into a device design by synthesis software. The device design, which is typically in the form of a schematic or netlist, describes the specific electronic devices (such as transistors, resistors, and capacitors) that will be used in the circuit, along with their interconnections. This device design generally corresponds to the level of representation displayed in conventional circuit diagrams. Preliminary timing estimates for portions of the circuit may be made at this stage, using an assumed characteristic speed for each device. In addition, the relationships between the electronic devices are analyzed, to confirm that the circuit described by the device design will correctly perform the desired functions. This analysis is sometimes referred to as "formal verification."
Once the relationships between circuit devices have been established, the design is again transformed, this time into a physical design that describes specific geometric elements. This type of design often is referred to as a "layout" design. The geometric elements, which typically are polygons, define the shapes that will be created in various materials to manufacture the circuit. Typically, a designer will select groups of geometric elements representing circuit device components (e.g., contacts, gates, etc.) and place them in a design area. These groups of geometric elements may be custom designed, selected from a library of previously-created designs, or some combination of both. Lines are then routed between the geometric elements, which will form the wiring used to interconnect the electronic devices. Layout tools (often referred to as "place and route" tools), such as Mentor Graphics' IC Station or Cadence's Virtuoso, are commonly used for both of these tasks.
With a layout design, each physical layer of the circuit will have a corresponding layer representation in the design, and the geometric elements described in a layer representation will define the relative locations of the circuit device components that will make up a circuit device. Thus, the geometric elements in the representation of an implant layer will define the regions where doping will occur, while the geometric elements in the representation of a metal layer will define the locations in a metal layer where conductive wires will be formed to connect the circuit devices. Typically, a designer will perform a number of analyses on the layout design. For example, the layout design may be analyzed to confirm that it accurately represents the circuit devices and their relationships as described in the device design. The layout design also may be analyzed to confirm that it complies with various design requirements, such as minimum spacings between geometric elements.
Still further, the layout design may be modified to implement one or more resolution enhancement techniques (RET). These implementation processes will modify the layout design data, to improve the usable resolution of the reticle or mask created from the design in a photolithographic manufacturing process. One such family of resolution enhancement technique (RET) implementation processes is sometimes referred to as optical proximity correction or optical process correction (OPC) processes. An OPC process may add features such as serifs or indentations to existing geometric elements in the layout design data, to compensate for diffractive effects that will occur during a lithographic manufacturing process. For example, an optical proximity correction process may modify a polygon in a layout design to include a "hammerhead" shape, in order to decrease rounding of the photolithographic image at the corners of the polygon.
After the layout design has been finalized, it is converted into a format that can be employed by a mask or reticle writing tool to create a mask or reticle for use in a photolithographic manufacturing process. Masks and reticles typically are made using tools that expose a blank reticle or mask substrate to an electron or laser beam (or to an array of electron beams or laser beams). Most mask writing tools are able to only "write" certain kinds of polygons, however, such as right triangles, rectangles or other trapezoids. Moreover, the sizes of the polygons are limited physically by the maximum beam (or beam array) size available to the tool. Accordingly, larger geometric elements in the layout design, or geometric elements that are not right triangles, rectangles or trapezoids (which typically are a majority of the geometric elements in a layout design) must be "fractured" into the smaller, more basic polygons that can be written by the mask or reticle writing tool. This process sometimes is referred to as "mask data preparation."
Once a layout design has been fractured into shots, then the fractured layout design data can be converted to a format compatible with the mask or reticle writing tool. Examples of such formats are MEBES, for raster scanning machines manufactured by ETEC, an Applied Materials Company, and various vector scan formats for Nuflare, JEOL, and Hitachi machines, such as VSB11 or VSB12. The written masks or reticles then can be used in a photolithographic process to expose selected areas of a wafer to light or other radiation in order to produce the desired integrated circuit devices on the wafer.
To meet the demand for more powerful microcircuits, designers have regularly increased the average density of devices in a conventional microcircuit. For example, the area that might once have contained 100 transistors may now be required to contain 1,000 or even 100,000 transistors. Some current microcircuit designs call for microcircuit devices to be packed so closely that it may be difficult to properly manufacture adjacent device components in a single lithographic process. For example, a current microcircuit design may specify a series of parallel conductive lines positioned so closely that a conventional mask writer cannot resolve the pitch between the lines.
To address this issue, the structures in a layer of a microcircuit device are now sometimes formed using two or more separate lithographic processes. This technique, referred to as "double patterning," partitions a layout design into two or more groups of geometric elements, each of which then is used to form a complementary lithographic mask pattern. Thus, if a layout design calls for as single geometric element having a series of closely-spaced parallel connective lines, this geometric element may be partitioned into multiple geometric elements so that adjacent lines are actually formed by different masks in separate lithographic processes. A "separation directive" may be employed to identify the geometric element edges that should be imaged by different masks. A separation directive may be, for example, a polygon (such as a rectangle) abutting both of the adjacent edges that will be formed by separate masks.
With some designs, like a series of closely-spaced parallel connective lines, it may be relatively easy to determine which edges should be formed by different masks. With other, more complex designs, however, it is often more difficult to determine which edges should be formed by different masks. For example, some designs may have geometric elements with substantial edges in two orthogonal directions (e.g., multiple geometrical elements with intermixed vertical and horizontal lines). With these more complex designs, it may be difficult to determine which pairs of edges should be formed using different masks.
To address this complexity, some separation techniques use specified rules to determine which edges in a layout design should be separately formed. For example, a rule-based separation technique may insert a separation directive between any two adjacent edges that are within a minimum distance of each other. Rule-based separation techniques are difficult to implement, however, because the rules must be developed on a case-by-case basis. This typically requires creating and manufacturing multiple circuit designs, identifying defects in the manufactured circuits, and then defining rules corresponding to the identified defects. Moreover, rule-based separation techniques can be prone to over-separate a circuit design (i.e., by separating edges that could, in fact, be formed using the same mask in a photolithographic process).

Forming separation directives using a printing feasibility analysis


Contrast and lightness measures are used to first classify the image as being one of non-turbid and turbid. If turbid, the original image is enhanced to generate a first enhanced image. If non-turbid, the original image is classified in terms of a merged contrast/lightness score based on the contrast and lightness measures. The non-turbid image is enhanced to generate a second enhanced image when a poor contrast/lightness score is associated therewith. When the second enhanced image has a poor contrast/lightness score associated therewith, this image is enhanced to generate a third enhanced image. A sharpness measure is computed for one image that is selected from (i) the non-turbid image, (ii) the first enhanced image, (iii) the second enhanced image when a good contrast/lightness score is associated therewith, and (iv) the third enhanced image. If the selected image is not-sharp, it is sharpened to generate a sharpened image. The final image is selected from the selected image and the sharpened image.

1. Field of the Invention
This invention relates to digital image processing. More specifically, the invention is a method for optimizing the visual quality of any digital image based on contrast, lightness and sharpness measures thereof.
2. Description of the Related Art
The image of a scene captured by imaging equipment is affected by the environments between the imaging equipment and the scene. For example, if the environment is a low-light environment, image features can be lost due to flow contrast and low lightness. If the environment is turbid (e.g., foggy, smoke, rain, snow, murky water, etc.), there is very little contrast in an image. The combination or low light and a turbid environment makes image feature detection even more difficult.
Conventional image processing approaches are typically designed to cope with one of these environments but not the effects caused by combinations of these environments. Further, conventional image processing approaches are either manual methods or passive automatic image enhancement methods that do not evaluate and adapt to visual qualities. The manual methods require significant operator training, are time consuming and expensive, and/or are inconvenient for some applications. Existing automatic methods include auto level enhancement, histogram enhancement, and retinex image processing as disclosed in U.S. Pat. Nos. 5,991,456, 6,834,125 and 6,842,543.
Auto level or "fixed gain" enhancement does not work with wide dynamic range images as saturation occurs. Histogram enhancement performance is unpredictable. Retinex image processing performs relatively well in terms of contrast and lightness enhancement across wide ranging imaging conditions. However, the effectiveness of retinex image processing is reduced for narrow dynamic range images generated in low-light or turbid environments. Finally, each of the automatic enhancement approaches operates on all images even when some images are visually acceptable. From a processing cost perspective, this is inefficient.

The United States of America as represented by the Administrator of the National Aeronautics and Space Administration