Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-21
2002-12-10
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06492371
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to novel therapeutic methods for treating Parkinson's Disease by administering cyclic GMP-specific phosphodiesterase inhibitor compounds.
BACKGROUND OF THE INVENTION
Parkinson's Disease (PD) is a progressive degenerative disorder of the central nervous system (CNS) characterized by tremor and impaired muscular coordination. It is fatal if untreated. PD has been reported to affect approximately one percent of Americans over fifty years of age, but unrecognized early symptoms of the disease may be present in as many as ten percent of those over 60 years of age. The current prediction is that one to one and one-half million persons in the United States may be suffering from PD. The disease may appear at any age, but the risk of developing it increases with age. The occurrence of PD is therefore expected to increase in the next one-half century as the average age of individuals in developed countries progressively increases. For the United States, this phenomenon of population aging is predicted to result in a threefold to fourfold increase in PD frequency or several million persons afflicted with PD.
Like some other CNS degenerative disorders, PD begins insidiously. Persons close to the patient may notice the problem before the patient does. The patient's facial expression may appear depressed or apathetic (masked faces) and their voice may become softer in volume and monotonous in tone. The patient may complain of muscular weakness or stiffness. Involuntary movements, such as tremor or the turning in of a foot (dystonia) may become a problem. These symptoms may be noticed during routine activities or they may be present only at certain times such as when the patient is walking or writing. In the initial stages of PD, many patients do not have movement problems. instead, they may complain of anxiety and difficulty sleeping. However, signs of motor system dysfunction become apparent upon neurologic and physical examination.
The hallmark physical signs of PD are tremor, cogwheel rigidity and bradykinesia. Poor postural reflexes are sometimes included as the fourth hallmark sign. When postural reflexes are inadequate, patients may fall if they are pushed even slightly forward or backward, or if they are standing in a moving vehicle such as a bus or train. In PD, tremor typically occurs at rest but may also be present when the arms are raised (postural tremor). Cogwheel rigidity refers to increased tone that is felt by the examiner as a ratchet-like resistance during passive range of motion. Bradykinesia means slowed nonvolitional and/or volitional movements. The masked faces of PD are an example of slowed nonvolitional movement.
The mean duration of PD is about fourteen years. However, without treatment, the period between presentation of clinical features and death is reduced to about nine years. The rate of disease progression is believed to be directly correlated to the rate of neuron loss.
Symptomatic therapies are the most common form of treatment for PD. These remedies attempt to fulfill the basic dictate of traditional medicine, to relieve suffering. These drugs are designed to be used as either monotherapy or adjunctive symptomatic therapy but have little, if any, beneficial effects on underlying disease cause or pathogenesis. The symptomatic compounds can be divided into two groups on the basis of their pharmacologic action—dopaminergic drugs and nondopaminergic drugs.
Most symptomatic PD drugs attempt to replenish, mimic, or enhance the effects of brain dopamine, a neurotransmitter, because PD is thought to be due to defective dopaminergic transmission in the substantia nigra of the basal ganglia. Dopamine itself is neither well absorbed in the gastrointestinal tract nor effectively transported across the blood-brain barrier. L-dopa is dopamine precursor therapy. L-dopa crosses the blood-brain barrier penetrating into the brain, where it is converted to dopamine via the enzyme dopa decarboxylase. L-dopa has poor bioavailability and a short half-life when administered as monotherapy. Less than 1% of orally administered L-dopa penetrates into brain because of rapid peripheral metabolism by the enzymes dopa decarboxylase and catechol-O-methyl transferase (COMT). To improve its bioavailability, L-dopa is formulated with a decarboxylase inhibitor. In the United States, the decarboxylase inhibitor carbidopa is contained in virtually all L-dopa products prescribed during the last 20 years. For the past three decades, L-dopa has served as the mainstay of PD therapy. However, long term treatment with L-dopa often results in disabling complications. Many patients develop unsustained or unpredictable responses to L-dopa along with drug-induced involuntary movements. It has even been postulated by Mena, et al.,
Mov Disord
7:23 (1992), that L-dopa may be neurotoxic and thereby accelerates nigral neuronal degeneration.
Because of the disadvantages of long term L-dopa use, dopamine agonists have been developed for use as monotherapy in early PD to postpone the need to initiate L-dopa therapy and for use as adjunctive therapy later in the disease to permit reduction of L-dopa dosing or enhancement of beneficial dopaminergic effects. Agonists directly stimulate dopamine receptors within the brain, and thus their action is independent of L-dopa.
The first two dopaminergic agonists to be studied, apomorphine, Cotzias, et al.,
Trans Am Neurol Ass
97:156 (1972), and pirebedil, Vakil, et al.,
Advan Neurol
3:121 (1973) have since been abandoned because of adverse side effects. Bromocriptine is an ergot derivative, dopamine agonist that has been found to be effective for the treatment of PD as described by Calne, et al.,
Lancet
2:1355-1356 (1974). In 1997, three new dopamine agonists were added to the armamentarium against PD: carbergoline and two nonergoline drugs, pramipexole and ropinirole. Interest in the use of dopamine agonists for treatment of PD continues to be high and several other such agonists are currently being tested in clinical trials.
Blockade of other metabolic enzymatic pathways can also be used to enhance the effects of L-dopa or to maintain brain dopamine levels. One of the central metabolic pathways for dopamine is mediated via the enzyme monoamine oxidase type B (MAOB). Wessel, et al.,
Clin Invest
70:459 (1992) demonstrated that the drug selegiline inhibits MAOB and is approved in the United States as adjunctive antiparkinson therapy to be used in conjunction with L-dopa. Another MAOB inhibitor, lazabemide, was initially tested as adjunctive therapy in PD, but it is not being actively developed at this time. Hubble, J P,
Med Clinics of North America
83(2):525-536 (1999). The compound rasagiline also inhibits the oxidative monoamine metabolic enzymes. Rasagiline's effects in early untreated PD are being investigated. Hubble, supra.
Another enzymatic pathway involves cyclic nucleotide phosphodiesterases. Cyclic nucleotide phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide-dependent signal transduction processes. They terminate the action of the second messengers adenosine 3′,5′-cyclic monophosphate (CAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) by hydrolyzing them to their respective 5′-nucleoside monophosphates. Based on their biological properties, the PDEs may be classified into several general families. For example, Ca
2+
/calmodulin-stimulated PDE (Type I), cGMP-stimulated PDE (Type II), cGMP-inhibited PDE (Type III), cAMP-specific PDE (Type IV), cGMP-specific PDE (Type V), and cGMP-specific photoreceptor PDE (Type VI).
The combination of dopamine agonists with phosphodiesterase inhibitors was examined after it was discovered that the striatal dopaminergic receptor was closely associated with an adenylate cyclase. The actions of dopamine are mediated by an adenylate cyclase which produces cyclic AMP. Therefore, patients suffering from PD may be helped by the administration of a phosphodiesterase inhibitor which ob
Henley III Raymond
Marshall Gerstein & Borun
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