Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-13
2002-04-02
Seidel, Marianne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06365618
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to medicine and to the administration of pharmaceuticals to relieve disorders of the brain and behavior. More particularly, the present invention relates to the treatment of movement disorders, including tardive dyskinesia, tardive dystonia and tardive akathisia.
BACKGROUND OF THE INVENTION
Tardive dyskinesia (TD) is an involuntary movement disorder which includes athetosis and chorea. It is usually caused by medication which blocks dopamine receptors, including many ordinary antipsychotic medications and antiemetic (antinausea) medications. Rarely is it caused by antidepressant medications. The “tardive” designation indicates that this disorder appears after persistent rather than acute exposure to such medication, typically at least six months in adults or three months in elderly patients. Athetosis is a slow writhing, and chorea is an undirected twitching movement. Commonly affected muscles include the tongue, the muscles around the mouth, the jaw, the neck, and the limbs, and the most visible TD movements include chewing, tongue protrusion, truncal and arm twisting, grimacing, and torticollis. TD is the most common of several tardive disorders of involuntary movement which occur in patients who take medication which blocks dopamine receptors.
Tardive dystonia tends to occur in patients who have TD, and it is characterized by long-sustained positions of muscle groups. Not only are the causes and circumstances of tardive dystonia indistinguishable from those of TD, but in medical practice the occurrence, manifestation, and treatment of tardive dystonia is not reliably distinguished from those of TD. Consequently, what refers to one refers as well to the other.
One group of medications notorious for causing TD is antipsychotic medications. Long-term use of antipsychotic medication which blocks dopamine receptors is a frequent part of the management of patients who have schizophrenia, schizoaffective disorder, psychotic mood disorders, postpartum psychosis, delusional disorder, Huntington's Disease, agitated dementias, psychoses consequent to chronic medical conditions, borderline personality disorder, porphyria, or Tourette's syndrome. Based on a 0.9% population prevalence for schizophrenia, 1-2% for psychotic mood disorders, 2% for agitated dementias, and 2-5% for the other conditions noted we expect that several million people in the USA have had persistent exposure to antipsychotic medications. The prevalence of TD increases with increasing exposure to such medication. Surveys report the prevalence of TD in patients with schizophrenia taking such medication as 32% after 5 years, 57% after 15 years, and 68% after 25 years (Glazer et al. 1993). In view of the increasing prevalence with greater drug exposure, the consensus among psychiatrists has long been that medication which blocks dopamine receptors is the most common cause of TD and tardive dystonia in patients they treat. Besides the duration of exposure to antipsychotic medication, advancing age increases the risk of TD (Yassa et al 1983; Hunt & Silverstone 1991); some elderly patients show persistent dyskinesia after a few weeks of an antipsychotic medication.
Antiemetic (antinausea) medications can similarly cause TD, particularly those which have antipsychotic properties or block dopamine receptors. Extended use of antidopamergic antiemetic medication can be used in the management of patients who suffer from nausea or vomiting. Nausea or vomiting can result from circumstances such as radiotherapy or chemotherapy for cancer, vertigo, pregnancy, Meniere's disease, peptic ulcer disease, panic disorder, irritable bowel syndrome or other gastrointestinal condition, or brain tumor. Based on the common nature of these conditions we expect that several million people in the USA have had persistent exposure to antiemetic medication that blocks dopamine receptors. Risk that a medication causes TD and other movement disorders is associated with its dopamine-blocking activity, rather than the reason for its administration, whether as an antiemetic, antipsychotic, or antianxiety agent; many dopamine-blocking drugs are usable for all these effects. Patients who receive these medications for antiemetic effect experience movement disorders including TD, tardive dystonia, and tardive akathisia just as those who receive these medications for antipsychotic effect do. More rarely, tardive dyskinesia is caused by other types of medications, particularly several types of antidepressants such as amoxapine, trazodone, nefazodone, tricyclics, and serotonin-reuptake inhibitors (SSRIs). Lithium has also been reported to exacerbate or cause TD.
TD is graceless and stigmatizing, and can disable a patient psychologically as well as physically. Many TD movements resemble expressions of rudeness, and suggest loss of ability to control one's self. These include tongue protrusion, lip puckering, facial grimacing, grunting, limb stiffening, and pelvic thrusting. These disfiguring movements are often obvious to even casual passers-by. TD can provoke repugnance, particularly in children and people with little education. This naturally leads people with TD to avoid exposure to people who are not knowledgeable friends, and to minimize their exposure to public places. This can cause substantial impairment of employability, household management, self-care, social function, and recreational function. In turn this can diminish earnings abilities, life satisfaction, and productivity, and cause unhappiness and anxiety symptoms.
In addition, long-term exposure to antipsychotic medication or dopamine-blocking antiemetic medication can produce adverse mental status changes together with or in place of TD. Analogous to the physical expressions of TD, such mental status changes are also graceless, stigmatizing, and debilitating. These mental status changes can include tardive psychosis, whose symptoms and signs are indistinguishable from schizophrenia, and other tardive psychopathology such as obsessions, compulsions, and depression (Chouinard et al 1978, Swartz 1995). Long-term exposure to dopamine-blocking medication can also produce tardive akathisia, which is a feeling of restlessness (Van Putten and Marder 1987). When akathisia is strong it is often accompanied by agitated movements, such as fidgeting, pacing, and leg-bouncing while sitting; such movements often vary considerably over the day (Sachdev and Loneragan 1993).
Akathisia differs from dyskinesia. Generally, patients do not pay attention to dyskinesia movements unless the movements are severe enough to substantially interfere with performance of a task. In contrast, akathisia generally impairs the patient's attention, and sometimes interrupts attention and concentration. The movements of dyskinesia generally do not resemble any movements made by people who are not ill. In contrast, the movements which are sometimes made in association with akathisia are the same as made by people who are normal but worried, frustrated, or disappointed.
Physical limitations caused by TD include dysphonia (Khan et al 1994), respiratory distress (Wils 1992), dysphagia (Hayashi et al. 1997), and deformation of bearing and posture (Maeda et al 1998). Because TD is often irreversible, the difficulties, limitations, and disfigurements it produces can be permanent. Indeed, permanent movement disorders develop in animals after long-term exposure to haloperidol and other dopamine-blocking medication, e.g., in Cebus monkeys (Casey 1996).
Trials of treatment for TD to date have proven no benefit (Soares & McGrath 1999), and there are no safe and effective treatments for TD (Najib 1999; Glazer 1999). “No treatment strategy . . . is successful in most patients” (Egan et al. 1997). The only method that will generally diminish the symptoms of TD is to stop the medication that caused the TD and hope for a decrease in symptoms with time. Unfortunately, before the symptoms decrease there is often at least a temporary increase which can be difficult to endure.
Kwon Brian-yong
Seidel Marianne C.
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