A method for treating the psychiatric disorders known as oppositional defiant disorder and conduct disorder is disclosed. The method comprises the administration of molindone or a pharmaceutically acceptable salt of molindone to a patient suffering from oppositional defiant disorder and/or conduct disorder. The molindone may be either a racemic mixture or the levorotatory form. It may be short acting or in a sustained release, long acting form.

Oppositional defiant disorder (ODD) and Conduct disorder (CD) are two of the most common psychiatric disorders affecting children and adolescents. Rates of ODD range from 2 to 16% depending on the nature of the population sample and methods of ascertainment. Rates of CD are in the same range. This translates into many millions of cases. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) characteristics of ODD include short temper, constant arguing with adults, defying rules, deliberately annoying others, blaming others for their own mistakes, being angry and resentful, spiteful and vindictive. In its severe form such children can be highly destructive to family life. Despite these characteristics no pharmaceutical companies market any medications specifically for ODD, and the majority of child psychiatrists feel it is largely a psychological disorder and make no effort to treat it medically.
The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) characteristics of CD are a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate norms or rules are violated, as manifested by the presence of three or more of a range of criteria for 12 months. These include aggression to people and animals (bullying, threatening, starting fights, using a weapon to cause harm, being cruel to animal or people, stealing, forcing others into sexual activity), destruction of property, fire setting, deceitfulness or theft (broken into homes or property, stealing things of value), and serious violation of rules (staying out over night when less than 13 years of age, running away from home, truant from school before age 13).
The instant invention is the finding that ODD and CD can be treated with the drug molindone (Moban) which is a short acting atypical antipsychotic. Molindone is a dihydroindolone neuroleptic which is structurally distinct from other classes of neuroleptics. It exhibits many similarities to other neuroleptics, including dopamine receptor blockade, antipsychotic efficacy, and extrapyramidal side effects, yet molindone has atypical properties such as inhibiting the enzyme monoamine oxidase. Molindone is generally used for the treatment of schizophrenia and other psychotic disorders. Studies have been published in which molindone was tested for treatment of schizophrenia, anxiety and depression, and conduct disorder.
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References.
Molindone, a neuroleptic drug generally used to treat schizophrenia and other psychotic disorders, has been tested on children diagnosed with oppositional defiant disorder and conduct disorder and has been found to be an effective, treatment. Use of a preferred dose of 1.25 to 10 mg every 4 hours eliminates the symptoms of ODD or CD with minimal or no side effects.
Oppositional Defiant Disorder
Oppositional Defiant Disorder is one of the most common psychiatric disorders affecting children and adolescents. Rates of ODD range from 2 to 16% depending on the nature of the populations sample and methods of ascertainment. The place of ODD in the classification system was controversial when first introduced by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, revised (DSM-III-R) (American Psychiatric Association 1987). According to Rey (1993), some authors questioned whether oppositional defiant disorder was sufficiently distinct from normal oppositional behavior to warrant its inclusion as a distinct diagnostic category (Rutter and Shaffer, 1980) while other authors argued that the criteria for ODD implied a milder form of conduct disorder (Werry et al., 1983; Werry et al., 1987). Despite this early controversy, ODD has become one of the diagnoses more commonly made in clinical setting and community samples (Rey, 1993).
Probably as a result of the original controversy concerning whether ODD was a distinct 15 diagnostic category, the concept of ODD underwent considerable changes. DSM-III introduced oppositional disorder in the category Disorders Usually First Evident in Infancy, Childhood or Adolescence to describe children who show a persistently disobedient, negativistic, and provocative opposition to authority figures, manifested by at least two of the following symptoms: 1) violations of minor rules, 2) temper tantrums, 3) argumentativeness, 4) provocative behavior, and 5) stubbornness. This diagnosis was placed under the heading Other Disorders of Infancy, Childhood and Adolescence, together with diagnoses such as schizoid disorder, elective mutism, and identity disorder (Rey, 1993). The International Classification of Diseases 9 (ICD-9 (World Health Organization)) did not contain a comparable diagnosis. Seven years later, DSM-I11-R changed the name to oppositional defiant disorder and placed it, together with conduct disorder and attention deficit hyperactivity disorder, under the heading Disruptive Behavior Disorders (Rey, 1993). The number of diagnostic criteria was increased to nine by the addition of 1) blames others for his or her own mistakes, 2) is touchy or easily annoyed, 3) is angry and resentful, 4) is spiteful or vindictive, and 5) swears, and by the removal of stubbornness; the remaining four criteria were reworded (e.g., temper tantrums became xe2x80x9coften loses temperxe2x80x9d) (Rey, 1993). Also, the number of criteria required for the diagnosis was increased to five. These modifications were designed to counter the criticism that ODD could not be distinguished from the behavior of many normal children and the changes were well received (Rey, 1993; Rutter, 1988). In both DSM-I11 and DSM-I11-R, a diagnosis of oppositional defiant disorder can be made only in the absence of conduct disorder (Rey, 1993).
The 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 5 came into use in 1994 (American Psychiatric Association, 1994). It defines the essential feature of ODD as a recurrent pattern of negativistic, defiant, disobedient, and hostile behavior toward authority figures that persists for at least 6 months (Criterion A) and is characterized by the frequent occurrence of at least four of the following behaviors: losing temper (Criterion Al), arguing with adults (Criterion A2), actively defying or refusing to comply with the requests or rules of adults (Criterion A3), deliberately doing things that will annoy other people (Criterion A4), blaming others for his or her own mistakes or misbehavior (Criterion AS), being touchy or easily annoyed by others (Criterion A6), being angry and resentful (Criterion A7), or being spiteful or vindictive (Criterion A8). To qualify for ODD, the behaviors must occur more frequently than is typically observed in individuals of comparable age and developmental level and must lead to significant impairment in social, academic, or occupational functioning (Criterion B). The diagnosis is not made if the disturbance in behavior occurs exclusively during the course of a Psychotic or Mood Disorder (Criterion C) or if criteria are met for Conduct Disorder or Antisocial Personality Disorder (in an individual over age 18 years) (DSM-IV, American Psychiatric Association, 1994) Although ODD includes some of the features observed in Conduct Disorder (e.g., disobedience and opposition to authority figures), it does not include the persistent pattern of the more serious forms of behavior in which either the basic rights of others or age-appropriate societal norms or rules are violated (DSM-IV, American Psychiatric Association, 1994). When the individual""s pattern of behavior meets the criteria for both Conduct Disorder and ODD, the diagnosis of Conduct Disorder takes precedence and ODD is not diagnosed (DSM-W, American Psychiatric Association, 1994). ICD-10 (World Health Organization, 1992) also includes a category of oppositional defiant disorder, defined by the presence of markedly defiant, disobedient, provocative behavior in the absence of severe dissocial or aggressive acts that violate the law or the rights of others. ICD-b conceptualizes oppositional defiant disorder as part of the dimension of conduct disorder (Rey, 1993). For the diagnosis of ODD, ICD-b requires that the child meet two of three criteria (frequent and marked lying, excessive fighting, and defiance of adult requests and commands) and not meet any of the other 12 criteria for conduct disorder (World Health Organization, 1990). Rey (1993) outlines the developmental patterns of both ODD and conduct disorder with the following being taken from the Rey (1993) publication. There is a substantial body of research showing that symptoms of oppositional defiant disorder typically appear during the preschool years, when they are considered normal (Rey, 1993). Temper tantrums reach their peak when children are 2-3 years of age (Goodenough, 1931; Shepherd et at., 1971). During the preschool years negativistic and oppositional behavior is common, resulting in angry outbursts and ensuing conflicts with parental authority about matters that vary with age, such as toilet training or possessions at age 2 and tidiness at age 5 (Rey, 1993). Destructiveness, bullying, and fighting decrease after the preschool years (Rutter and Oiler, 1983). Early adolescence is often associated with an increase in rebellious behavior (Looney and Oldham, 1989). Teachers"" reports indicate that most oppositional symptoms, such as arguing, screaming, disobedience, and defiance, peak between the ages of 8 and 11 years and then decline in frequency (Achenbach and Edelbrock, 1986). According to parents, swearing and argumentativeness become more prevalent during adolescence, particularly among girls (Achenbach, 1991). By contrast, most symptoms of conduct disorder (truancy, stealing, drug and alcohol use, etc.), with the exception of lying, do not occur during the preschool years but become increasingly frequent during late childhood and adolescence (Rutter and Giller, 1983; Looney and Oldham, 1989; Achenbach and Edelbrock, 1986; Achenbach, 1991; Loeber et at., 1991). Boys are significantly more aggressive than girls, but sex differences change with age: they are large in 4- to 5-year-olds, moderate in 9- to 12-year-olds, and small in college students (Cohn, 1991). Thus, developmental patterns of behavior in oppositional defiant disorder and conduct disorder appear to follow a different course (Lahey et at., 1992). This indicates that ODD and conduct disorder are in fact distinct from each other.
Several clinicians and researchers have expressed the belief that ODD is a mild form of conduct disorder (Rutter and Shaffer, 1980; Werry et at., 1987), but this issue has been reviewed (Loeber et al., 1991; Quay, 1986) with the authors of the reviews concluding that there is considerable agreement across factor analytical studies in the finding that symptoms of disruptive behavior consistently aggregate in two groupings: one consists of all oppositional defiant disorder behavior plus some symptoms of mild physical aggression, such as fighting and bullying, while the other consists of covert, nonaggressive conduct disorder behavior, such as stealing, truancy, and running away (Rey, 1993). This aggregation into two groupings further enforces the idea that ODD and conduct disorder are distinct from each other. Loeber et al. (1991) stated that the possible distinction between ODD and conduct 5 disorder (CD) can be conceptualized in at least three ways: (a) the diagnostic categories may be entirely distinct entities; (b) they may be more or less severe expressions of the same etiology, wherein some youths progress over time from the less severe symptoms (ODD) to the more severe symptoms (CD); or (c) ODD and CD may be largely distinct disorders with partially related etiologies. The authors addressed these alternative conceptualizations by reviewing evidence on patters of behavioral covariation, age of onset, the developmental course, correlates and risk factors, stability and predictability, seriousness ratings, and treatment implications (Loeber et al., 1991). The conclusions which were reached include the following: 1) in terms of behavioral covariation, much of the literature suggests that most symptoms of CD and ODD are distinct; 2) the mean age of onset for ODD symptoms is earlier than that for CD symptoms; 3) the familial correlates of ODD and CD are very similar in terms of history of antisocial behavior and family adversity, but youths with CD tend to show a larger number of these correlates than youths with ODD; 4) developmentally, ODD symptoms predict CD symptoms, in analogy with CD""s predicting antisocial personality; with the authors stating that in general, the various vantage points reviewed suggest that ODD and CD are different disorders although developmentally related (Loeber et al., 1991).
Rey (1993) discusses several more aspects of ODD including diagnosis, epidemiology, comorbidity, validity, etiology and treatment. The reliability of the diagnosis was found to depend upon the diagnostic criteria. A threshold of five criteria fulfilled had the best combination of sensitivity (80%) and specificity (79%), discriminating between patients with and without ODD (Rey, 1993; Spitzer et at., 1990). Studies of ODD in community samples based on the use of specified criteriaxe2x80x94mostly those of DSM-IIIxe2x80x94and standardized interviews show a prevalence of ODD between 1.7% and 9.9%, with a weighted average of 5.7%. Approximately one-third of all of the children with any disorder had a diagnosis of ODD (Rey, 1993; Anderson et al., 1987; Kashani et at., 1987; Cohen et al., 1987; Bird et at., 1988; McGee et al., 1990). Overall, ODD is diagnosed more often in boys than in girls although this depends on the age of the child, studies of children 12 years of age or younger showing a prevalence of ODD in boys double that seen in girls (Anderson et at., 1987; Cohen et al., 1987) while studies of adolescents (Kashani et al., 1987; Cohen et al., 1987; McGee et al., 1990) showed a higher prevalence of ODD in girls. These changes parallel those reported for aggressive behavior (Cohn, 1991). By comparison, conduct disorder was diagnosed more often in boys in all age groups in most studies (Rey, 1993). This difference is yet further confirmation of the distinction between ODD and conduct disorder.
Studies trying to assess the effect of age on ODD are contradictory with one study (Cohen et al., 1987) showing an increase of ODD with increased age while another (McGee et al., 1990) showed a decline. Another study (Pelham et al., 1992) reported a gradual increase in ODD with increasing age in a community sample. By contrast, there is little doubt that conduct disorder becomes more prevalent during adolescence (Rey, 1993). There is a high comorbidity between ODD and attention deficit hyperactivity disorder and also a high comorbidity between ODD and conduct disorder (Rey, 1993). Some overlap was seen between ODD and separation anxiety, generalized anxiety disorder and major depressive disorder and there appears to be an association between ODD and communication disorders (Rey, 1993). It is unresolved whether comorbidity between ODD and conduct disorder is higher than between ODD and other disorders. Having one psychiatric disorder increases the probability of having a second disorder (Caron and Rutter, 1991; Robins et al., 1991), therefore a specific association between oppositional defiant disorder and another disorder can be assumed only if comorbidity is significantly higher than that expected when another diagnosis is present. The diagnosis of ODD remains stable over time. Cantwell and Baker (1989) did a 4-year follow-up study of a group of children who had been diagnosed as suffering from DSM-III disorders and found that ODD, together with autism and attention deficit hyperactivity disorder, was one of the most stable diagnoses. ODD also showed the poorest recovery rate of all the behavioral psychiatric disorders (Rey, 1993). This underscores the need for an effective medication for persons diagnosed with ODD.
The stability of ODD was shown in two more studies. Cohen et at. (1991) showed that a diagnosis of ODD predicted a significant increase in the use of mental health services 2 years later. A follow-up study of children with attention deficit hyperactivity disorder into adolescence reported that most differences between children with attention deficit hyperactivity disorder and normal control subjects were attributable to the group with comorbid ODD at follow-up (Barkley et al., 1991). The degree of aggression in childhood predicted symptoms of ODD in adolescence, and these were very stable (Rey, 1993). These findings show that children with ODD do not necessarily develop conduct disorder when they grow older (Rey, 1993; Lahey et al., 1992; Cantwell and Baker, 1989). As of 1993, Rey (1993) reports that no study was identified that used medication for 5 children with ODD. Rey (1993) states that it is widely accepted that response to treatment of patients with conduct disorder is very poor, citing Kazdin (1987), and that if it were shown that children with ODD respond to specific treatments more consistently than those with conduct disorder then there would be even greater support that ODD and conduct disorder are different from each other. Loeber (1991) published an article contrasting ODD and conduct disorder. This reference states that symptoms of ODD can resemble normal problem behaviors, but the symptoms of ODD are distinguished from normal behavioral problems if they occur at a rate and intensity that is atypical for the child""s age group or persist through a later age than for most youngsters.
In contrast, symptoms of conduct disorder are usually considered undesirable at any period in a youngster""s life because they tend to result in personal harm or property loss or damage (Loeber, 1991). Symptoms of ODD consist of overt or conirontive problem behaviors, while most conduct disorder symptoms, such as theft and truancy, are of a covert, concealing nature (Loeber, 1991). Furthermore, the developmental course of ODD generally differs from that of conduct 20 disorder. Symptoms of ODD usually appear before the onset of the majority of conduct disorder symptoms whereas serious overt conduct disorder symptoms, such as rape and mugging, tend to emerge during late adolescence and early adulthood (Loeber, 1991). According to Loeber (1991), early onset of serious theft or substance use predicts a high persistence, variety, and seriousness of conduct problems later, but early onset does not appear to indicate persistence of ODD symptoms. Also, the prevalence of symptoms of the two disorders changes over time in an orderly fashion, with the prevalence of ODD in samples not referred for treatment decreasing with age whereas by contrast the prevalence of several conduct disorder symptoms increases from middle childhood onward and accelerates in adolescence (Loeber, 1991).
A study was performed recently to determine whether ODD is a precursor to conduct 30 disorder (Biederman et al., 1996). To perform the study, assessments from multiple domains were used to examine 140 children with attention-deficit hyperactivity disorder (ADHD) and 120 normal controls at baseline and 4 years later. It was seen that of all children who had ADHD at baseline, 65% had comorbid ODD and 22% had CD. Among those with ODD, 32% had comorbid CD. All but one child with CD also had ODD that preceded the onset of CD by several years. ODD plus CD children had more severe symptoms of ODD, more comorbid psychiatric disorders, lower Global Assessment of Functioning Scale scores, more bipolar disorder, and more abnormal Child Behavior Checklist clinical scale scores compared with ADHD children with non-CD ODD and those without ODD or CD. In addition, ODD without CD at baseline assessment in childhood did not increase the risk for CD at the 4-year follow-up, by midadolescence. The authors conclude that two subtypes of ODD associated with ADHD were identified: one that is prodromal to CD and another that is subsyndromal to CD but not likely to progress into CD in later years (Biederman et at., 1996).
Molindone
Molindone (3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4-(5H)-one) is a dihydroindolone neuroleptic which is structurally distinct from the other 15 classes of neuroleptics, and having the following structure:
The compound can be prepared in its racemic form or as the levorotatory enantiomer. Molindone can be prepared according to the procedures described in U.S. Pat. No. 3,491,093 and U.S. Pat. No. 4,065,453. Analogues of molindone which are dihydroindolones may also be administered according to the present invention for the treatment of oppositional defiant disorder and conduct disorder. Such analogues, especially those with longer-lasting effects than molindone, will be especially useful in treating persons with ODD.
Owen and Cole (1989) reviewed the laboratory and clinical findings of studies of molindone and found the following: 1) it exhibits many similarities to other neuroleptics, including dopamine receptor blockade, antipsychotic efficacy and extrapyramidal side effects; 2) it has atypical properties and inhibits the enzyme monoamine oxidase in vitro and in vivo; 3) it causes less dopainine receptor supersensitivity than other neuroleptics and thus may be less likely to cause tardive dyskinesia; 4) it appears to have a greater effect on mesolimbic and mesocortical dopamine neurons than on those in the nigrostriatal dopamine system; and 5) clinically it has a tendency to cause weight loss and may have less effect on seizure threshold than conventional antipsychotic agents.
The pharmacology of molindone in humans has been studied and reported in several 25 articles and summarized in Owen and Cole (1989) as set out in the following. Absorption of molindone is rapid after both oral and intramuscular administration, with maximal serum concentration occurring at approximately 1.1 and 0.6 hours, respectively (Owen and Cole, 1989; Zetin et at., 1985; Fann and Moreira, 1985). Molindone is less lipophilic than other neuroleptic agents and approximately 24% of molindone in plasma is not bound to protein, compared with 9% for haloperidol and 0.13% for chlorpromazine (Owen and Cole, 1989; Freedberg et al.,1979). Accordingly, the elimination half-life of molindone is approximately 2 hours, which is much shorter than the half-lives of traditional antipsychotic agents (Zetin et al., 1985; Wolf et al., 1985; Claghom, 1985). Even at steady state doses of 50 mg twice per day or 100-150 mg in a single daily dose, molindone concentrations are negligible at 12 hours after the last dose (Wolf et at., 1985; Zetin et al., 1985). Concomitant lithium therapy prolongs the half-life of molindone 5 at least fourfold (Wolf and Mosnaim, 1986).
Despite its short plasma half-life, the clinical duration of action of a therapeutic dose of molindone is at least 24 hours (Ayd, 1974). This has been attributed to the activity of molindone being mediated by an active metabolite (Koe, 1979; Meller and Friedman, 1982; Balsara et al., 1984; Wolf et al., 1985; Greengard, 1975). Molindone has been used to treat several illnesses. Owen and Cole (1989) summarize these studies. They state that more than 20 studies of the antipsychotic efficacy of molindone were performed in schizophrenic patients, with most studies showing minimal to moderate improvement in a majority of patients. In these studies, 2 mg of molindone appeared to be equivalent to 1 mg of trifluoperazine with respect to both antipsychotic efficacy and side effects (Owen and Cole, 1989). Intramuscular molindone has been shown to be as effective as intramuscular halopendol in the treatment of acutely psychotic or agitated patients (Owen and Cole, 1989; Binder etal., 1981; Smythies etal., 1982; Escobar et al., 1985). Owen and Cole (1989) also summarize studies testing the use of molindone to treat anxiety and depression. They cite two pilot studies which suggested that molindone may have some antianxiety effects although the differences between molindone and placebo did not reach statistical significance (Case et at., 1970; Keliner et al., 1972). Molin4one at a dosage of as little as 3 mg/day showed antianxiety effects in patients suffering from premenstrual tension (Shader and Harmatz, 1975). Two studies are cited by Owen and Cole (1989) relating to the use of molindone as an antidepressant. In a placebo-controlled trial using low-dose molindone (mean dose 14.5 mg/day), the patient showed some improvement in both anxiety and depression ratings, although the changes were not statistically significant (Goldstein and Brauzer, 1971). Molindone (10-30 mg/day) was compared with tranylcypromine in a single-blind parallel study of 19 patients with refractory depression and in which the patients had not responded to or had not tolerated tricyclic antidepressant agents (Small et al., 1981). Five of the 10 patients treated with molindone were described as showing definite improvement whereas only two of the tranylcypromine-treated patients were described as being definitely better (Small et al., 1981).
Studies have been performed with molindone being used to treat children and geriatric patients. Owen and Cole (1989) cite 3 studies involving children. These are a small pilot study showing molindone to be effective in treating schizophrenic children, ages 3-5 years (Campbell et al., 1971), an open trial with six patients (ages 6-11 years) diagnosed as having undersocialized conduct disorder, aggressive type, who showed some improvement in aggressive behavior and in the Nurses"" Global Assessment Scale (Greenhill Ct al., 1981), and a double-blind study comparing molindone with thioridazine in 31 children (ages 6-11 years) with undersocialized conduct disorder, aggressive type, this study reporting improvement in behavior ratings with both drugs and no significant differences in effectiveness between the drugs (Greenhill et al., 1985).
Molindone was shown to be both effective and well-tolerated in a sample of geriatric patients with a variety of psychiatric disorders, including dementia (Peper, 1985) with an average daily dose in the last week of the study of 100 mg, which is comparable to doses used in young adults (Owen and Cole, 1989).
Owen and Cole (1989) report just six published cases of tardive dyskinesia associated 15 with molindone treatment (Camp, 1977; Ananth and Carrillo, 1983; Cole et al., 1987). In these cases, although the movement disorder emerged during treatment with molindone in these cases, each patient had received at least one other antipsychotic agent at some time prior to receiving molindone (Owen and Cole, 1989). Thus, no case of tardive dyskinesia had been reported (as of 1989) in which molindone was the only possible causative agent (Owen and Cole, 1989). Molindone is associated with side effects similar to other antipsychotic agents. Owen and Cole (1989) report that extrapyramidal side effects have been reported in every study and include rigidity, tremor, and akathisia. Drowsiness was reported as a common side effect (Sugerman and Herrmann, 1967; Krumholz et al., 1970; Ab1177ahab, 1973), while dry mouth (Sugerman and Herrmann, 1967; Abuzzahab, 1973), blurred vision (Shelton et al., 1968; Abuzzahab, 1973), and 25 orthostatic hypotension (Shelton et al., 1968; Turek et al., 1970) appeared to be much less frequent. One side effect unique to molindone appears to be significant weight loss (Krumholz et al., 1970; Gallant et al., 1973; Freeman and Frederick, 1969; Clark et al., 1970; Escobar et al., 1985; Gardos and Cole, 1977), although one study found no difference between molindone and other neuroleptics and suggested that higher doses of molindone may cause weight gain (Parentet al., 1986).
Formulations Comprising the Active Ingredient
The compound of the present invention can be formulated into compositions comprising the compound together with a pharmaceutically suitable carrier. The carrier can be either a solid or liquid and the compositions can be in the form of tablets, liquid-filled capsules, dry-filled capsules, aqueous solutions, non-aqueous solutions, injectables, suppositories, syrups, suspensions and the like. The compositions can contain suitable preservatives and coloring and flavoring agents. Some examples of the carriers which can be used in the preparation of the products of this invention are gelatin capsules; sugars, such as lactose and sucrose; starches; dextrans; cellulosics, such as methyl cellulose, cellulose acetate phthalate; gelatin; talc; steric acid salts; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; liquid petrolateum; polyethylene glycol; glycerin, sorbitol; propylene glycol; ethanol; sodium metabisulfite, disodium ethylenediaminetetraacetic acid; agar; water; and isotonic saline.
Owen and role (1989) cite a few studies which reported mild to moderate euphoria in some patients taking molindone although the number of affected patients was small and has examples of the carriers which can be used in the preparation of the products of this invention are gelatin capsules; sugars, such as lactose and sucrose; starches; dextrans; cellulosics, such as methyl cellulose, cellulose acetate phthalate; gelatin; talc; stearic acid salts; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; liquid petrolateum; polyethylene glycol; glycerin, sorbitol; propylene glycol; ethanol; sodium metabisulfite, disodium ethylenediaminetetraacetic acid; agar; water; and isotonic saline.
In formulating the compounds, conventional practices and precautions are used. The composition intended for parenteral administration must be sterile either by using sterile ingredients and carrying out the production under aseptic conditions or by sterilizing the final composition by one of the usual procedures such as autoclaving under appropriate temperature and pressure conditions. Customary care should be exercised so that no incompatible conditions exist between the active components and the diluent preservative or flavoring agent, or in the conditions employed in preparation of the compositions.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, 15 sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either atone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA (ethylenediaminetetraacetic acid). In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Molindone can be prepared and administered in the form of a pharmaceutically acceptable salt, preferably an acid addition salt. It will be understood by the skilled reader that the compound used in the present invention is capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them.
Since the compound used in this invention is an amine, and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.
Suppositories contain the active ingredient in a suitable oleaginous or water-soluble base. The oleaginous class includes cocoa butter and fats with similar properties: the water-soluble class includes polyethylene glycols. Suitable pharmaceutical carriers are described in Remington""s Pharmaceutical Sciences, 5 E. W. Martin, a standard reference text in this field.
Molindone or its salt can be administered as treatment by any means that produces contact of the active agent with the agent""s site of action in the body. Molindone can be administered orally, parenterally, percutaneously, intravenously, intramuscularty, intranasally or rectally. It can be administered formulated as a cream or in a patch which slowly delivers the drug in a time-release fashion. Because molindone is a short-acting drug, it is preferred that it be administered in a long-acting form such as in a time-release capsule, a patch or sustained release formulations. Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The dosage administered will vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
When administering molindone, it is preferred that a low dosage is first administered and that the dosage is raised until an effect is seen. In this manner, the lowest effective dose can be used which will avoid or minimize any side effects. Although the reverse procedure of beginning a patient at a high dosage and lowering the dosage until side effects disappear or are minimized can also be used, it has been seen that after once experiencing side effects the patients are less likely to take the medication. Therefore the method of beginning a patient at a low dosage and increasing it until an effective dosage is reached is preferable to beginning at a high dosage and then lowering the dosage.
Typically the effective dose in a human patient is 50-150 mg/day, preferably 1.25 to 10 mg every four hours, especially 5-10 mg every four hours.
Use of Molindone to Treat Patients with Oppositional Defiant Disorder and Conduct Disorder
It has now been found that oppositional defiant disorder and conduct disorder can be effectively treated by the administration of molindone. More than 50 patients with ODD have been successfully treated with molindone with the usual therapeutic dose to be 1.25 to 10 mg every 4 hours. A number of recently marketed atypical antipsychotics such as risperidone (Risperdal) and olanzapine (Zyprexia) are also capable of effectively treating ODD (unpublished observations). However,unlike molindone, these drugs also antagonize serotonin 2 receptors. Their combination of a higher level of antagonism of dopamine receptors than molindone and antagonism of serotonin 2C receptors, makes them act like xe2x80x9canti-phen-fenxe2x80x9d the recently discontinued pair of diet medications. As such these two drugs are associated, especially in children, with an unacceptable level of weight gain, sometimes approaching a pound a day. The side effect is totally unacceptable to teenagers. Molindone rarely, if ever, causes weight gain. One side effect unique to molindone appears to be significant weight loss (Krxc3xcnuholz et al., 1970; Gallant et al., 1973; Freeman and Frederick, 1969; Clark et al., 1970; Escobar et. al., 1985; Gardos and Cole, 1977), although one study found no difference between molindone and other neuroleptics and suggested that higher doses of molindone may cause weight gain (Parent et al, 1986).

Use of molindone to treat oppositional defiant disorder and conduct disorder


A NOx, catalyst combination for treating a lean exhaust gas stream comprising an alkaline earth-alumina catalyst and an alkaline earth-zeolite catalyst, arranged on a substrate such that the gas stream first contacts the alkaline earth-alumina catalyst prior to contacting the alkaline earth-zeolite catalyst.

The present invention relates to a catalyst for purifying exhaust gases from an internal combustion engine. In particular, it relates to a lean NOx catalyst.
It is well known in the art to use catalyst compositions, including those commonly referred to as three-way conversion catalysts (xe2x80x9cTWC catalystsxe2x80x9d) to treat the exhaust gases of internal combustion engines. Such catalysts, containing precious metals like platinum, palladium, and rhodium, have been found both to successfully promote the oxidation of unburned hydrocarbons (HC) and carbon monoxide (CO) and to promote the reduction of nitrogen oxides (NOx) in exhaust gas, provided that the engine is operated around balanced stoichiometry for combustion (xe2x80x9ccombustion stoichiometryxe2x80x9d; i.e., between about 14.7 and 14.4 air/fuel (A/F) ratio).
However, fuel economy and global carbon dioxide (CO2) emissions have made it desirable to operate engines under lean-bum conditions, where the air-to-fuel ratio is somewhat greater than combustion stoichiometry to realize a benefit in fuel economy. Diesel and lean-burn gasoline engines generally operate under highly oxidizing conditions (i.e., using much more air than is necessary to burn the fuel), typically at air/fuel ratios greater than 14.7 and generally between 19 and 35. Under these highly lean conditions, typical three-way catalysts exhibit little activity toward NOx reduction, as their reduction activity is suppressed by the presence of excess oxygen.
The control of NOx emissions from vehicles is a worldwide environmental problem. Lean-burn, high air-to-fuel ratio, and diesel engines are certain to become more important in meeting the mandated fuel economy requirements of next-generation vehicles. Development of an effective and durable catalyst for controlling NOx emissions under net oxidizing conditions accordingly is critical.
Recently, copper-ion exchanged zeolite catalysts have been shown to be active for selective reduction of NOx by hydrocarbons in the presence of excess oxygen. Platinum-ion exchanged zeolite catalyst is also known to be active for NOx reduction by hydrocarbons under lean conditions. However, this catalytic activity is significant only in a narrow temperature range around the lightoff temperature of hydrocarbon oxidation. All the known lean-NOx catalysts reported in the literature tend to lose their catalytic activity for NOx reduction when the catalyst temperature reaches well above the lightoff temperature of hydrocarbon oxidation. This narrow temperature window of the lean-NOx catalysts is considered to be one of the major technical obstacles, because it makes practical application of these catalysts difficult for lean-burn gasoline or diesel engines. As an example, the Cu-zeolite catalysts deactivate irreversibly if a certain temperature is exceeded. Catalyst deactivation is accelerated by the presence of water vapor in the stream and water vapor suppresses the NO reduction activity even at lower temperatures. Also, sulfate formation at active catalyst sites and on catalyst support materials causes deactivation. Practical lean-NOx catalysts must overcome all three problems simultaneously before they can be considered for commercial use. In the case of sulfur poisoning, some gasoline can contain up to 1200 ppm of organo-sulfur compounds. Lean-NOx catalysts promote the conversion of such compounds to S02 and S03 during combustion. Such S02 will adsorb onto the precious metal sites at temperatures below 300xc2x0 C. and thereby inhibits the catalytic conversions of CO, CxHy(hydrocarbons) and NOx. At higher temperatures with an Al2O3 catalyst carrier, SO2 is converted to SO3 to form a large-volume, low-density material, Al2(SO4)3, that alters the catalyst surface area and leads to deactivation. In the prior art, the primary solution to this problem has been to use fuels with low sulfur contents.
Another alternative is to use catalysts that selectively reduce NOx in the presence of a co-reductant, e.g., selective catalytic reduction (SCR) using ammonia or urea as a co-reductant. Selective catalytic reduction is based on the reaction of NO with hydrocarbon species activated on the catalyst surface and the subsequent reduction of NOx to N2. More than fifty such SCR catalysts are conventionally known to exist. These include a wide assortment of catalysts, some containing base metals or precious metals that provide high activity. Unfortunately, just solving the problem of catalyst activity in an oxygen-rich environment is not enough for practical applications. Like most heterogeneous catalytic processes, the SCR process is susceptible to chemical and/or thermal deactivation. Many lean-NOx catalysts are too susceptible to high temperatures, water vapor and sulfur poisoning (from SOx).
Yet another viable alternative involves using co-existing hydrocarbons in the exhaust of mobile lean-burn gasoline engines as a co-reductant and is a more practical, cost-effective, and environmentally sound approach. The search for effective and durable non-selective catalytic reduction xe2x80x9cNSCRxe2x80x9d catalysts that work with hydrocarbon co-reductant in oxygen-rich environments is a high-priority issue in emissions control and the subject of intense investigations by automobile and catalyst companies, and universities, throughout the world.
A leading catalytic technology for removal of NOx from leanburn engine exhausts involves NOx storage reduction catalysis, commonly called the xe2x80x9clean-NOx trapxe2x80x9d. The lean-NOx trap technology can involve the catalytic oxidation of NO to NO2 by catalytic metal components effective for such oxidation, such as precious metals. However, in the lean NOx trap, the formation of NO2 is followed by the formation of a nitrate when the NO2 is adsorbed onto the catalyst surface. The NO2 is thus xe2x80x9ctrappedxe2x80x9d, i.e., stored, on the catalyst surface in the nitrate form and subsequently decomposed by periodically operating the system under stoiciometrically fuel-rich combustion conditions that effect a reduction of the released NOx (nitrate) to N2.
The lean-NOx-trap technology has been limited to use for low sulfur fuels because catalysts that are active for converting NO to NO2 are also active in converting SO2 to SO3. Lean NOx trap catalysts have shown serious deactivation in the presence of SOx because, under oxygen-rich conditions, SOx adsorbs more strongly on NO2 adsorption sites than NO2, and the adsorbed SOx does not desorb altogether even under fuel-rich conditions. Such presence of SO3 leads to the formation of sulfuric acid and sulfates that increase the particulates in the exhaust and poison the active sites on the catalyst. Attempts with limited success to solve such a problem have encompassed the use of selective SOx adsorbents upstream of lean NOx trap adsorbents. Furthermore, catalytic oxidation of NO to NO2 is limited in its temperature range. Oxidation of NO to NO2 by a conventional Pt-based catalyst maximizes at about 250xc2x0 C. and loses its efficiency below about 100 degrees and above about 400 degrees. Thus, the search continues in the development of systems that improve lean NOx trap technology with respect to temperature and sulfur considerations.
Another NOx removal technique comprises a non-thermal plasma gas treatment of NO to produce NO2 which is then combined with catalytic storage reduction treatment, e.g., a lean NOx trap, to enhance NOx reduction in oxygen-rich vehicle engine exhausts. In the lean NOx trap, the NO2 from the plasma treatment is adsorbed on a nitrate-forming material, such as an alkali material, and stored as a nitrate. An engine controller periodically runs a brief fuel-rich condition to provide hydrocarbons for a reaction that decomposes the stored nitrate into benign products such as N2. By using a plasma, the lean NOx trap catalyst can be implemented with known NOx adsorbers, and the catalyst may contain less or essentially no precious metals, such as Pt, Pd and Rh, for reduction of the nitrate to N2. Accordingly, an advantage is that a method for NOx emission reduction is provided that is inexpensive and reliable. The plasma-assisted lean NOx trap can allow the life of precious metal lean NOx trap catalysts to be extended for relatively inexpensive compliance to NOx emission reduction laws. Furthermore, not only does the plasma-assisted lean NOx trap process improve the activity, durability, and temperature window of lean NOx trap catalysts, but it allows the combustion of fuels containing relatively high sulfur contents with a concomitant reduction of NOx, particularly in an oxygen-rich vehicular environment. What is needed in the art is an exhaust gas catalyst system having improved durability, as well as effective NOx management, over extended operating time. The present invention overcomes many of the shortcomings of the prior art.
A NOx catalyst structure typically includes 2 parts: a matrix support and an active catalyst component. The matrix is the backbone that allows the gasses to flow easily through the entire catalyst bed. The matrix generally consists of large particles with large pores; the active catalysts generally are much smaller particles and have much smaller pore sizes.
Diesel engines and engines that are lean burn usually operate in the range of 150xc2x0 C. to about 350xc2x0 C. Barium alumina typically has NOx to N2 conversions of xcx9c40% at 300xc2x0 C., xcx9c80% at 350xc2x0 C. and xcx9c40% at 400xc2x0 C. Barium zeolite typically has NOx to N2 conversion of xcx9c40% at 175xc2x0 C., xcx9c70 at 250xc2x0 C. and xcx9c40% at 350xc2x0 C. As a vehicle warms to 150xc2x0 C., 100% of the N2 is formed on the barium zeolite. As the temperature increases to 250xc2x0 C., 60% of the N2 formed is on barium zeolite and 40% is on barium-alumina. As the temperature increases further to 350xc2x0 C., 80% of the N2 is formed on the barium-alumina and only 20% of the N2 is formed on the barium-zeolite.
Now, according to the present invention, a lean NOx catalyst is provided for use in a non-thermal plasma exhaust gas treatment system. The presently invented catalyst comprises a combination of an alkaline earth-zeolite catalyst with an alkaline earth-alumina catalyst.
The alumina catalyst preferably comprises coarse aluminum oxide particles are having an average size ranging from about 10 to about 30 microns. The zeolite catalyst preferably comprises zeolite particles having an average size ranging from about 0.1 to about 0.3 microns. In an admixture of the alumina catalyst and the zeolite catalyst, the fine zeolites tend to fill in the void spaces around the coarse alumina particles. The small zeolites particles are densely packed. Exhaust does not flow easily through the dense packed zeolites. The aluminum oxide particles are mostly porous. Gasses can easily pass through the aluminum oxide particles to reach the zeolite particles.
The aluminum oxide particles providing the admixture matrix generally comprise agglomerations of small psuedocrystalline alumina particles typically of about 0.3 microns or less. The agglomerations preferably are larger than about 10 microns and less than about 30 microns. The alumina matrix is mixed with a Ba-zeolite catalyst component, typically featuring a particulate size ranging from about 0.1 to about 0.3 microns. In general, the smaller the zeolite particle, the more hydrothermally stable the zeolite becomes, thereby improving its long term activity. Preferably, pursuant to the invention, the zeolite active catalysts are dispersed throughout the alumina matrix.
When the catalyst structure is disposed as an exhaust gas treatment catalyst, large gaseous molecular materials are enabled to enter the large pores of the alumina matrix without plugging the small pores of the zeolite catalyst. The large gaseous molecular materials are decomposed through action of the alumina matrix to small fractions, whereby the small fractions then are able to enter the micropores of the active zeolite catalysts. Large heteroatoms, such as sulfur and nitrogen, remain are adsorbed onto and remain on the reactive alumina matrix surface, such that the more active zeolite is not neutralized or poisoned by these heteroatoms and accordingly remains highly active. The matrix of alumina further is especially reactive to and can trap deposited metals such as nickel. Poisons will deposit on the first high surface area material that they are exposed to. SEM of engine aged catalysts show poison deposition throughout the large aluminum oxide particles. The zeolite particles show little poison deposition. This demonstrates that exhaust flows through the aluminum oxide before reaching the zeolite.
The above-described and other features and advantages of the present invention will be appreciated and understood by those skilled in the art from the following detailed description, and appended claims.
The catalyst of the present invention preferably comprises a barium alumina fraction in a proportion ranging from about 30 wt % to about 50 wt %, and a barium zeolite fraction in a proportion ranging from about 50 wt % to about 70 wt %. A particularly preferred admixture comprises a barium alumina fraction in a proportion ranging from about 35 wt % to about 45 wt %, and a barium zeolite fraction in a proportion ranging from about 55 wt % to about 65 wt %. Inclusion of an alkaline binder in the admixture is preferred to prevent agglomerated alumina particles being broken down into primary aggregates.
As described above, the aluminum oxide particles generally are agglomerates of about 0.3 micron or less aluminum oxide grains. If low pH aluminum compounds are used as binders, the aluminum oxide agglomerates tend to be broken down to the primary particles. If that happens, for example, a mixture of about 0.3 micron aluminum oxide and about 0.3 micron zeolite would result. The washcoat from such a mixture would be densely packed. This type of washcoat would be easily poisoned and diffusion limited at the surface.
Preferably, high pH aluminum compounds are used as binders. Using such binders, the aluminum oxide agglomerates appear stable and maintain their integrity as about 10 to 30 micron particles. A mixture, for example, of such 10-30 micron alumina particles and 0.3 micron particles provides a preferred washcoat. Accordingly, a binder comprising an alkaline aluminum, such as a barium aluminum hydroxide or an ammonium aluminum hydroxide is preferred. An ammonium aluminum hydroxide is particularly preferred. When calcined, it is preferred that the ammonium aluminum hydroxide should provide at least about 2 wt % of the washcoat mass. Inclusion of an ammonium aluminum hydroxide binder that provides at least about 4 wt % washcoat mass is more preferred, and about 6 wt % washcoat mass is particularly preferred.
Any alkaline earth element may be used as the active catalyst. For example, the active catalyst element may comprise calcium, strontium, and/or barium. The use of barium is particularly preferred. Tests have indicated that calcium-doped catalysts generally convert about 30% NOx to N2; strontium-doped catalysts generally convert about 50% NOx to N2; barium-doped catalysts generally convert about 70% NOx to N2. Based on a desire in the industry to optimize conversion of NOx to N2 at about 90% or better, barium is the particularly preferred occluding catalyst material.
Accordingly, Ba is the preferred occluding catalyst for both the zeolite and the alumina components of the present catalyst. The alumina matrix features enhanced trapping efficiency if it is doped with a material such as barium. In specific, nitrogen species can neutralize catalytically active sites. Barium is the most robust alkaline earth element for resistance to nitrogen poisoning. The alumina matrix provides sacrificial sites for nitrogen poisoning, thus precluding large polycyclic nitrogen compounds from entering and poisoning the small pores of the zeolite catalyst component.
The zeolite catalyst component preferably comprises a barium content of about 18 wt % to about 36 wt %; about 24 wt % to about 30 wt % is particularly preferred. Any type zeolite may be used; preferred zeolites include X type zeolite, Y type zeolite, and/or ZSM-5 type zeolite. A Y type zeolite is particularly preferred. A zeolite surface area of at least about 300 m2/gram is preferred, at least about 400 m2/g is more preferred, and a surface area of at least about 500 m2/g is particularly preferred. The preferred zeolite average particle size is less than about 0.9 microns; more preferred are zeolite particles of an average size less than about 0.6 microns; and particularly preferred are zeolites having an average particle size less than about 0.3 microns. The zeolite particles preferably feature average pore sizes ranging from about 4 to about 10 angstroms (xe2x80x9cAxe2x80x9d), with average pore sizes ranging from about 7 to 8. A particularly preferred. It is preferred to stabilize the zeolite catalyst with the inclusion of a rare earth element. Inclusion of a lanthanum oxide stabilizer is particularly preferred. Preferably, the zeolite has a silica to alumina ratio of at least about 2; a ratio of at least about 4 is more preferred; and, a ratio of at least about 7 is particularly preferred.
A ZSM-5 zeolite with pores of about 4 to 5 A is preferred and a lanthanum stabilized X zeolite is more preferred and a Y-type zeolite with pores of about 7 to 8 A is greatly preferred and a rare earth stabilized Y-type zeolite is especially preferred. Lanthanum oxide is the rare earth stabilizer of choice.
The alumina matrix catalyst component preferably has a barium content of at least about 14 wt %; at least about 21 wt % is more preferred; and, at least about 28 wt % is particularly preferred. Exhaust deposits of oil derived xe2x80x9cglassyxe2x80x9d compounds such as calcium phosphate and zinc phosphate can greatly reduce diffusion. High levels of alkaline earths, such as barium, prevent formation of these diffusion limiting barriers.
Preferably, the alumina has a surface area of at least about 150 m2/gram; a surface area of at least about 200 m2/g is more preferred; and, a surface area of at least about 250 m2/g is particularly preferred. An average alumina pore size of at least about 40 A is preferred; a pore size of at least about 60 A is more preferred; and, a pore size of at least about 80 A is particularly preferred. Specific acidity ranging from about 50 mmoles (millimoles) n-butylamine/m2xc3x9710xe2x88x924 to about 500 mmoles n-butylamine/m2xc3x9710xe2x88x924 is preferred; a specific acidity of about 350 mmoles n-butlyamine/m2xc3x9710xe2x88x924 is particularly preferred.
Suitable barium sources for preparation of a barium-alumina component include barium nitrate, barium acetate, barium hydroxide, barium ethoxide, barium isopropoxide, and/or barium 2-ethylhexanoate. Barium acetate, barium isopropoxide, and barium 2-ethylhexanoate are preferred. Barium 2-ethylhexanoate is particularly preferred.
Suitable aluminum sources are aluminum oxide, aluminum hydroxide (AIOOH) boehmite and pseudoboehmite, aluminum methoxide, aluminum n-butoxide, aluminum ethoxide, and/or aluminum isopropoxide. Aluminum isopropoxide, aluminum oxide, and aluminum hydroxide are preferred. Aluminum hydroxide is particularly preferred.
The surface acidity of the alumina may be increased by the addition of silica. Suitable silica stabilized aluminas include Condea Vista""s SIRAL 5 with 5 wt % silica, SIRAL 10 with 10 wt % silica, SIRAL 20 with 20 wt % silica, SIRAL 30 with 30 wt % silica, and/or SIRAL 40 with 40 wt % silica. SIRAL 30, SIRAL 20, and SIRAL 10 are preferred. SIRAL 10 is particularly preferred.
The alumina preferably includes additional doping ions, such as M+3 cations. Lanthanum, yttrium, and/or scandium are the preferred dopants; scandium is particularly preferred. A doping level of less than about 3 wt % is preferred; less than about 2 wt % is more preferred; and, about 1 wt % is particularly preferred. Suitable doping reagents include lanthanum 2-ethylhexanoate, yttrium 2-ethylhexanoate, and scandium 2ethylhexanoate.


An electro-surgical instrument for excision of a tissue specimen from the transformation zone of the uterine cervix includes an elongated body member with an endocervical portion at one end, a contact portion at the other end, and a vaginal portion therebetween. A stop arm extends at a right angle to the body member at the juncture of the endocervical and vaginal portions, and a wire electrode extends diagonally between the stop arm and endocervical portion. Preferably the stop arm has a laterally offset portion intermediate its length to enable observation of the electrode cutting action over most of its length. In using the instrument, the endocervical portion is inserted through the vaginal canal and into the endocervical canal of the uterine cervix until the electrode contacts an area of the ectocervix without colposcopically evident pathology. Current is imparted to the electrode and the instrument is advanced into the endocervical canal until the stop arm abuts the ectocervix, after which the instrument is rotated one full revolution to cut a conically shaped tissue specimen from the transformation zone of the uterine cervix which is withdrawn with the instrument.

The present invention relates to an electro-surgical excisor, and more particularly, to an electro-surgical excisor used for excising a tissue specimen from the transformation zone of the uterine cervix.
Cervical intraepithelial neoplasia has been on the increase in recent years, but successful ablation treatment has been provided by procedures such as electrocoagulation, electrodiathermy, cryosurgery, and laser surgery. With such procedures, it is important for the physician to recognize and biopsy invasive cancers to avoid their unintentional ablation.
Recently, biopsy specimens of this type of lesion has been successfully obtained by use of wire loop electrodes. Such electrodes allow the lesions and the transformation zone to be removed in their entirety and made available for a pathological analysis.
In using a loop electrode on the end of a handle, there is typically no guiding support during the excision. As a result, there is a risk of injury to the surrounding tissue which would result in a longer recovery period for the patient. Further, the amount of tissue obtained may vary in amount and definition, leading to difficulties in the pathological analysis.
It is an object of the present invention to provide a novel electro-surgical excisor which permits the complete severance of a controlled tissue specimen in a single revolution of the excisor.
It is also an object to provide such an electro-surgical excisor which minimizes the potential for injury to adjacent healthy tissue.
It is a further object to provide such an electro-surgical excisor which obtains a more defined and controlled amount of cervical tissue, making excision of the lesion and pathological interpretation easier.

Instrument for electro-surgical excisor for the transformation zone of the uterine cervix and method of using same


The invention relates to a transport device for welding wire feed for welding equipment, in particular arc sheild-gas welding tools on manipulators. The welding wire is transported from a magazine or reel with the aid of two separate drives. The main drive determines the feed and it is mounted near the application welding die, while the auxiliary is arranged spaced therebehind. The motor of the main drive is controlled to a constant speed corresponding to the selected feed, while the auxiliary drive acts on the welding wire with slip. The motor of the auxiliary drive is also controlled to a constant speed, the speed adjustment of the drives being, however, control-technologically connected for maintenance of a certain difference of the transport speeds.

The invention relates in general to welding and in particular to a new and useful transport device for welding wire feed at welding equipment, in particular arc shield-gas welding tools disposed as manipulators.
Welding equipment, in particular automatic welding machines or welding robots, have a disadvantage that, despite the diverse movements of the welding tool, the wire must be supplied to and emerge from the welding die or tip always at the same speed and with the same force. This is true in particular for arc shield-gas welding equipment. The welding die moves over a relatively long guide distance. In track welding, the welding die must often follow complicated paths in space, the welding wire guide being moved along. These changes of direction of the wire guide complicate the wire transport and lead to vibrations in the wire feed system even if the die moves fast. Due to these factors, the wire feed is no longer constant, and hence the welding quality suffers.
It is known for hand-held torches to use two mutually independent drives for the transport of the welding wire. The rear drive, arranged near the wire roll, then constitutes the main drive, which essentially determines the wire feed. The front drive is located near the welding die and, being a small size auxiliary drive, is integrated in the torch handle. Thereby mainly welding wires of soft materials susceptible to buckling are conveyed. It has been found in the practice that the known transport device cannot meet the requirements for constant welding wire supply. Besides, high motor loads result, which shorten the life of this device.

Transport device for a welding wire, particularly for robots


A method for consumption-optimized operation of an internal combustion engine of a motor vehicle is described, an engine output of the internal combustion engine being set as a function of a position of a gas pedal according to a manipulated variable, the gas pedal being adjustable in a first mechanically defined adjustment range between an initial position and a specific gas pedal position, the internal combustion engine being controlled with a consumption-optimized engine output with regard to the instantaneous engine speed by adjusting the gas pedal to the specific gas pedal position, the consumption-optimized engine output causing a minimal fuel consumption at the instantaneous engine speed.

In a motor vehicle, the driver specifies a driver-intended torque or a driver-intended engine output of a vehicle with which the vehicle is to be driven by operating the gas pedal, i.e., via the gas pedal position. In a motor vehicle having an internal combustion engine, the gas pedal position corresponds to a position of a mechanical throttle valve which controls the air supply to the engine. The connection between the gas pedal and the throttle valve may be designed to be mechanical as well as electrical. In the latter case, the gas pedal position is assigned a throttle valve position in the form of a provided manipulated variable via an assignment characteristic curve. Gas pedal values are assigned to the gas pedal position, a maximum gas pedal value corresponding either to the absolutely maximum possible torque or to the instantaneously maximum possible torque, which means that the driver operates the gas pedal "by feeling" for engine outputs which are lower than the maximum possible engine output, and the gas pedal is displaced to the maximum for triggering the maximum possible engine output.
However, it is not possible for the driver to operate the gas pedal in such a way that the motor vehicle is operated in a consumption-optimized manner since the consumption-optimized maximum engine output is typically lower than the maximum possible engine output by an amount not determinable by the driver and a corresponding assignment to a gas pedal position is therefore not determinable offhand by a driver of the motor vehicle.

Method and device for optimizing the consumption in a motor vehicle


The invention relates to a fishing float having a magnetic lock mechanism within the float to allow for the adjustment of a fishing line through the float to adjust the length of the fishing line through the float to select the appropriate depth of the bait or lure below the fishing float without having to reel in the bait and adjust the depth from the shore. The float, once attached, is locking into place by a rocking magnetic lock wedge having an internal-non-magnetic metal ball inside the magnetic lock wedge to motivate the magnetic lock wedge either away from or towards a magnetic lock channel, capturing fishing line placed between the magnetic lock wedge and the magnetic lock channel, the lock wedge and the lock channel being magnetically attracted to each other.

1. Field of Invention
The invention relates to a fishing float having a magnetic lock mechanism within the float to allow for the adjustment of a fishing line through the float to adjust the length of the fishing line through the float to select the appropriate depth of the bait or lure below the fishing float without having to reel in the bait and adjust the depth from the shore. The float, once attached, is locking into place by a rocking magnetic lock wedge having an internal non-magnetic metal ball inside the magnetic lock wedge to motivate the magnetic lock wedge either away from or towards a magnetic lock channel, capturing fishing line placed between the magnetic lock wedge and the magnetic lock channel, the lock wedge and the lock channel being magnetically attracted to each other.
2. Description of Prior Art
The following United States patents were discovered and are disclosed within this application for utility patent. All relate to fishing floats, with some having adjustable means within the float. In U.S. Pat. No. 5,361,532 to Moff, a fishing float is disclosed having a metal ball and a magnetic ring which allows for the bobber to be cast, then fill with water orienting the device in a vertical position causing the ball to travel to the end of a hollow tube within which it is situated, catching the fishing line run through the tube between the ball and the tube opening, locking the line into position.
Finger activated adjustable bobbers, knot adjustable bobbers, and snap-together adjustable bobbers are disclosed in respective U.S. Pat. No. 4,047,319 to Duncan, U.S. Pat. No. 4,195,435 to Kern and U.S. Pat. No. 5,713,152 to Domack, which have manual adjustment means. A remote adjustable means for a fishing bobber using a ball within a cylinder to trap the fishing line between the ball and the inner cylinder wall is disclosed in U.S. Pat. No. 5,117,576 to Lasiter. U.S. Pat. No. 4,030,223 to Loesch discloses an ice fishing line control apparatus that causes an arm to drop when the line has a bite or downward tug releasing a magnetically attached arm.
None of them provide the same elements as the current invention, which comprises a magnetic catch between two elements to retain a line, the magnetic catch being release and reactivated by minor tugs on the fishing line.
The primary objective of the invention is to provide a fishing bobber having an inner release mechanism allowing for adjustment of the fishing line to a variety of depths without having to reel in the fishing line.
A second objective is to provide the device with a magnetic catch means to hold and release the line traveling through the magnetic catch means.
A third objective is to provide the device with a means to engage and disengage the magnetic catch with a light tug on the fishing line from the shore by the fisherman.


A hand tool for applying adhesive strip material to a glass sheet in the fabrication of double glazed windows has a body with a channel extending through the lower side thereof to guide an adhesive strip therethrough and a positioning member adjacent the channel for guiding the tool along the edge of a glass sheet. An adjustable wheel applies pressure on the strip to urge it to adhere with the glass sheet and a cutting mechanism mounted on the body is selectively operable for partially cutting the strip (as when the strip has to be bent through 90xc2x0 at a corner of the glass sheet) and for fully cutting the strip (as when the strip applying step has been completed). The tool includes a pusher element carried adjacent one side of the channel and selectively operable to push the strip in the channel laterally into a side extension into full registration with the cutter when it is desired to settle the strip at the end of the strip applying operation. When the cutter is actuated without the pusher element being operated, the strip is only partially cut.

1. Field of the Invention
This invention relates to a manual method and apparatus for applying a flexible adhesive strip around the perimeter edge of a rigid substrate. More particularly, the present invention relates to an improved manual method and apparatus for applying an insulating edge strip onto glass sheets as part of the manufacturing process of insulating glass units.
2. Description of the Prior Art
Insulating glass units can be manufactured using a horizontal or vertical production line.
The advantages of vertical unit production include: higher productivity; lower equipment costs; less floor space; convenient glass handling, including; large glass sheets, easy on-line gas filling, and simpler automation of various unit production operations, including, glass feed, glass movement, unit assembly and sealant gunning.
To simplify the production of insulating glass units, various adhesive strip products have been developed. One such product is described in U.S. Pat. 4,831,799. The product is manufactured from flexible thermoset rubber foam that incorporates desiccant fill material and features a vapor barrier backing film and acrylic side adhesive. The side adhesive is protected by a flexible release liner that allows the material to be packaged on reels. This adhesive strip product has been commercialized by Edgetech IG Inc and is marketed under the registered trademark of Super Spacer(copyright).
Adhesive strip products are typically applied with the glass in a horizontal position. As described in U.S. Pat. No. 5,246,331 issued to Hallahan et al, an air flotation assembly table is typically used. To reduce worker movement to a minimum, the air flotation table features a moveable suction cup that successively rotates the glass through 90xc2x0 and linearly moves the glass to a convenient position close to the perimeter edge of the table. Although the glass is located close to the operator, the hand tool must be held in position as the glass is rotated around. As a result, there can be abnormal movement of the operator""s body including: prolonged spinal curvature; unnatural trunk rotation, and hyperextension of the shoulder, elbow and arm. In the long term, this abnormal movement may potentially cause repetitive stress disorders and related health problems.
For manual application of adhesive strip products on a vertical production line, the glass sheets are tilted down to a horizontal position for strip application and the strip is applied using conventional rotating tables and hand tools. For unit assembly, the glass sheets must then be tilted back into a vertical position and because of this extra glass movement, productivity is reduced.
The adhesive strip product described in U.S. Pat. No. 4,831,799 incorporates a vapor barrier backing. To provide corner continuity of the vapor barrier, a half circular notch is made in the spacer and this creates a flex point that allows for easy corner formation. Various application tools have been developed for forming these notched corners and as documented in photographs of a prototype Edgetech application tool, one way of forming these corner notches is through the use of a slidable circular punch. When activated, the hollow punch removes a half circular portion or slug of strip material. Because of the acrylic side adhesive, these slugs adhere together and as a result, the slug material can be easily ejected from the tool. The advantage is that the tool can remain in continuous contact with the glass and the productivity of strip application is improved.
At the final corner, there are further productivity advantages if the tool can also incorporate a blade for cutting through the adhesive strip. As described in U.S. Pat. No. 5,472,558 issued to Lafond, one approach is add a separate blade that operates in combination with the punch to both notch and cut through the adhesive strip at the final corner.
Although productivity is improved, experience has shown that this simultaneous operation of the punch and cutting blade requires a complicated punch design that is expensive to manufacture and is prone to wear and damage.
Compared to the earlier Edgetech tools, another new feature of the Lafond tool is that both the pneumatic cylinder and strip feeding channel are steeply inclined at angle and this has the advantage of a reduced channel length between the pneumatic cylinder and the pressure wheel. However, the drawback is that after strip cut-off, the tool requires to be re-threaded and this can be a time consuming operation.
For operating the pneumatic cylinder, the Lafond tool also features a finger trigger that is located below a cylindrical handle and operated by means of a finger pulling action. With horizontal strip application using a rotary table, there are three main ergonomic drawbacks to this arrangement. First, it provides for wrist deviation with rapid finger movement. Second, it combines forceful gripping with a twisting action and third, it requires rapid and forceful pronation with strong elbow and wrist flexion.
The tool of U.S. Pat. No. 5,472,558 Lafond is also limited to producing a notched corner. An alternative corner application detail is to partially cut through the back face of the adhesive strip and create an open-ended corner. Although in this arrangement the barrier film is not continuous, the open-ended corner allows for additional sealant material to be applied at the corners and this ensures that the edge-seal integrity of the insulating glass unit is not downgraded.
The present invention provides a hand tool for applying adhesive strip material to a substrate having an edge and a major face, said hand tool comprising: a body having a lower surface and a channel extending therethrough adjacent said lower surface for receiving a strip of material therein; a substrate positioning member located close to said channel on said lower surface of said body for guiding said tool along said edge of said substrate, said lower surface of said body being elevated from said major face by said strip when said strip is fed through said channel; an adjustable wheel for applying pressure on said strip to urge said strip to adhere with said substrate major face; and a cutting mechanism mounted on said body, said cutting mechanism being selectively operable for partially cutting said strip and for fully cutting said strip.
The cutting mechanism is preferably provided by a cutter and a displacement means that is selectively operable to shift relative alignment of the strip with respect to the cutter so that the cutter can partially or fully cut through the strip as desired. For example when applying a spacer strip around a rectangular glass sheet, starting at one corner and extending successively along each edge, at the second, third and fourth corners the spacer strip will be partially cut to facilitate its bending through a right angle at that corner, whereas when all four sides have been complete, the strip will be severed at the first corner.
In a preferred embodiment of the hand tool the cutter is in the form of a reciprocating punch or knife oriented substantially at right angles to the channel, and a displacement means is effective to displace the strip laterally in the channel so that the strip which is normally partially aligned with the cutter, but when the strip is to be severed, it is moved to become fully aligned with the cutter. It will be appreciated that the same effect can be achieved by arranging for the cutter rather than the strip to be displaceable laterally with respect to the channel.
The cutter can be in the form of a hollow tubular punch aligned to cut an arcuate notch out of the strip to facilitate bending thereof at a corner of the substrate, but capable of alignment to fully sever the strip when required. With this arrangement the strip is bent at the corner in a direction to close up or reduce the arcuate notch. In an alternative configuration the cutter is in the form of a knife which partially cuts through the strip to form a slit at a location where a corner is to be formed. It will be understood that in this configuration the strip is bent so that the sides of the slit lie approximately 90xc2x0 and face outwards at the corner of the substrate.
Where the strip within the channel is to be laterally displaced, this is readily effected by a simple pusher element carried in the side of the body and operable to displace the strip laterally when desired. While it is possible for the pusher element to be spring loaded and to engage a U-shaped cradle in the channel through which the strip is passed, displacing this cradle laterally when the strip is to be severed, in a simpler and much cheaper arrangement it is sufficient for the pusher element to be a plastic part loosely guided in a wall of the body adjacent the channel and having a pad surface that can engage the side of the strip material and push it laterally into an extension on the opposite side of the channel. No springs are necessary, and when the pusher element is released it will be restored to its non-actuated condition simply by the resilience of the strip material. The pusher element is furthermore preferably designed to clamp within the channel the severed end of the strip material leading from the supply, so that the strip material does not have to be re-threaded into the tool in subsequent application operations.
A method for use by an operator in applying an adhesive strip to a surface border area around the periphery of a rigid substrate having a flat major face, may involve the steps (a) locating the substrate in a generally upright position to present said major face towards the operator; (b) providing a hand tool which is adapted for manipulation by the operator for applying said adhesive strip to said substrate; (c) supplying a continuous length of adhesive strip material from a supply to said hand tool; (d) wherein the operator manipulates said hand tool to pass along said periphery to apply said strip of adhesive material to said border surface area of said major face around the entire periphery of the substrate.
The adhesive strip material is delivered from a reel behind the operator through an overhead guide to a discharge position above and in front of the substrate. Release liners on the strip are preferably peeled off as the strip exits from the guide.
Where the substrate is of rectangular outline with four corners, adhesive strip typically is applied starting at one corner and then continuously along the lengths of the four sides, the strip being notched or partially cut to facilitate its bending through 90xc2x0 at each of the second, third and fourth corners, and finally severed when it is returned to the first corner.
Conveniently where strip application is being done by a right handed operative, the starting point is typically the upper end of the left hand edge of the substrate. To facilitate the strip application operation and reduce operator fatigue the substrate is preferably mounted so that it can be moved vertically to a preferred working height. For example, use may be made of moveable suction cups which engage the substrate so that it can be adjusted vertically during application so that the instantaneous point of application of the strip is at all times conveniently located with respect to the operator.
The body and handle of the tool are preferably ergonomically shaped for comfort in use and to allow engagement of the tool by multiple and changing hand positions. The punch is preferably selectively operated by the fingers or thumb of the hand in which the tool is held, suitable actuators requiring pushing action from a finger or thumb onto a lever or button.
The components of the hand tool preferably are detachable, and the tool has a body to which the components can be attached alternatively for use in right handed or left handed mode. The tool includes a removable front face plate which at its lower end incorporates a slot at the top of which is a for guiding the strip into the tool channel, the face plate also including a large opening through which slugs cut from the strip by the punch are ejected.
The lower face of the tool is preferably provided as a removable wear plate, and the positioning member as a reversible pad that is releasably attached to the lower surface of the body, these parts being of plastic material which will minimize damage to the substrate.
The pressure wheel which rides on the strip within the tool channel is preferably height adjustable by means of a finger actuated rotatable nut carried by a threaded stem on which the pressure wheel is supported.
The invention will further be described, by way of example only, with reference to the embodiments illustrated in the accompanying drawings, wherein:

Hand tool for adhesive strip application