... CHLORPHENTERMINE IS METABOLIZED VIA UNRECOGNIZED ROUTE TO AFFORD UNUSUAL CONJUGATE, WHICH IS NEITHER GLUCURONIDE NOR N-ACETYL DERIV, IN URINE OF MOUSE, WHEREAS IN RAT CHLORPHENTERMINE IS EXCRETED UNCHANGED.
IDENTIFICATION: Chlorphentermine hydrochloride is a centrally acting antiobesity drug. HUMAN EXPOSURE: Main risks and target organs: Acute central nervous system stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse. High risk of dependency and abuse. Summary of clinical effects: Cardiovascular: Palpitation, chest pain, tachycardia, arrhythmias and hypertension are common; cardiovascular collapse can occur in severe poisoning. Myocardial ischemia, infarction and ventricular dysfunction are described. Central Nervous System (CNS): Stimulation of CNS, tremor, restlessness, agitation, insomnia, increased motor activity, headache, convulsions, coma and hyperreflexia are described. Stroke and cerebral vasculitis have been observed. Gastrointestinal: Vomiting, diarrhea and cramps may occur. Genitourinary: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. Renal failure can occurs secondary to dehydration or rhabdomyolysis. Renal ischemia may be noted. Dermatologic: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Endocrine: Transient hyperthyroxinemia may be noted. Metabolism: Increased metabolic and muscular activity may result in hyperventilation and hyperthermia. Weight loss is common with chronic use. Fluid/Electrolyte: Hypo- and hyperkalemia have been reported. Dehydration is common. Musculoskeletal: Fasciculations and rigidity may be noted. Rhabdomyolysis is an important consequence of severe amphetamine poisoning. Psychiatric: Agitation, confusion, mood elevation, increased wakefulness, talkativeness, irritability and panic attacks are Tourette syndrome and other disorders, hyperthyroidism, narrow angle glaucoma typical. Chronic abuse can cause delusions and paranoia. A withdrawal syndrome occurs after abrupt cessation following chronic use. Contraindications: Anorexia, insomnia, psychopathic personality disorders, suicidal tendencies, diabetes mellitius and cardiovascular diseases such as angina, hypertension and arrythmias. Routes of exposure: Oral: Readily absorbed from the gastro-intestinal tract and buccal mucosa. It is resistant to metabolism by monoamine oxidase. Inhalation: Amphetamine is rapidly absorbed by inhalation and is often abused by this route. Parenteral: Frequent route of entry in abuse situations. Absorption by route of exposure: Amphetamine is rapidly absorbed after oral ingestion. Peak plasma levels occur within 1 to 3 hours, varying with the degree of physical activity and the amount of food in the stomach. Absorption is usually complete by 4 to 6 hours. Sustained release preparations are available as resin-bound, rather than soluble, salts. These compounds display reduced peak blood levels compared with standard amphetamine preparations, but total amount absorbed and time to peak levels remain similar. Distribution by route of exposure: Amphetamines are concentrated in the kidney, lungs, cerebrospinal fluid and brain. They are highly lipid soluble and readily cross the blood-brain barrier. Biological half-life by route of exposure: Under normal conditions, about 30% of amphetamine is excreted unchanged in the urine but this excretion is highly variable and is dependent on urinary pH. When the urinary pH is acidic (pH 5.5 to 6.0), elimination is predominantly by urinary excretion with approximately 60% of a dose of amphetamine being excreted unchanged by the kidney within 48 hours. When the urinary pH is alkaline (pH 7.5 to 8.0), elimination is predominantly by deamination (less than 7% excreted unchanged in the urine); the half-life ranging from 16 to 31 hours. Metabolism: The major metabolic pathway for amphetamine involves deamination by cytochrome P450 to para-hydroxyamphetamine and phenylacetone; this latter compound is subsequently oxidized to benzoic acid and excreted as glucuronide or glycine (hippuric acid) conjugate. Smaller amounts of amphetamine are converted to norephedrine by oxidation. Hydroxylation produces an active metabolite, O-hydroxynorephedrine, which acts as a false neurotransmitter and may account for some drug effect, especially in chronic users. Elimination and excretion: Normally 5 to 30% of a therapeutic dose of amphetamine is excreted unchanged in the urine by 24 hours, but the actual amount of urinary excretion and metabolism is highly pH dependent. Mode of action: Amphetamine appears to exert most or all of its effect in the CNS by causing release of biogenic amines, especialy norepinephrine and dopamine, from storage sites in nerve terminals. It may also slow down catecholamine metabolism by inhibiting monoamine oxidase. Teratogenicity: The use of amphetamine for medical indications does not pose a significant risk to the fetus for congenital anomalies. Amphetamines generally do not appear to be human teratogens. Mild withdrawal symptoms may be observed in the newborn, but the few studies of infant follow-up have not shown long-term sequelae, although more studies of this nature are needed. Illicit maternal use or abuse of amphetamine presents a significant risk to the fetus and newborn, including intrauterine growth retardation, premature delivery and the potential for increased maternal, fetal and neonatal morbidity. These poor outcomes are probably multifactorial in origin, involving multiple drug use, life-styles and poor maternal health. However, cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties of amphetamines. Sixty-five were followed children whose mothers were addicted to amphetamine during pregnancy, at least during the first trimester. Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those children exposed throughout pregnancy tended to be more aggressive. Interactions: Acetazolamide: administration may increase serum concentration of amphetamine. Alcohol: may increase serum concentration of amphetamine. Ascorbic acid: lowering urinary pH, may enhance amphetamine excretion. Furazolidone: amphetamines may induce a hypertensive response in patients taking furazolidone. Guanethidine: amphetamine inhibits the antihypertensive response to guanethidine. Haloperidol: limited evidence indicates that haloperidol may inhibit the effects of amphetamine but the clinical importance of this interaction is not established. Lithium carbonate: isolated case reports indicate that lithium may inhibit the effects of amphetamine. Monoamine oxidase inhibitor: severe hypertensive reactions have followed the administration of amphetamines to patients taking monoamine oxidase inhibitors. Norepinephrine: amphetamine abuse may enhance the pressor response to noradrenaline. Phenothiazines: amphetamine may inhibit the antipsychotic effect of phenothiazines, and phenothiazines may inhibit the anorectic effect of amphetamines. Sodium bicarbonate: large doses of sodium bicarbonate inhibit the elimination of amphetamine, thus increasing the amphetamine effect. Tricyclic antidepressants: theoretically increases the effect of amphetamine, but clinical evidence is lacking. /Chlorphentermine hydrochloride/
The effect of chlorphentermine, in the form of chlorphentermine hydrochloride, induced alveolar changes on nitrogen dioxide toxicity was studied in mice. Male Swiss Webster mice were given 0 or 120 mg/kg chlorphentermine hydrochloride daily for 14 days followed by 48 hr exposure to 20 ppm nitogen dioxide. The animals were observed for clinical signs of toxicity. Selected mice were killed immediately or 1, 3, 5, and 7 days after nitogen dioxide exposure, the lungs were removed, sectioned, and examined by light and electron microscopy. In a second study using the same protocol, the total numbers of type I, type II, and alveolar macrophages were counted in lung sections. Chlorphentermine hydrochloride alone induced a diffuse accumulation of large foaming macrophages within alveoli. The cytoplasm of the macrophages contained vacuoles some of which had lamellar inclusions. Nitogen dioxide alone caused 20.8% mortality in the histopathology study and 18.5% mortality in the cell count study. No deaths occurred in any groups receiving chlorphentermine hydrochloride. nitogen dioxide caused type II cell hyperplasia and pulmonary edema, most notably in mice killed during the first 24 hr. These effects were less pronounced in mice pretreated wit phentermine. In the cell count study, nitogen dioxide alone significantly increased the number of type I and type II cells. These increases were not as large in animals given chlorphentermine hydrochloride. All treatments increased the number of macrophages. The largest increase occurred in mice given chlorphentermine hydrochloride plus nitogen dioxide on day 0; this leve changed only slightly through day five. The number of macrophages induced by nitogen dioxide alone increased steadily through day three. Changes induced by chlorphentermine hydrochloride partially protect against nitogen dioxide toxicity.
We have previously demonstrated that the chlorphentermine induced impairment in lymphocyte blastogenesis involves drug-induced inhibition of an event which occurs very early during lymphocyte activation. An early event, which is associated with mitogen induced lymphocyte activation, involves the hydrolysis of phosphatidylinositol by phospholipase C to yield inositol phosphates and diacylglycerol as products. Inositol phosphates and diacylglycerol then function as mediators of a trans-membrane signal for the continuation of the cellular response. It was the purpose of the present study to determine the effects of chlorphentermine on this phosphatidylinositol pathway. We demonstrated that formation of inositol phosphates in lymphocytes increases progressively above control over a 2 hr period following concanavalin A (Con A)-stimulation. In contrast, lymphocytes pre-incubated with 10(-5)M chlorphentermine for 60 min, then stimulated with Con A for 2 hr in the presence of 10(-5)M chlorphentermine, exhibit a significantly depressed inositol phosphate formation. In addition, chlorphentermine also inhibited the activity of phospholipase C (IC50 = 0.58 mM), the enzyme responsible for the formation of inositol phosphates during lymphocyte activation. Further, lymphocytes activated in a manner that bypasses the phosphatidylinositol pathway are not inhibited by 10(-7)M or 10(-9)M chlorphentermine as are cells activated with Con A. These results suggest that the suppression of the phosphatidylinositol pathway may be involved in the inhibition by chlorphentermine of lymphocyte blastogenesis induced by Con A.
A study was done in mice to assess any morphological, biochemical, or functional changes in alveolar macrophages following induction of lipidosis by chlorphentermine and/or inhalation of nitrogen dioxide. Male Swiss Webster mice were treated with 120 mg/kg chlorphentermine or water by gavage daily for 14 days. Following this, mice were exposed to air or 20 ppm nitrogen dioxide for 48 hr. Alveolar macrophages were obtained by bronchoalveolar lavage and tested for viability and function. Significantly greater numbers of total white cells and macrophages were obtained from mice treated with chlorphentermine and/or nitrogen dioxide. The percentage of macrophages was significantly lower in mice receiving the combination treatment. Neither treatment altered macrophage viability. The percentage of positive cells in the metabolic reduction assay was not altered by any treatment, while the total number positive was significantly increased by combined treatment. Decreased 5'-nucleotidase activity was found with chlorphentermine and/or nitrogen dioxide, and phagocytic capacity and activity were increased in these groups. Combination treatment gave the greatest total phagocytic capacity. Yeast killing was decreased by chlorphentermine and/or nitrogen dioxide, particularly with combined treatment. Increases found in total reduction and total yeast killing were related to increased macrophage numbers. The authors conclude that large increases in alveolar macrophages in lipidotic lung airways may protect the alveolar epithelium by quenching free radicals produced during nitrogen-dioxide induced lipid peroxidation.
Diazepam may be given to control central nervous system stimulation and convulsions. For marked excitement or hallucinations chlorpromazine may be necessary and, in addition, its alpha-adrenoceptor blocking properties may be useful for the management of hypertension. Severe hypertension may call for the administration of an alpha-adrenoceptor blocking agent, such as phentolamine. Measures should be taken to control increased body temperature.
CHLORPHENTERMINE HAS GREATER TISSUE:BLOOD RATIO IN RATS THAN PHENTERMINE, & TISSUE ACCUMULATION OF CHLORO-DERIV INCR RELATIVE TO PLASMA LEVELS AFTER CHRONIC DOSING.
IN MICE, UNIDENTIFIED CONJUGATE (60% OF DOSE), WHICH IS NEITHER GLUCURONIDE NOR N-ACETYL DERIV, WAS NOT FORMED BY LIVER MICROSOMES, BUT IN RATS, CHLORPHENTERMINE IS EXCRETED UNCHANGED IN URINE.
FOLLOWING ORAL ADMIN TO MAN, N-OXIDATION TAKES PLACE & UNDER NORMAL CONDITIONS OF URINARY PH, URINE IS MAIN ELIMINATION ROUTE FOR CHLORPHENTERMINE; ACIDIFYING THE URINE INCR URINARY EXCRETION OF UNCHANGED DRUG @ EXPENSE OF N-OXIDIZED PRODUCTS.
(ALPHA-SUBSTITUTED ARALKYLAMINO AND HETEROARYLALKYLAMINO) PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR USE IN TREATING PROLIFERATIVE DISEASES
[EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2010104818A1
公开（公告）日：2010-09-16
MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
The present invention relates to compounds of formula I
wherein R
1
to R
4
and G are as defined in the description and claims and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
The present invention relates to compounds of formula I
wherein A and R
1
to R
4
are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
BENZOFURAN AND BENZOTHIOPHENE-2-CARBOXYLIC ACID AMIDE DERIVATIVES
申请人：Mohr Peter
公开号：US20090029976A1
公开（公告）日：2009-01-29
The present invention relates to compounds of formula I
wherein X, A and R
1
to R
4
are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
