Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonamide (PEMA) was applied to investigate the differences of primidone metabolism among humans, rats, and mice. The model simulated previously published pharmacokinetic data of the parent chemical and its metabolites in plasma and brain tissues from separate studies of the three species. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies. Estimated primidone metabolism, as expressed by the maximal velocity Vmax, ranged from 0 to 0.24 mg/kg/min for the production of phenobarbital and from 0.003 to 0.02 mg/kg/min for the production of PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primidone and its metabolites in mice indicated that mice were at higher risk of toxicity owing to higher residence of phenobarbital in their tissues and owing to the carcinogenic potential of phenobarbital as illustrated in long-term bioassays. ...
The placental transfer of primidone and metabolites was investigated in 14 women treated for epilepsy with primidone (and additionally phenytoin, ethosuximide or valproate in 5 women) throughout pregnancy. Primidone, PEMA /phenylethylmalonamide/, phenobarbital, and polar metabolites (p-hydroxyphenobarbital and p-hydroxyphenobarbital glucuronide) were found in similar concentrations in maternal and cord blood at birth.
The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 hr and 34.8 +/- 9.0 vs 33.2 +/- 7.2 mL/kg/hr respectively. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.
Although phenobarbital was not detected after administration of single doses of primidone, long-term administration of primidone (at various doses) in 46 epilepsy patients showed serum accumulation of phenobarbital, and PEMA /phenylethylmalonamide/. Although there was significant inter-individual variability, concentrations of the two metabolites showed correlation with those of the parent drug, and concentrations of phenobarbital were consistently higher than those of PEMA. Two of the subjects had been on a daily dose of primidone (750 mg in divided doses) for more than 3 years. After a single dose of 750 mg in this study, peak serum concentrations of primidone were achieved rapidly (by 0.5 hour), and declined slowly (half-lives, 5.3 and 7.0 hours). In both subjects, peak concentrations of metabolites, PEMA (12 and 10 ug/mL) and phenobarbital (33 and 11 ug/mL), remained relatively constant. In the cerebrospinal fluid, binding to protein by PEMA and by primidone was negligible, and approximately 60% by phenobarbital.
IDENTIFICATION AND USE: Primidone is anticonvulsant, which is used alone or concomitantly with other anticonvulsants. It is indicated in the control of grand mal, psychomotor, and focal epileptic seizures. Primidone can be used for seizure control in dogs. HUMAN STUDIES: Overdosage of primidone results in symptoms similar to those of acute barbiturate intoxication. In addition, primidone crystalluria may occur and may facilitate the diagnosis. A case was reported of a patient who developed megaloblastic anemia caused by folate deficiency during treatment with primidone. In one study, children of epileptic women on medication with primidone were of lower weight and had smaller heads than children from epileptic mothers without medication and children from parents without epilepsy. Fetal exposure to primidone was associated with Goldenhar syndrome, hemifacial microsomia, tetralogy of Fallot, aqueductal stenosis, and anterior encephalocele in male infant. There is a report of the acardiac acephalic fetus of an epileptic mother who was on primidone therapy. In vitro studies showed no chromosomal aberration in human lymphocytes. ANIMAL STUDIES: Primidone caused a significant increase in the incidence of follicular cell adenoma of the thyroid in male rats. There was a small but significant increase in the incidence of renal tubule adenoma or carcinoma. The incidence of renal tubule hyperplasia was also increased in all groups of males receiving primidone. There was no significant increase in the incidence of any neoplasm in females. In mice, primidone caused significant increases in the incidence of hepatocellular adenoma, of hepatocellular carcinoma, and of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma (combined) in all dosed groups of males and females compared with controls. Primidone caused significant increases in the incidence of hepatoblastoma in all dosed groups of males. In males, there was also a significant positive trend in the incidence of follicular cell adenoma of the thyroid in mice receiving pyrimidone. There was an increased incidence in follicular cell hyperplasia of the thyroid in males and females receiving primidone. In pregnant rats treated with primidone the findings were consistent with the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that primidone produced its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system. Primidone was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of metabolic activation. The compound was positive in strain TA1535 without activation. Because primidone is rapidly metabolized to phenobarbital in dogs, similar clinical signs (sedation to coma, anorexia, vomiting, nystagmus) are seen and corresponding procedures should be used for the treatment of acute primidone overdose.
In clinical trials in epilepsy, therapy with primidone was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. Primidone therapy can lead to increases in gamma glutamyltranspeptidase (GGT) levels. Elevations in alkaline phosphatase levels were largely due to bone isoforms of the enzyme. There have been no convincing reports of hepatotoxicity due to primidone in humans and no reports of its association with acute liver failure. Interestingly, primidone appears to cause cirrhosis in dogs. Because of its similarity in structure to phenytoin and phenobarbital (aromatic anticonvulsant), it has been suspected to cross react with those agents in causing anticonvulsant hypersensitivity syndrome, but convincing case reports have not been published.
Oral primidone is up to 80% bioavailable with a Tmax if 2-4h. A 500mg oral dose of primidone Reaches a Cmax of 2.7±0.4µg/mL with a Tmax of 0.5-7h. Data regarding the AUC of primidone is not readily available.
来源:DrugBank
吸收、分配和排泄
消除途径
普里米多尼在尿液中回收率为72.9-80.6%。
Primidone is 72.9-80.6% recovered in urine.
来源:DrugBank
吸收、分配和排泄
分布容积
普里米多尼的分布容积为0.5-0.8L/kg。
The volume of distribution of primidone is 0.5-0.8L/kg.
Mice were treated with a teratogenic dose of primidone (100 mg/kg) by gastric intubation at three different times during pregnancy, viz. days 6-14, days 12-14 on day 14 only. Blood samples were taken on day 14 at 1, 4, 8 and 24 hr after dosage. Primidone and its metabolites phenylethylmalondiamide (PEMA), and phenobarbitone, were assayed by GLC. There was no accumulation of the parent compound or the metabolites after repeated administration of primidone; each of the substances was cleared from the plasma within 24 hr. The rate of metabolism of primidone increased with prolonged treatment. The peak concentration of the metabolites was higher in the two multiple-dose groups than in the single dose group. The concentration of PEMA exceeded that of primidone between 3-8 hr and then began to decrease in the multiple-dose groups, a similar pattern was established for phenobarbitone also, although the concentrations were lower than those of PEMA.
[EN] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE<br/>[FR] PROCÉDÉS UTILES POUR LA SYNTHÈSE DE LA (R)-1-{2-[4'-(3-MÉTHOXYPROPANE-1-SULFONYL)-BIPHÉNYL-4-YL]-ÉTHYL}-2-MÉTHYL-PYRROLIDINE
申请人：ARENA PHARM INC
公开号：WO2009128907A1
公开（公告）日：2009-10-22
Processes useful for making a pharmaceutically useful compound according to Formula (I), forms of such a compound, and intermediates useful in such processes are described.
根据公式（I）制备药用化合物的有用过程，以及该化合物的形式和在这些过程中有用的中间体被描述。
Substituted 1,3-thiazole compounds, their production and use
申请人：——
公开号：US20040053973A1
公开（公告）日：2004-03-18
(1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.
Compounds, compositions and methods are provided that are useful in the treatment or prevention of conditions or disorders associated with a neuropeptide receptor. The subject methods are particularly useful in the treatment and/or prevention of endocrine, metabolic, cardiovascular, neurologic, psychiatric, gastrointestinal, genitourinary and other disorders.
ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
申请人：Meng Charles Q.
公开号：US20140142114A1
公开（公告）日：2014-05-22
The present invention relates to novel anthelmintic compounds of formula (I) below:
wherein
Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X
1
, X
2
, X
3
, X
4
, X
5
, X
6
, X
7
and X
8
are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.
Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I
as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
