Ketotifen is extensively metabolized in humans and three distinct metabolites have been detected in human urine. The main metabolite is the N-glucuronide, comprising roughly 50% of urinary drug product, with the N-demethylated nor-ketotifen and the 10-hydroxyl derivative comprising 2% and <1%, respectively. Nor-ketotifen appears to be equally as active as its parent drug, though the clinical relevance of this is unclear given the relatively small proportion in which nor-ketotifen is found in the plasma. Formation of the N-glucuronide metabolite is carried out by several UGT enzymes, including UGT1A3, UGT1A4, and UGT2B10.
The main metabolite found in both plasma and urine is the inactive ketotifen-N-glucuronide. Nor-ketotifen, the N-demethylated metabolite, and the 10-hydroxyl derivative are the only other metabolites detectable in human urine. Both the 10-hydroxyl derivative and N-glucuronide conjugate may reform the intact product by in vivo reversibility. The pattern of metabolism in children over the age of 3 years is the same as in adults, but the clearance is higher in children. /Ketotifen fumarate (systemic)/
Ketotifen has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[1-methyl-4-(8-oxo-6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-2-ylidene)piperidin-1-ium-1-yl]oxane-2-carboxylic acid and Ketotifen N-glucuronide.
◉ Summary of Use during Lactation:Because absorption from the eye is limited, ketotifen would not be expected to cause any adverse effects in breastfed infants after maternal use of ketotifen eye drops. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Concurrent use /of alcohol, antihistamines, hypnotics, or sedatives/ with /oral/ ketotifen may potentiate the CNS depressant effects of these medications. /Ketotifen fumarate/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
与口服抗糖尿病药物同时使用口服酮替芬可能会导致可逆性血小板减少... 酮替芬富马酸盐
Concomitant use /of oral antidiabetic agents/ with /oral/ ketotifen may result in reversible thrombocytopenia ... /Ketotifen fumarate/
... Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin.
...Ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate /in mice/.
Following oral administration, absorption is relatively quick (with a Tmax of ~3 hours) and nearly complete as judged by plasma concentrations and urinary excretion levels - despite this, oral bioavailability is only ~50% due to a significant first-pass effect in the liver.
More than 60% of an administered dose is excreted in the urine, primarily as metabolites - of this material, <1% is found as unchanged drug, while the glucuronide and pharmacologically active nor-ketotifen metabolites account for 50% and 10%, respectively.
Within 48 hours, urinary excretion amounts to 1% as unchanged drug and 60% to 70% as metabolites. Clearance is higher in children. /Ketotifen fumarate/
Following oral administration absorption is at least 60% ... The rate of absorption is rapid with an absorption half life of 1 hour. Bioavailability is about 50%, due to a large first pass effect. Bioavailability is not affected by the intake of food. /Ketotifen fumarate/
... A study conducted with 15 healthy volunteers dosed bilaterally with ketotifen fumarate ophthalmic solution twice daily for 14 days demonstrated plasma concentrations generally below the quantitation limit of assay (< 20 pg/mL). /Ketotifen fumarate/
Untersuchungenüber合成Arzneimittel 9-和10-Oxo-衍生物von 9,10-Dihydro-4 H -benzo [4,5] cyclohepta- [1,2- b ]噻吩的合成药物。9,10-二氢-4 H-苯并-[4,5]-环庚[1,2 b ]噻吩的9-和10-氧代衍生物
摘要：
Verschiedene Synthesen zur Herstellung von 9-Oxo-9,10-dihydro-4 H -benzo [4,5] cyclohepta [1,2- b ]噻吩17和10-Oxo-9,10-dihydro-4 H -benzo [ 4,5] cyclohepta [1,2- b ]噻吩18（25），在4-Stellung中的1-烷基-4-piperidyliden-Gruppe分子，9,10-Dihydro-4 H-苯并[4,5] ]环庚[1,2- b ]噻吩-4- onen 1 bzw. 达芬（Folgestufen davon），韦登·贝希里本（werden beschrieben）。ALS weitere导数信德死-N-氧化物26，模具9- UND 10-羟基-衍生物27 UND 28，模具9- UND 10肟29 UND 30sowie ein
Untersuchungenüber合成Arzneimittel 9-和10-Oxo-衍生物von 9,10-Dihydro-4 H -benzo [4,5] cyclohepta- [1,2- b ]噻吩的合成药物。9,10-二氢-4 H-苯并-[4,5]-环庚[1,2 b ]噻吩的9-和10-氧代衍生物
摘要：
Verschiedene Synthesen zur Herstellung von 9-Oxo-9,10-dihydro-4 H -benzo [4,5] cyclohepta [1,2- b ]噻吩17和10-Oxo-9,10-dihydro-4 H -benzo [ 4,5] cyclohepta [1,2- b ]噻吩18（25），在4-Stellung中的1-烷基-4-piperidyliden-Gruppe分子，9,10-Dihydro-4 H-苯并[4,5] ]环庚[1,2- b ]噻吩-4- onen 1 bzw. 达芬（Folgestufen davon），韦登·贝希里本（werden beschrieben）。ALS weitere导数信德死-N-氧化物26，模具9- UND 10-羟基-衍生物27 UND 28，模具9- UND 10肟29 UND 30sowie ein
[EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：GALAPAGOS NV
公开号：WO2017012647A1
公开（公告）日：2017-01-26
The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.
[EN] PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS<br/>[FR] DÉRIVÉS DE PYRROLOTRIAZINONE EN TANT QU'INHIBITEURS DES PI3K
申请人：ALMIRALL SA
公开号：WO2014060432A1
公开（公告）日：2014-04-24
New pyrrolotriazinone derivatives having the chemical structure of formula (I), are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks)
Imidazole and benzimidazole derivatives useful as histamine H3 antagonists
申请人：Aslanian G. Robert
公开号：US20060166960A1
公开（公告）日：2006-07-27
Disclosed are compounds of the formula
or a pharmaceutically acceptable salt or solvate thereof, wherein: n is 2-5;
R is R
3
-aryl, R
3
-heteroaryl, R
3
-cycloalkyl, R
3
-heterocycloalkyl, alkyl, haloalkyl, —OR
4
, —SR
4
or —S(O)
1-2
R
5
;
R
1
and R
2
are H or optionally substituted phenyl or optionally substituted
and X is —O— or —S—;
or R
1
and R
2
, together with the carbon atoms to which they are attached form optionally substituted
and X is —O—, —S— or —NR
7
—;
Z is
and the remaining variables are as defined in the specification; also disclosed are pharmaceutical compositions comprising the compounds of formula I; also disclosed are methods of treating allergy, allergy-induced airway responses, congestion, obesity and metabolic syndrome using the compounds of Formula I, as well as combinations with other drugs useful for treating those diseases.
[EN] 1-(4-PIPERIDINYL) BENZIMIDAZOLONES AS HISTAMINE H3 ANTAGONISTS<br/>[FR] 1-(4-PIPERIDINYL) BENZIMIDAZOLONES UTILISES EN TANT QU'ANTAGONISTES DU RECEPTEUR H3 DE L'HISTAMINE
申请人：SCHERING CORP
公开号：WO2003103669A1
公开（公告）日：2003-12-18
Disclosed are histamine H3 antagonists of the formula (I) wherein
R1 is benzimidazolone derivative, M1 and M2 are
optionally substituted carbon or nitrogen, R2 includes optionally
substituted aryl or heteroaryl, and the remaining variables are as defined in
the specification. Also disclosed are pharmaceutical compositions comprising
the compounds of formula (I). Also disclosed are methods of treating various
diseases or conditions, such as, for example, allergy, allergy-induced airway
responses, and congestion (e.g., nasal congestion) using the compounds of Formula
(I). Also disclosed are methods of treating various diseases or conditions,
such as, for example, allergy, allergy-induced airway responses, and congestion
(e.g., nasal congestion) using the compounds of formula (I) in combination with
a H1 receptor antagonist.
Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
