THC and CBD are metabolized in the liver by a number of cytochrome P450 isoenzymes, including CYP2C9, CYP2C19, CYP2D6 and CYP3A4. They may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream and metabolized via the renal and biliary systems. The main primary metabolite of CBD is 7-hydroxy-cannabidiol.
In prelicensure studies, serum aminotransferase elevations arose during cannabidiol therapy for epilepsy in 34% to 47% of patients compared to 18% of controls who were receiving other anticonvulsant medications. Elevations above 3 times ULN occurred in 13% of cannabidiol treated compared to 1% on placebo. ALT and AST elevations were more frequent with higher doses and were particularly common (and sometimes delayed) in patients who were receiving valproate and clobazam. The aminotransferase elevations typically arose within the first two months of treatment and were transient, mild-to-moderate in severity, and not associated with symptoms or jaundice. There have been no convincing reports of clinically apparent liver injury with jaundice attributable to prescription forms of cannabidiol, but it has had very limited general use.
There have been few studies of liver test abnormalities during therapy with lower doses of CBD or with commercially available, over-the-counter CBD products. In doses between 200 and 400 mg daily, mild-to-moderate serum aminotransferase elevations have occasionally been reported, but there have been no reports of clinically apparent liver injury. Furthermore, liver injury arising in persons taking supplements with CBD must also consider the possibility of contaminants in the products or other herbal and dietary supplement use.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury, particularly with high doses).
◉ Summary of Use during Lactation:Cannabidiol is a component of cannabis. Cannabidiol has not been studied in nursing women taking the pharmaceutical product, but it has been detected in the breastmilk of some mothers who used cannabis products. Because no published information is available with cannabidiol use as an antiepileptic during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ 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.
◉ Summary of Use during Lactation:The main psychoactive component of cannabis, tetrahydrocannabinol (THC), is excreted into breastmilk in small quantities. The duration of detection of THC in milk has ranged from 6 days to greater than 6 weeks in various studies. Concern has been expressed regarding the possible effects of cannabis on neurotransmitters, nervous system development and endocannabinoid-related functions. One preliminary study found a decrease in secretory IgA (SIgA) levels in the milk of cannabis users. A 1-year study found that daily or near daily use might retard the breastfed infant's motor development, but not growth or intellectual development. This and another study found that occasional maternal cannabis use during breastfeeding did not have any discernable effects on breastfed infants, but the studies were inadequate to rule out all long-term harm. Although cannabis can affect serum prolactin variably, it appears not to adversely affect the duration of lactation. However, maternal perception that their use of cannabis is harmful to their infants are likely to discontinue breastfeeding earlier than mothers who do not believe it is harmful. Other factors to consider are the possibility of positive urine tests in breastfed infants, which might have legal implications, and the possibility of other harmful contaminants in street drugs.
Because of insufficient long-term data on the outcome of infants exposed to cannabis via breastmilk, health professionals' opinions on the acceptability of breastfeeding by cannabis-using mothers varies. In general, professional guidelines recommend that cannabis use should be avoided by nursing mothers, and nursing mothers should be informed of possible adverse effects on infant development from exposure to cannabis compounds in breastmilk. In addition to possible adverse effects from cannabinoids in breastmilk, paternal cannabis use may also increase the risk of sudden infant death syndrome in breastfed infants. Cannabis should not be smoked by anyone in the vicinity of infants because the infants may be exposed by inhaling the smoke.
◉ Effects in Breastfed Infants:Twenty-seven mothers reported smoking marijuana during breastfeeding. Twelve of them smoked once a month or less, 9 smoked weekly, and 6 smoked daily. Six of their infants were compared at 1 year of age to the infants of mothers who did not smoke marijuana during pregnancy or breastfeeding. No differences were found in growth, or on mental and motor development.
Sixty-eight infants whose mothers reported smoking marijuana during breastfeeding were compared to 68 matched control infants whose mothers did not smoke marijuana. The duration of breastfeeding varied, but the majority of infants were breastfed for 3 months and received less than 16 fluid ounces of formula daily. Motor development of the marijuana-exposed infants was slightly reduced in a dose-dependent (i.e., number of reported joints per week) manner at 1 year of age, especially among those who reported smoking marijuana on more than 15 days/month during the first month of lactation. No effect was found on mental development.
A small, case-control study found that paternal marijuana smoking postpartum increased the risk of sudden infant death syndrome. In this study, too few nursing mothers smoked marijuana to form any conclusion.
A study of women taking buprenorphine for opiate substitution during pregnancy and lactation found that 4 of the women were also using cannabis as evidenced by positive urine screens for THC between 29 and 56 days postpartum. One was also taking unprescribed benzodiazepines. One infant was exclusively breastfed and the other 3 were mostly breastfeeding with partial supplementation. Infants had no apparent drug-related adverse effects and showed satisfactory developmental progress.
Fifty women who reported using cannabis in the prior 14 days donated milk samples for analysis of THC and its major metabolites. THC was detectable in 66% of the samples and below the limit of quantification in 32% of samples. Preliminary evidence found no differences in infant adverse reactions, postnatal growth, or neurodevelopmental outcomes were found between the groups with quantifiable and nonquantifiable THC in breastmilk.
A 6-month-old infant was exclusively breastfed by a mother who was a chronic cannabis user. She presented to the emergency department with somnolence after falling off a couch and developed seizure-like activity and minimally responsive dilated pupils. Laboratory values and a head CT scan were normal except for carboxy-THC found in urine and blood. The infant returned to baseline in 72 hours.
◉ Effects on Lactation and Breastmilk:Acute one-time marijuana smoking suppresses serum concentrations of luteinizing hormone and prolactin in nonpregnant, nonlactating women. The effects of long-term use is unclear, with some studies finding no effect on serum prolactin. However, hyperprolactinemia has been reported in some chronic cannabis users, and galactorrhea and hyperprolactinemia were reported in a woman who smoked marijuana for over 1 year. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Of 258 mothers who reported smoking marijuana during pregnancy, 27 who had smoked marijuana during breastfeeding were followed-up at 1 year. No difference was found in the age of weaning between these mothers and 35 who reported not smoking marijuana during pregnancy or breastfeeding.
The US state of Colorado legalized medical cannabis in 2001 and recreational cannabis in 2012. A cross-sectional survey conducted in Colorado in 2014 and 2015 found that both prenatal and postnatal cannabis use were associated with a shorter duration of breastfeeding. Among women who reported using cannabis during pregnancy, 64% breastfed for 9 or more weeks compared with 78% of women who did not use cannabis during pregnancy. Among women who reported postpartum cannabis use, 58% breastfed for 9 or more weeks compared with 79% of women who did not use cannabis postpartum. Both differences were statistically significant.
A study using a database of 4969 postpartum women found that those who reported using marijuana were more likely to smoke cigarettes, experience postpartum depressive symptoms, and breastfeed for less than 8 weeks. Tobacco smoking is known to decrease the duration of breastfeeding, so the effect of marijuana is not clear. Most of the women who smoked marijuana postpartum also used it during pregnancy.
Among a group of 14 women who used cannabis postpartum by inhalation, lactose levels were higher in the milk of cannabis users compared to the milk of non-users. The milk of cannabis users had lower levels of sIgA relative to non-users; however, when adjusted for BMI, there was no difference in sIgA levels between the groups. Subjects who used both cannabis and cigarettes had lower carbohydrate levels and greater crude protein and true protein levels in their milk. Cannabis-using mothers reported lower levels of milk production in the first, second, fourth, and sixth weeks postpartum, compared to non-users.
Following a single buccal administration, maximum plasma concentrations of both CBD and THC typically occur within two to four hours. When administered buccally, blood levels of THC and other cannabinoids are lower compared with inhalation of smoked cannabis. The resultant concentrations in the blood are lower than those obtained by inhaling the same dose because absorption is slower, redistribution into fatty tissues is rapid and additionally some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, a psycho-active metabolite. The CBD component of sublingual Sativex was found to have a Tmax of 1.63hr and a Cmax of 2.50ng/mL, while buccal Sativex was found to have a Tmax of 2.80hr and a Cmax of 3.02ng/mL.
Elimination from plasma is bi-exponential with an initial half-life of one to two hours. The terminal elimination half-lives are of the order of 24 to 36 hours or longer. Sativex is excreted in the urine and faeces.
Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life.
Provided are synthesis processes and intermediates for preparing cannabinoids and analogs.
提供了制备大麻素和类似物的合成过程和中间体。
[EN] DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS<br/>[FR] DIARYLURÉES EN TANT QUE MODULATEURS ALLOSTÉRIQUES DE CB1
申请人：RTI INT
公开号：WO2018209030A1
公开（公告）日：2018-11-15
The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.
[EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
申请人：ARIYA THERAPEUTICS INC
公开号：WO2019046491A1
公开（公告）日：2019-03-07
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.
D-AMINO ACID OXIDASE INHIBITORS AND THERAPEUTIC USES THEREOF
申请人：Tsai Guochuan Emil
公开号：US20190112289A1
公开（公告）日：2019-04-18
The present invention relates to compounds of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein: each of A, B, C, D, and E, independently, is C, N, N—H, O, S, or absent
is a single bond or a double bond; each of X, Y, and Z, independently, is aryl, heteroaryl, aralkyl, H, or absent; each of L
1
and L
2
, independently, is a moiety selected from O, CH
2
, C═O, C
2-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, —((CH
2
)
n
—W)—, wherein n=0, 1, 2, 3, 4, or 5, and W is O or S, or absent; and when L
2
is absent, Z is aryl or heteroaryl fused with B
C. Also provided in the present invention is a method for inhibiting, treating and/or reducing the risk of a neuropsychiatric disorder, comprising administering a subject in need a composition comprising a compound of Formula (I).
本发明涉及以下式（I）的化合物：
或其药学上可接受的盐，其中：A、B、C、D 和 E 中的每一个独立地是 C、N、N—H、O、S 或不存在
是单键或双键；X、Y 和 Z 中的每一个独立地是芳基、杂环芳基、芳基烷基、H 或不存在；L
1
和 L
2
中的每一个独立地是从 O、CH
2
、C═O、C
2-10
烷基、C
2-10
烯基、C
2-10
炔基、—((CH
2
)
n
—W)— 中选择的基团，其中 n=0、1、2、3、4 或 5，W 是 O 或 S，或不存在；当 L
2
不存在时，Z 是与 B 相融合的芳基或杂环芳基。本发明还提供了一种用于抑制、治疗和/或减少神经精神障碍风险的方法，包括向需要的受试者施用包含式（I）化合物的组合物。
[EN] 2-CYCLOALKYL RESORCINOL CANNABINERGIC LIGANDS<br/>[FR] LIGANDS CANNABINERGIQUES DE 2-CYCLOALKYL RÉSORCINOL
申请人：UNIV NORTHEASTERN
公开号：WO2014062965A1
公开（公告）日：2014-04-24
The present invention relates to novel 2-cycloalkyl resorcinol compounds; to pharmaceutical compositions comprising the compounds; and to methods of preparing the compounds and uses thereof. The disclosed compounds can bind to and modulate the cannabinoid receptors and thus, they are specific ligands for these receptors. The invented compounds, when administered in a therapeutically effective amount to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a physiological response. The physiological response may be useful to treat a number of physiological conditions.
