Ignite Creation Date:
2024-05-05 @ 11:58 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00196131
Status:
UNKNOWN
Last Update Posted:
2008-04-10
First Post:
2005-09-12
Brief Title:
Problems With Morphine Use in Patients With a Severe Brain Injury
Sponsor:
Dalhousie University
Organization:
Dalhousie University
Study Overview
Official Title:
Changes in Morphine Handling and Response in Patients With Brain Trauma
Status:
UNKNOWN
Status Verified Date:
2006-09
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hypothesis During severe brain trauma injury surgery the ensuing inflammatory response in the central nervous system CNS results in a decrease in the expression of the transporter protein p-glycoprotein PGP in the blood brain barrier This loss results in the penetration into the brain of certain drugs that are normally excluded by the transporter protein In this study the working hypothesis is that the agitation observed in patients with CNS trauma treated with morphine is related to the inflammation evoked loss of PGP in the blood brain barrier and the accumulation of the morphine metabolite 3-morphine glucuronide
Detailed Description:
It is well established that the metabolism distribution and elimination of certain drugs is affected by inflammatory processes This results from the expression of cytochrome and drug transporter proteins that are altered during the generation of host defense mechanisms This has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs are severely compromised From studies in animals individual cytochrome P450 isozymes and p-glycoprotein PGP are down regulated at the level of gene transcription with a resulting decrease in the corresponding mRNA protein and enzymetransporter activity The loss in drug metabolism and transport is channeled predominantly through the production of cytokines which ultimately modify specific transcription factors Other proposed mechanisms that apply to specific cytochrome P450s involve post translational steps including enzyme modification and increased degradation When inflammatory responses are confined to the brain there is a loss of cytochrome P450 and PGP not only in the brain but also in peripheral tissues This involves a yet to be identified mode of signaling between the brain and periphery but it does involve the production of cytokines from a peripheral source
In clinical medicine there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component This often results in altered drug responses and increased toxicities Inflammation mediated alterations in the metabolism of endogenous compounds can also lead to altered physiology Recently it has been shown in rodents that inflammatory responses within the brain alter drug disposition in the brain and in peripheral systems Of particular note to the use of drugs in patients with a brain trauma is a recent study in our laboratory carried out in rodents showing that the transport of some drugs across the blood brain barrier is dramatically changed during a CNS inflammatory response The reason this occurs is the loss in expression of the drug transporter protein PGP This allows drugs which are normally transported out of the brain by PGP to enter and cause CNS toxicity Such changes in drug handling capacity during inflammationinfection will continue to be one of the many factors that complicate therapeutics
In humans with a severe CNS trauma injury surgery an inflammatory response commonly occurs within the brain It has also been our clinical observation that when these patients receive morphine as part of their care the drug is tolerated for a few days but many patients develop agitation that we believe is related to morphine therapy Our working hypothesis is that a metabolite of morphine which is a CNS irritant 3-morphine glucuronide can enter the brain in increased amounts because of the inflammation evoked loss in the transporter protein PGP in the blood brain barrier In normal circumstances morphine is metabolized in the liver to two major metabolites 3-morphine glucuronide and 6-morphine glucuronide These metabolites are excluded to some extent by a functioning PGP in the blood brain barrier If the PGP diminishes in the blood brain barrier as a result of CNS inflammation then these morphine metabolites will increase in concentration in the brain Some support for this idea can be taken from the recent studies showing that the inhibition of PGP by chemical means increases the concentration of the 6-glucuronide of morphine following the administration of morphine to rats Although the 6-glucuronide is more potent than morphine with similar actions the 3-glucuronide is a CNS irritant and may cause the agitation observed in these patients We propose to measure these metabolites on both sides of the blood brain barrier in patients with CNS traumainflammation to determine if the agitation correlates with the build up of metabolites If we can demonstrate that these metabolites increase in the CNS as a result of inflammation this study will have far reaching consequences to many other drugs that are normally excluded from the brain in this manner eg digoxin cyclosporine A HIV protease inhibitors during their use in any condition that involves an inflammatory component in the CNS
In clinical medicine there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component This often results in altered drug responses and increased toxicities Inflammation mediated alterations in the metabolism of endogenous compounds can also lead to altered physiology Recently it has been shown in rodents that inflammatory responses within the brain alter drug disposition in the brain and in peripheral systems Of particular note to the use of drugs in patients with a brain trauma is a recent study in our laboratory carried out in rodents showing that the transport of some drugs across the blood brain barrier is dramatically changed during a CNS inflammatory response The reason this occurs is the loss in expression of the drug transporter protein PGP This allows drugs which are normally transported out of the brain by PGP to enter and cause CNS toxicity Such changes in drug handling capacity during inflammationinfection will continue to be one of the many factors that complicate therapeutics
In humans with a severe CNS trauma injury surgery an inflammatory response commonly occurs within the brain It has also been our clinical observation that when these patients receive morphine as part of their care the drug is tolerated for a few days but many patients develop agitation that we believe is related to morphine therapy Our working hypothesis is that a metabolite of morphine which is a CNS irritant 3-morphine glucuronide can enter the brain in increased amounts because of the inflammation evoked loss in the transporter protein PGP in the blood brain barrier In normal circumstances morphine is metabolized in the liver to two major metabolites 3-morphine glucuronide and 6-morphine glucuronide These metabolites are excluded to some extent by a functioning PGP in the blood brain barrier If the PGP diminishes in the blood brain barrier as a result of CNS inflammation then these morphine metabolites will increase in concentration in the brain Some support for this idea can be taken from the recent studies showing that the inhibition of PGP by chemical means increases the concentration of the 6-glucuronide of morphine following the administration of morphine to rats Although the 6-glucuronide is more potent than morphine with similar actions the 3-glucuronide is a CNS irritant and may cause the agitation observed in these patients We propose to measure these metabolites on both sides of the blood brain barrier in patients with CNS traumainflammation to determine if the agitation correlates with the build up of metabolites If we can demonstrate that these metabolites increase in the CNS as a result of inflammation this study will have far reaching consequences to many other drugs that are normally excluded from the brain in this manner eg digoxin cyclosporine A HIV protease inhibitors during their use in any condition that involves an inflammatory component in the CNS
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| CIHRMOP-74451 | None | None | None |