Multiple CYPs catalyze the oxidation of chemicals of endogenous and exogenous origin, including drugs, steroids, prostanoids, eicosanoids, fatty acids, and environmental toxins [[ 1 ]]. If a drug that is metabolized by a particular CYP isozyme is coadministered with an inhibitor of that same enzyme, changes in its pharmacokinetics can occur, which can give rise to adverse effects [[ 2 - 5 ]]. It is therefore important to predict and prevent the occurrence of clearance changes caused by metabolic inhibition.
During the drug discovery process, it has become routine practice in the pharmaceutical industry to assess CYP inhibition potential of drug candidates in order to exclude potent inhibitors from further development [[ 6 - 8 ]]. The extent of metabolic interaction between two drugs depends on their relative Km and Ki values and concentrations at the site of metabolism [[ 3 ]].
In recent years, substantial progress has been made in the development of in vitro screening methods to quantitatively determine kinetic parameters of CYP inhibition.
Using either recombinant CYP proteins or liver microsomes, together with appropriate probe substrates, these assays can be used to measure Ki values for competitive CYP inhibitors [[ 7 , 9 , 10 ]]. It is not entirely clear, however, whether these systems accurately and quantitatively reflect drug interactions that occur in vivo.
One possible drawback of recombinant enzymes is that inhibitory potency may depend on interactions with multiple CYPs present in the microsomal, but not recombinant, systems. The intracellular concentration of drugs substrates and inhibitors that is available for interacting with a particular CYP may also depend on processes lacking in microsomes, such as drug transport across the plasma membrane, metabolism by cytosolic enzymes, and binding to intracellular proteins.
However, there are few reports of CYP inhibition studies using this system see for example [[ 13 , 16 - 18 ]] , probably because of the technical challenge posed by the lower specific activity of CYP in cultured cells relative to microsomal preparations. Proponents of the euphemism "recreational use" appear to rail against any suggestion that drug abuse is bad. Well, it is bad. Any hint otherwise should be immediately quashed, as there is no excuse for improper drug use.
One might be of the opinion that drug abuse is perfectly acceptable, but that opinion will run right up against the moral stand that it's not acceptable, and that's a tough one to get past.
You, my friend, when you are operating on a neutral encyclopedia project and at the same time screaming such biases as "drug abuse is bad" represents a totally uninformed view against that which is not understood. Use of products intended for medical use to achieve psychedelic effects could be described within the literature as 'misuse' at best.
But to outright label all informed recreational use as "abuse" would be totally unencyclopedic. This molecule is being studied as a possible treatment for depression, for example. Improper treatment or usage; application to a wrong or bad purpose; misuse; perversion". The other definition of abuse that would apply here is "2. Physical maltreatment; injury" which in my opinion also implies a negative tone. It should be made clear that everyone who uses drugs is not a "drug abuser" and there are such people as " drug users ".
The term abuse should be replaced with misuse - "1. An incorrect, improper or unlawful use of something", which seems to describe people who use dextromethorphan in anyway other than the recommended in the least biased fashion. Introduction The rising prevalence of osteoarthritis OA is a major medical concern worldwide [ 1 ]. Although the factors causing arthritis vary, cartilage damage exists in both OA and rheumatoid arthritis RA [ 2 ].
Cartilage is a major component of joints and has a buffering role to relieve the stress applied to the joints. Chondrocytes, which are the only cell type found in the cartilage, produce collagen and glycosaminoglycan that form a concentrated and highly coordinated extracellular matrix ECM , which plays critical roles in OA development [ 3 ]. Among ECM, manipulating collage II provides a potential implication for cartilage therapeutics [ 4 ]. The inflammatory process results in overproduction of metalloproteases that leads to damage of the ECM and joint instability.
Although clinically relevant overdoses mandate immediate management, generally the UDS turnaround time is not rapid enough to dictate treatment. However, it is still important for the clinical staff to be aware of possible interferences if performing patient follow-up.
Most if not all assay kit inserts have a list of suspected agents and medications that can induce interference or cross-reactivity, and it is always important to consult with the clinical laboratory if results are suspicious. Whether or not these criteria can be determined, all initial screens testing positive should always be confirmed with more sophisticated, precise, and accurate methods, such as gas chromatography-mass spectrometry GC-MS , liquid chromatography-mass spectrometry LC-MS , or high-performance liquid chromatography HPLC.
These methods can definitively rule out any false positives and confirm the presence and amount of the illicit substance. Figure 2 The structural similarities between dextromethorphan and 2 common opiates: morphine and codeine.Well, it is bad. Concerning both in vitro cell synthesis and in almost mice model studies, we suggest that repurposing DXM to be one of the others for treatment of OA may need clinical trials. Influx: A separate article on Higher use once existed see herebut pdf entranced into this article on 10 Febsee AfD reader. Feasible ATP concentrations were 2.
During the drug discovery process, it has become routine practice in the pharmaceutical industry to assess CYP inhibition potential of drug candidates in order to exclude potent inhibitors from further development [[ 6 - 8 ]]. Introduction The rising prevalence of osteoarthritis OA is a major medical concern worldwide [ 1 ]. Improper treatment or usage; application to a wrong or bad purpose; misuse; perversion". The therapeutic efficacy is due to its main demethylated metabolite, dextrorphan DXO Figure 1. The side effects of DXM use are generally mild, such as diaphoresis, fever, dizziness, nausea, vomiting, and mydriasis.
Physical maltreatment; injury" which in my opinion also implies a negative tone. Studies of CYP inhibition in intact hepatocytes may be warranted for compounds that concentrate in the liver as the result of cellular transport. Finally, I saw above that someone requested synthesis information in the Chemistry section, and I am working on getting together some sources on that topic, which I plan on using to add a synthesis subsection in the future. The reaction rate as a function of substrate concentration was fitted to the Hill equation: 2 where v and Vmax are the observed and maximal rates of metabolism, S50 is the substrate concentration at half Vmax, and n is the Hill coefficient.
The other definition of abuse that would apply here is "2. In support of the usefulness of DXM in neurological disorders, DXM treatment decreases the number of immune cells entering the spinal cord and provides therapeutic benefits in experimental autoimmune encephalomyelitis [ 8 ].
Removed dubious historical info[ edit ] I just removed the claim that the FDA "approved dextromethorphan as a prescription antitussive drug on September 24, " their citation for this fact does not contain the date September 24, and I cannot find an authoritative source to support it, I suspect all other instances of this date being used in DXM histories online are simply repeating misinformation from this wiki. So I appreciate having someone paying attention who knows this stuff. From a clinical laboratory perspective, it is important to remember this when performing an initial screen for drugs of abuse-urine DAU , as structural similarities can many times cause false positive results to occur.
The selected inhibitor concentrations were based on the above literature references. Using either recombinant CYP proteins or liver microsomes, together with appropriate probe substrates, these assays can be used to measure Ki values for competitive CYP inhibitors [[ 7 , 9 , 10 ]].