Special Assignment: CO & Dronabinol

PPt Template [CO & Dronabinol]

Carbon Monoxide

CO is not an acidic oxide [unlike CO2] it is only slightly soluble in H2O. The use
of molecular oxygen as an electron acceptor is why it really isn’t soluble in H2O.

Lipids closely relate to hydrocarbons but have other atoms which limit solubility.

The 2nd Law of Thermodynamics states that spontaneous run-down hill increasing
entropy or disorder.

Van der Waal force:

Carbonic acid => weak
 [ H2CO3 ]
 [ CO2 + H2O ]

Metabolic release of CO2 reduces pH in the surrounding cellular fluids which must
be buffered in order to proceed. This is accomplished by the hemoglobin protein.

It burns readily in Oxygen. It is used in organic synthesis & production of

hydrocarbon fuels.

Stimuli detected by the olfactory system (odors,smells) are volatile substances in

the air sensitive enough to detect 1-part in 50-billionths of air; thusly it is added to
odorless natural gas so we may detect gas leaks.

Dronabinol
Synhexy was the 1st synthetic
Nabilone used to alleviate nausea & distress from chemotherapy, anorexia, & glacoma
Marinol
Levonantradol not yet on market

In addition, orexigenic agents help to stimulate appetite and are often used to treat
anorexia. There are several different types of orexigenic agents including
cannabinoids, progestational agents and corticosteroids.

Marijuana kills pain by activating a set of proteins known as cannabinoid receptors,

which can also regulate appetite, inflammation, and memory. The body also has
Special Assignment: CO & Dronabinol

chemicals known as endocannabinoids that naturally activate these same receptors,

namely N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG).

AEA's activity has been well understood for years. In past research, Cravatt and his team
identified an enzyme called fatty acid amide hydrolase, or FAAH, that breaks down AEA,
effectively reducing its pain killing activity. A number of compounds are now in clinical
development that target and breakdown FAAH, allowing AEA to build up, reducing pain.
However, FAAH does not control 2-AG metabolism in vivo, and therefore, the potential
biological functions and therapeutic potential of this second endocannabinoid have remained
largely unknown.
Teasing out 2-AG's specific impacts have proven challenging. Comparable to FAAH, an enzyme
called monoacylglycerol lipase (MAGL) breaks down 2-AG. But, despite numerous attempts, no
group had been able to develop a chemical that inhibits MAGL specifically
now, a MAGL-specific inhibitor is finally available, thanks to the lab's new work. Key
to this success was Activity-Based Protein Profiling, a unique chemical technique the
group devised and has used fruitfully in other inhibitor hunts. This system enables
the rapid engineering and testing of chemical compounds against many members of
enzyme families, in hope of finding effective and selective inhibitors.
or this project, the group developed about 200 compounds and found that one was a highly
effective block for MAGL. The scientists dubbed the compound JZL184, named after Long's
initials and the order in the series of potential inhibitors tested. JZL184 effectively blocks only
MAGL among more than 40 related brain enzymes, which opened the door for the first definitive
study of 2-AG's activity.
Unlike increased AEA, which causes only reduced pain sensation, the team found that MAGL
inhibition using JZL184, and the resulting increase in 2-AG concentration, not only reduced pain
in mice, but also induced other effects associated with the cannabinoid receptors, namely
hypothermia and decreased movement.
Long et al. Selective blockade of 2-arachidonoylglycerol hydrolysis
produces cannabinoid behavioral effects. Nature Chemical
Biology, Online November 24, 2008; DOI: 10.1038/nchembio.129
Scripps Research Institute (2008, November 27). Marijuana-inspired
Painkiller? New Chemical Pathway Discovered. ScienceDaily. Retrieved
March 17, 2010, from http://www.sciencedaily.com
/releases/2008/11/081123150249.htm
Special Assignment: CO & Dronabinol

Xerostomia (pronounced /ˌzɪəroʊˈstoʊmɪə/) is the medical term for the subjective

complaint of dry mouth due to a lack of saliva.

Tetrahydrocannabinol
Marijuana (cannabis)
Euphoria, drowsiness, relaxation
Impairs memory and mental activity
Xerostomia, hallucinations, delusions
Dependence
Tetra hydro cannabinol is an appetite stimulant and antiemetic.
Marinol/Dronabinol (a synthetic version of THC)

In 1986, the U.S. Food and Drug Administration approved Marinol® (dronabinol), an oral
synthetic form of THC, to treat severe weight loss associated with AIDS (HIV/AIDS wasting)
and nausea and vomiting associated with chemotherapy for patients who fail to respond to other
antiemetics. Clinical trials have demonstrated that both oral and smoked marijuana stimulate
appetite, increase caloric intake, and result in weight gain among patients experiencing HIV
wasting (6–9). Studies of chemotherapy patients with nausea and vomiting found THC to be
equivalent or superior to other antiemetics (including prochlorperazine or metoclopramide) for
symptom reduction (10). Research has also found that administration of THC along with another
antiemetic was more effective that either drug alone, suggesting opportunities for combined
therapy. The IOM concluded that cannabinoids are “modest” antiemetics but may be effective
for those who respond poorly to other available antiemetics. THC and other cannabinoids may
offer relief not found in other drugs (11).
Special Assignment: CO & Dronabinol

Only 2 cannabinoid drugs are currently licensed for sale in the U.S. (dronabinol [Marinol ®] and
nabilone [Cesamet ®]), and both are only available in oral form. While useful for some, these
drugs have serious limitations. The oral route of administration hampers the effectiveness of
THC because of slow absorption. In addition, swallowing a pill may not be feasible for patients
with severe nausea and vomiting, for whom oral THC is indicated. To overcome the limitations
of oral administration, researchers have focused on developing other nonsmoked, rapid-onset
formulations. Sativex® , an oromucosal spray of natural cannabis, was approved in June 2006
for prescription use in Canada to treat neuropathic pain in patients with MS. The manufacturer,
GW Pharmaceuticals, received FDA approval to begin a U.S. clinical trial of Sativex for cancer
patients in 2007. The development of a vapor route for THC delivery offers promise for the
future of medical marijuana research. A recent study found that THC administered through the
Volcano® vaporizer resulted in higher plasma THC levels than smoked marijuana at both 30 and
60 minutes after administration. It also found that exhaled carbon monoxide increased very little
after vapor compared with smoking (37).

Vaporization of THC offers the rapid onset of symptom relief without the negative effects from
smoking. It allows patients to self-regulate their dosage immediately by ceasing inhalation when
or if psychoactive effects become unpleasant. Scientists are also developing a pulmonary
dronabinol to be delivered with a pressurized metered-dosed inhaler. Preliminary studies show
rapid absorption, but FDA approval remains distant.

Dronabinol, oral THC, is classified as a Schedule III substance. Recently, the DEA proposed a
rule that would allow for classification of both synthetic and natural (derived from the cannabis
plant) dronabinol products in Schedule III. Opiates are highly addictive yet medically effective
substances and are classified as Schedule II substances. There is no evidence to suggest that
medical use of opiates has increased perception that their illicit use is safe or acceptable (42).
Given marijuana’s proven efficacy at treating certain symptoms and its relatively low toxicity,
reclassification would reduce barriers to research and increase availability of cannabinoid drugs
to patients who have failed to respond to other treatments.

Beal J, Olson R, Lefkowitz L, Laubenstein, et al.

Long-Term Efficacy and Safety of Dronabinol for Acquired Immunodeficiency Syndrome-
Associate Anorexia. Journal of Pain and Symptom Management 1997; 14(1): 7-14 10.

Musty R, Rossi R.
Effects of Smoked Cannabis and Oral  9- Tetrahydrocannabinol on Nausea and Emesis After
Cancer Chemotherapy: A Review of State Clinical Trials. Journal of Cannabis Therapeutics
2001; 1(1): 29-42. 11.

Joy JE, Watson SJ, Benson JA. Marijuana and Medicine: Assessing the Science Base. National
Academy of Sciences, Institute of Medicine. Washington, DC; 1999. 12.

Grant I, Cahn BR. Cannabis and Endocannabinoid Modulators: Therapeutic Promises and
Challenges. Clinical Neuroscience Research 2005; 5: 185-99