Duodote

The U.S. Food and Drug Administration (FDA) today approved Duodote
(atropine and pralidoxime chloride injection) for use by trained
emergency medical services personnel to treat civilians exposed to life-
threatening organophosphorus-containing nerve agents, such as sarin,
and insecticides.  Duodote is manufactured by Meridian Medical
Technologies, Inc., Columbia, Md.

FDA previously approved atropine and pralidoxime chloride injection
under the name Antidote Treatment--Nerve Agent Auto-Injector (ATNAA)
for military use.  Developed by the U.S. Army and manufactured by
Meridian Medical Technologies, Inc., ATNAA is not available for use in
civilians.  ATNAA was approved on Jan. 17, 2002, for use by the military
to treat troops who have been exposed to toxic nerve agents that cause
loss of muscle control and death from respiratory failure.  The two
constituent drugs in ATNAA were previously approved for use
separately.  Atropine autoinjector has been approved for use in adults
since 1973, and its use in children and adolescents was approved in
June 2003.  Pralidoxime was first approved for use in 1964.

"Today's approval facilitates the stockpiling of the product so that it can
be used to treat civilians in an emergency," said Douglas Throckmorton,
M.D., deputy director of FDA's Center for Drug Evaluation and Research.
"The approval contains two caveats: the primary protection against
exposure to chemical nerve agents and insecticide poisoning is the
wearing of protective clothing; and Duodote may be administered only by
well-trained emergency medical personnel."

The manufacturer will distribute Duodote directly to emergency medical
service organizations or their suppliers.

ABOUT ATROPINE

Atropine, an anticholinergic agent (muscarinic antagonist), occurs as
white crystals, usually needle-like, or as a white, crystalline powder. It is
highly soluble in water with a molecular weight of 289.38. Atropine, a
naturally occurring belladonna alkaloid, is a racemic mixture of equal
parts of d- and l-hyoscyamine, whose activity is due almost entirely to the
levo isomer of the drug. Chemically, atropine is designated as 1 H,5 H-
Tropan-3 –ol (±) -tropate. Its empirical formula is C17H23NO3.

Atropine is commonly classified as an anticholinergic or
antiparasympathetic(parasympatholytic) drug. More precisely, however, it
is termed an antimuscarinic agent since it antagonizes the muscarine-like
actions of acetylcholine and other choline esters. Atropine inhibits the
muscarinic actions of acetylcholine on structures innervated by
postganglionic cholinergic nerves, and on smooth muscles, which
respond to endogenous acetylcholine but are not so innervated. As with
other antimuscarinic agents, the major action of atropine is a competitive
or surmountable antagonism, which can be overcome by increasing the
concentration of acetylcholine at receptor sites of the effector organ (e.
g., by using anticholinesterase agents, which inhibit the enzymatic
destruction of acetylcholine). The receptors antagonized by atropine are
the peripheral structures that are stimulated or inhibited by muscarine, (i.
e., exocrine glands and smooth and cardiac muscle). Responses to
postganglionic cholinergic nerve stimulation may also be inhibited by
atropine, but this occurs less readily than with responses to injected
(exogenous) choline esters.

About Pralidoxime

Pralidoxime chloride occurs as an odorless, white, nonhygroscopic,
crystalline powder which is soluble in water. Stable in air, it melts between
215C and 225C, with decomposition. The specific activity of the drug
resides in the 2-formyl-1-methylpyridinium ion and is independent of the
particular salt employed. The chloride is preferred because of physiologic
compatibility, excellent water solubility at all temperatures, and high
potency per gram, due to its low molecular weight.

The principal action of pralidoxime is to reactivate cholinesterase (mainly
outside of the central nervous system) which has been inactivated by
phosphorylation due to an organophosphate pesticide or related
compound. The destruction of accumulated acetylcholine can then
proceed, and neuromuscular junctions will again function normally.
Pralidoxime also slows the process ofaging of phosphorylated
cholinesterase to a nonreactivatable form, and detoxifies certain
organophosphates by direct chemical reaction. The drug has its most
critical effect in relieving paralysis of the muscles of respiration. Because
pralidoxime is less effective in relieving depression of the respiratory
center, atropine is always required concomitantly to block the effect of
accumulated acetylcholine at this site. Pralidoxime relieves muscarinic
signs and symptoms, salivation, bronchospasm, etc., but this action is
relatively unimportant since atropine is adequate for this purpose.

Pralidoxime is distributed throughout the extracellular water; it is not
bound to plasma protein. The drug is rapidly excreted in the urine partly
unchanged, and partly as a metabolite produced by the liver.
Consequently, pralidoxime is relatively short acting, and repeated doses
may be needed, especially where there is any evidence of continuing
absorption of the poison.

SOURCES
FDA Approves Nerve-Poisoning Agents for Use by Trained Emergency Medical Services
PersonnelFDA News September 29, 2006
AtroPen Auto-Injector NDA 17-106/S-028 Package Insert
Protopam Injection Supplement S-024 DRAFT Package Insert
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