HaCKeRz Kr0nlcKLeZ 1/HaCKeRz Kr0nlcKLeZ.iso/drugs/mptp.article

Text File | 1996-05-06 | 10.8 KB | 221 lines

Newsgroups: alt.drugs
From: [e-mail] (H-Man)
Subject:  MPTP article
Message-ID: <[e-mail]>
Date: Sat, 3 Jul 1993 17:53:48 GMT

                  MPTP-CONTAMINATED DESIGNER DRUGS - TREATMENT


PATIENT DATA:

   Please review the presentation and treatment of patients who
have used MPTP-contaminated designer drugs.

RESPONSE:

   DESIGNER DRUGS are analogs of known pharmacological agents,
synthesized by underground chemists, for sale on the street.

   The concept of designer drugs is to manipulate the chemical
structure of a narcotic, for example, and create a totally new
compound.  The "underground" chemist has two goals.  First, is
the belief that the nature and duration of the "high"

   experienced can be changed through chemical manipulations.
Although the science of medicinal chemistry involves predictions
of structure-activity relationships regarding psychodynamic
effects, associated toxicities are frequently unexpected.

   Second, since there are no laws against newly formulated
compounds, legal ramifications are bypassed.  Fortunately,
emergency laws have been implemented against such agents and new
regulations are being processed (Baum, 1985).  This consult
includes a brief overview of designer drugs and a discussion of
DESIGNER MEPERIDINE, proposed mechanisms of its toxicities and
some treatment possibilities.

   There are at least three popular types of designer drugs:
 MDMA  (3,4-METHYLENEDIOXYMETHAMPHETAMINE), FENTANYL
ANALOGS, and MEPERIDINE ANALOGS.   MDMA  is not a true designer
drug, as this agent is a schedule I agent that was once used in
psychiatry.  Street names for  MDMA  include:  MDA, ADAM,
 ECSTASY  and XTC.   MDMA  interacts with serotonergic neurons.
 MDMA  produces effects that are similar to those of LSD without
hallucinatory properties.  These include increased
self-awareness and decreased communication barriers.  Side
effects consist of increased heart rate and blood pressure,
irregular heart beat, panic attacks, anxiety, sleep disorders,
drug craving, paranoia, and rebound depression.

   Fentanyl analogs include the following:
alpha-methyl-p-fluoro-3-methyl and alpha-methyl-acetylfentanyl.
In 1979 the alpha-methyl analog was found in users of "CHINA
WHITE".  The effects of these compounds are similar to heroin
in terms of the nature of the "high" and its duration of action.
However, these analogs can be up to 40 times more potent than
heroin.  This potency makes overdose a serious risk.  The
drug-induced respiratory depression can be fatal (Baum, 1985).
Adverse Drug Reactions of Designer Meperidine
Designer meperidine is sold as SYNTHETIC HEROIN.  The primary
street analog of meperidine is MPPP
(1-methyl-4-phenyl-4-propionpiperidine).  Very specific chemical
reaction conditions are required to produce MPPP.  In the event
of sloppy synthesis, where the pH is too low or the temperature
is too high, a contaminant, MPTP
(1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) is formed.  MPTP
is a known industrial toxin which affects the dopaminergic
neurons of the substantia nigra.  Cases of PARKINSON'S DISEASE
caused by MPTP have been reported (Baum, 1985).

   The proposed biochemical mechanism of action of MPTP involves
the rapid oxidation of MPTP to MPP+ after systemic
administration.  This conversion takes place in all tissues
studied (brain and systemic), except for the eye, and is
necessary for MPTP to exert its toxic effects (Irwin & Langston,
1985).  Monoamine oxidase catalyzes this reaction.  Highly
reactive intermediates may also be formed in the conversion.
MPP+ is then taken up by neurons in the substantia nigra where
it destroys dopaminergic neurons in this area.  Although the
formation of MPP+ occurs in many parts of the brain, it remains
unclear as to why it selectively accumulates in the substantia
nigra and not in other dopaminergic areas of the brain such as
the striatum (Langston, 1985).  These biochemical mechanisms are
undergoing further studies.

   MPTP exposure is suspected if the patient answers "yes" to the
following questions on initial presentation:  1.  Did the pure
form of the drug resemble brown sugar?  2.  Was there a burning
sensation on intravenous injection at the injection site and up
through the vein?  3.  Was the "high" more "spacey and giddy"
than that of heroin?  These questions can help identify MPTP
exposures (Latimer, 1985).  Other symptoms of MPTP toxicity are
discussed below.

   Three phases of MPTP toxicity have been identified (Langston,
1985a).  The first is an acute phase which occurs on initial
exposure to MPTP.  Symptoms include disorientation,
hallucinations, blurred vision, "nodding off" (a slow downward
drifting of the head, and drooping and closure of the eyelids),
difficulties in speech and swallowing, intermittent jerking of
the limbs, slow movement, and tremor at rest.  The second phase
is a subacute event which occurs after exposure to the drug.

   Two to three days post-exposure there are reports of increased
bradykinesia and rigidity of extremities, abrupt onset of
"freezing up" and inability to move.  Up to three weeks after
exposure, awkward posture, progressive slowness of movement and
"freezing up" have been reported.  Finally, if there is no
recovery from the above two phases, a chronic syndrome results.

   A permanent Parkinsonian syndrome evolves consisting of
classical Parkinsonian symptoms such as bradykinesia, rigidity,
resting tremor, fixed stare, and loss of postural reflexes.
Recovery from the acute or subacute phase may occur, but it is
unlikely once the chronic phase has been reached.

   Several mechanisms have been proposed to explain the
manifestations of each of the three phases.  Possible mechanisms
regarding the acute phase include an opiate receptor interaction
with MPTP, serotonergic effects of the substance, and a slight
dopaminergic deficiency caused by MPTP.  Because MPTP is a
meperidine analog, an opiate receptor interaction is probably
responsible for the "nodding off" which takes place.  This
phenomenon is typical of exposure to heroin and is due to the
same type of opiate receptor interaction.  An initial
suppression of serotonin in the central nervous system by MPTP
is the suggested cause for the hallucinations and retropulsions
which occur (Ballard et al, 1985).  Motor symptoms are
attributed to MPTP's effect on the dopaminergic neurons in the
substantia nigra, but the dopamine deficiency is not yet
substantial.

   The subacute phase is thought to occur once MPTP accumulation
reaches a critical threshold before killing cells in the
substantia nigra.  This theory thus offers an explanation for
the delayed onset of symptoms and for the continuation of
symptoms after exposure.  Metabolic damage, such as impaired
dopamine synthesis, is also suggested as a cause of dopamine
depletion.  Further study of this delayed phase is in progress.
The likely cause of the chronic phase is actual nigral cell
death.  This, in turn, leads to a permanent hypodopaminergic
state, and thus permanent Parkinsonism.

   Recovery from the acute and subacute phases has two possible
explanations.  A critical toxic threshold of MPTP may not be
reached intracellularly in the substantia nigra, thus the cells
can return to normal once exposure is stopped.  Or, perhaps less
than a critical number of dopaminergic neurons are lost and the
remaining cells are able to compensate by overproduction of
dopamine, therefore resolving the clinical symptoms.

   Typical Parkinsonian treatment modalities are employed in
patients who present with MPTP toxicity.  Anticholinergic agents
only help to reduce the tremor, and thus are of little benefit.
CARBIDOPA and LEVODOPA therapy, with or without dopamine
agonists, such as BROMOCRIPTINE, are helpful, but
complications typical of this therapy have resulted.  These
problems include dyskinesias, end of dose deterioration, and
on-off swings between choreathetosis and Parkinson's symptoms.
Studies with monoamine oxidase type B inhibitors, such as
PARGYLINE and SELEGILINE, suggest a possible alternative
treatment (Tetrud & Langston, 1989; Langston et al, 1984; Fuller
& Hemrick-Lueck, 1985).  If monoamine oxidase (MAO) is
inhibited, the conversion of MPTP to MPP+ is prevented.  Thus,
MAO inhibitor drugs may provide a protecting effect if given
prior to MPTP and may be effective in retarding the progression
of symptoms if given after MPTP.  Further research is underway
concerning drug therapy for MPTP toxicities.

CONCLUSION:

   Several significant points can be noted regarding MPTP
contamination.  First, the risks of designer drugs are great due
to the lack of purification after synthesis, the lack of
knowledge about what is actually being created, and the presence
of possible adulterants.  Secondly, MPTP is a very specific
neurotoxin which can induce irreversible Parkinson's symptoms at
any age.  Finally, MPTP administration to laboratory animals,
provides scientists an opportunity to study the function of
dopamine on the nervous system, the effects of chronic dopamine
deficiency, and the effects of chronic dopamine agonist therapy,
and other areas of interest.  It is hopeful that understanding
the mechanisms of MPTP will provide further understanding of
Parkinsonism and offer new insights to the understanding and
management of this disease.

REFERENCES:

1.  Ballard PA, Tetrud JW & Langston JW:  Permanent human
    Parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    (MPTP):  seven     cases.  Neurology 1985; 35:949-956.
2.  Baum RM:  New variety of street drugs poses growing problem.
    Chem Eng 1985; 9:7-16.
3.  Fuller RW & Hemrick-Lueck SK:  Influence of selective
    reversible inhibitors of monoamine oxidase on the prolonged
    depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,
    6-tetrahydropyridine in mice.  Life Sci 1985; 37:1089-1095.
4.  Irwin I & Langston JW:  Selective accumulation of MPP+ in
    the substantia nigra:  a key to neurotoxicity?  Life Sci
    1985; 36:207-212.
5.  Langston JW:  MPTP and Parkinson's disease.  Trends in
    Neurosciences 1985; 8:79-83.
6.  Langston JW:  MPTP neurotoxicity:  an overview and
    characterization of phases of toxicity.  Life Sci 1985a;
    36:201-206.
7.  Langston JW, Irwin I & Langston EB:  Pargyline prevents MPTP
    induced Parkinsonism in primates.  Science 1984;
    225(4669):1480-1482.
8.  Latimer D:  MPTP "brain damage dope" floods west coast
    suburbs.  High Times 1985; 122:19-27.
9.  Tetrud JW & Langston JW:  The effect of deprenyl
    (selegiline) on the natural history of Parkinson's disease.
    Science 1989; 245:519-522.
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