221 lines
11 KiB
Plaintext
221 lines
11 KiB
Plaintext
Newsgroups: alt.drugs
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From: an13187@anon.penet.fi (H-Man)
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Subject: MPTP article
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Message-ID: <1993Jul4.032852.25925@fuug.fi>
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Date: Sat, 3 Jul 1993 17:53:48 GMT
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MPTP-CONTAMINATED DESIGNER DRUGS - TREATMENT
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PATIENT DATA:
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Please review the presentation and treatment of patients who
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have used MPTP-contaminated designer drugs.
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RESPONSE:
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DESIGNER DRUGS are analogs of known pharmacological agents,
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synthesized by underground chemists, for sale on the street.
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The concept of designer drugs is to manipulate the chemical
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structure of a narcotic, for example, and create a totally new
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compound. The "underground" chemist has two goals. First, is
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the belief that the nature and duration of the "high"
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experienced can be changed through chemical manipulations.
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Although the science of medicinal chemistry involves predictions
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of structure-activity relationships regarding psychodynamic
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effects, associated toxicities are frequently unexpected.
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Second, since there are no laws against newly formulated
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compounds, legal ramifications are bypassed. Fortunately,
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emergency laws have been implemented against such agents and new
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regulations are being processed (Baum, 1985). This consult
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includes a brief overview of designer drugs and a discussion of
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DESIGNER MEPERIDINE, proposed mechanisms of its toxicities and
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some treatment possibilities.
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There are at least three popular types of designer drugs:
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MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE), FENTANYL
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ANALOGS, and MEPERIDINE ANALOGS. MDMA is not a true designer
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drug, as this agent is a schedule I agent that was once used in
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psychiatry. Street names for MDMA include: MDA, ADAM,
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ECSTASY and XTC. MDMA interacts with serotonergic neurons.
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MDMA produces effects that are similar to those of LSD without
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hallucinatory properties. These include increased
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self-awareness and decreased communication barriers. Side
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effects consist of increased heart rate and blood pressure,
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irregular heart beat, panic attacks, anxiety, sleep disorders,
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drug craving, paranoia, and rebound depression.
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Fentanyl analogs include the following:
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alpha-methyl-p-fluoro-3-methyl and alpha-methyl-acetylfentanyl.
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In 1979 the alpha-methyl analog was found in users of "CHINA
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WHITE". The effects of these compounds are similar to heroin
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in terms of the nature of the "high" and its duration of action.
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However, these analogs can be up to 40 times more potent than
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heroin. This potency makes overdose a serious risk. The
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drug-induced respiratory depression can be fatal (Baum, 1985).
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Adverse Drug Reactions of Designer Meperidine
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Designer meperidine is sold as SYNTHETIC HEROIN. The primary
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street analog of meperidine is MPPP
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(1-methyl-4-phenyl-4-propionpiperidine). Very specific chemical
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reaction conditions are required to produce MPPP. In the event
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of sloppy synthesis, where the pH is too low or the temperature
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is too high, a contaminant, MPTP
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(1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) is formed. MPTP
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is a known industrial toxin which affects the dopaminergic
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neurons of the substantia nigra. Cases of PARKINSON'S DISEASE
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caused by MPTP have been reported (Baum, 1985).
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The proposed biochemical mechanism of action of MPTP involves
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the rapid oxidation of MPTP to MPP+ after systemic
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administration. This conversion takes place in all tissues
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studied (brain and systemic), except for the eye, and is
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necessary for MPTP to exert its toxic effects (Irwin & Langston,
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1985). Monoamine oxidase catalyzes this reaction. Highly
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reactive intermediates may also be formed in the conversion.
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MPP+ is then taken up by neurons in the substantia nigra where
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it destroys dopaminergic neurons in this area. Although the
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formation of MPP+ occurs in many parts of the brain, it remains
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unclear as to why it selectively accumulates in the substantia
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nigra and not in other dopaminergic areas of the brain such as
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the striatum (Langston, 1985). These biochemical mechanisms are
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undergoing further studies.
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MPTP exposure is suspected if the patient answers "yes" to the
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following questions on initial presentation: 1. Did the pure
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form of the drug resemble brown sugar? 2. Was there a burning
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sensation on intravenous injection at the injection site and up
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through the vein? 3. Was the "high" more "spacey and giddy"
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than that of heroin? These questions can help identify MPTP
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exposures (Latimer, 1985). Other symptoms of MPTP toxicity are
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discussed below.
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Three phases of MPTP toxicity have been identified (Langston,
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1985a). The first is an acute phase which occurs on initial
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exposure to MPTP. Symptoms include disorientation,
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hallucinations, blurred vision, "nodding off" (a slow downward
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drifting of the head, and drooping and closure of the eyelids),
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difficulties in speech and swallowing, intermittent jerking of
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the limbs, slow movement, and tremor at rest. The second phase
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is a subacute event which occurs after exposure to the drug.
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Two to three days post-exposure there are reports of increased
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bradykinesia and rigidity of extremities, abrupt onset of
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"freezing up" and inability to move. Up to three weeks after
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exposure, awkward posture, progressive slowness of movement and
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"freezing up" have been reported. Finally, if there is no
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recovery from the above two phases, a chronic syndrome results.
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A permanent Parkinsonian syndrome evolves consisting of
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classical Parkinsonian symptoms such as bradykinesia, rigidity,
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resting tremor, fixed stare, and loss of postural reflexes.
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Recovery from the acute or subacute phase may occur, but it is
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unlikely once the chronic phase has been reached.
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Several mechanisms have been proposed to explain the
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manifestations of each of the three phases. Possible mechanisms
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regarding the acute phase include an opiate receptor interaction
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with MPTP, serotonergic effects of the substance, and a slight
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dopaminergic deficiency caused by MPTP. Because MPTP is a
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meperidine analog, an opiate receptor interaction is probably
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responsible for the "nodding off" which takes place. This
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phenomenon is typical of exposure to heroin and is due to the
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same type of opiate receptor interaction. An initial
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suppression of serotonin in the central nervous system by MPTP
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is the suggested cause for the hallucinations and retropulsions
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which occur (Ballard et al, 1985). Motor symptoms are
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attributed to MPTP's effect on the dopaminergic neurons in the
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substantia nigra, but the dopamine deficiency is not yet
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substantial.
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The subacute phase is thought to occur once MPTP accumulation
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reaches a critical threshold before killing cells in the
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substantia nigra. This theory thus offers an explanation for
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the delayed onset of symptoms and for the continuation of
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symptoms after exposure. Metabolic damage, such as impaired
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dopamine synthesis, is also suggested as a cause of dopamine
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depletion. Further study of this delayed phase is in progress.
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The likely cause of the chronic phase is actual nigral cell
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death. This, in turn, leads to a permanent hypodopaminergic
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state, and thus permanent Parkinsonism.
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Recovery from the acute and subacute phases has two possible
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explanations. A critical toxic threshold of MPTP may not be
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reached intracellularly in the substantia nigra, thus the cells
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can return to normal once exposure is stopped. Or, perhaps less
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than a critical number of dopaminergic neurons are lost and the
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remaining cells are able to compensate by overproduction of
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dopamine, therefore resolving the clinical symptoms.
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Typical Parkinsonian treatment modalities are employed in
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patients who present with MPTP toxicity. Anticholinergic agents
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only help to reduce the tremor, and thus are of little benefit.
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CARBIDOPA and LEVODOPA therapy, with or without dopamine
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agonists, such as BROMOCRIPTINE, are helpful, but
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complications typical of this therapy have resulted. These
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problems include dyskinesias, end of dose deterioration, and
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on-off swings between choreathetosis and Parkinson's symptoms.
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Studies with monoamine oxidase type B inhibitors, such as
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PARGYLINE and SELEGILINE, suggest a possible alternative
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treatment (Tetrud & Langston, 1989; Langston et al, 1984; Fuller
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& Hemrick-Lueck, 1985). If monoamine oxidase (MAO) is
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inhibited, the conversion of MPTP to MPP+ is prevented. Thus,
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MAO inhibitor drugs may provide a protecting effect if given
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prior to MPTP and may be effective in retarding the progression
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of symptoms if given after MPTP. Further research is underway
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concerning drug therapy for MPTP toxicities.
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CONCLUSION:
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Several significant points can be noted regarding MPTP
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contamination. First, the risks of designer drugs are great due
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to the lack of purification after synthesis, the lack of
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knowledge about what is actually being created, and the presence
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of possible adulterants. Secondly, MPTP is a very specific
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neurotoxin which can induce irreversible Parkinson's symptoms at
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any age. Finally, MPTP administration to laboratory animals,
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provides scientists an opportunity to study the function of
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dopamine on the nervous system, the effects of chronic dopamine
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deficiency, and the effects of chronic dopamine agonist therapy,
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and other areas of interest. It is hopeful that understanding
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the mechanisms of MPTP will provide further understanding of
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Parkinsonism and offer new insights to the understanding and
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management of this disease.
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REFERENCES:
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1. Ballard PA, Tetrud JW & Langston JW: Permanent human
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Parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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(MPTP): seven cases. Neurology 1985; 35:949-956.
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2. Baum RM: New variety of street drugs poses growing problem.
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Chem Eng 1985; 9:7-16.
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3. Fuller RW & Hemrick-Lueck SK: Influence of selective
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reversible inhibitors of monoamine oxidase on the prolonged
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depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,
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6-tetrahydropyridine in mice. Life Sci 1985; 37:1089-1095.
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4. Irwin I & Langston JW: Selective accumulation of MPP+ in
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the substantia nigra: a key to neurotoxicity? Life Sci
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1985; 36:207-212.
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5. Langston JW: MPTP and Parkinson's disease. Trends in
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Neurosciences 1985; 8:79-83.
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6. Langston JW: MPTP neurotoxicity: an overview and
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characterization of phases of toxicity. Life Sci 1985a;
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36:201-206.
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7. Langston JW, Irwin I & Langston EB: Pargyline prevents MPTP
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induced Parkinsonism in primates. Science 1984;
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225(4669):1480-1482.
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8. Latimer D: MPTP "brain damage dope" floods west coast
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suburbs. High Times 1985; 122:19-27.
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9. Tetrud JW & Langston JW: The effect of deprenyl
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(selegiline) on the natural history of Parkinson's disease.
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Science 1989; 245:519-522.
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