by H-Man
July 1993
Newsgroups: alt.drugs
From: an13187@anon.penet.fi (H-Man)
Subject: MPTP article
Message-ID: <1993Jul4.032852.25925@fuug.fi>
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
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).
Meperidine Analogs
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:
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.
From: an13187@anon.penet.fi (H-Man)
Subject: MPTP article
Message-ID: <1993Jul4.032852.25925@fuug.fi>
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
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).
Meperidine Analogs
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:
- Did the pure form of the drug resemble brown sugar?
- Was there a burning sensation on intravenous injection at the injection site and up through the vein?
- 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.