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Drug Abuse

ドキュメント内 Amphetamins(原文) (ページ 59-63)

A REPORT OF ThE CERhR AmPhETAmINES ExPERT PANEL:

2.1 Pharmacodyamics and Pharmacokinetics

2.2.1.4 Drug Abuse

Abuse. of. amphetamines. and. methamphetamines. is. associated. with. development. of. tolerance,.

psychological.dependence,.and.social.disability.(6, 8, 10)..There.are.reports.of.some.patients.greatly.

increasing.dosages.above.recommended.levels..Abrupt.withdrawal.following.prolonged.intake.of.

high.doses.can.result.in.extreme.fatigue,.mental.depression,.and.sleep.electroencephalogram.(EEG).

changes..Toxicity.associated.with.chronic.intoxication.can.include.dermatoses,.insomnia,.irritability,.

hyperactivity,.and.personality.changes..Though.rare.with.oral.intake,.psychosis.that.is.indistinguishable.

from.schizophrenia.has.been.reported..Repetitive.and.stereotypic.behavior.that.can.advance.to.self-injurious.behavior.has.been.observed.with.high.or.repeated.dosing.with.amphetamines.(reviewed.in.

(27))..Animal.models.used.to.investigate.self-injurious.behavior.in.humans.are.discussed.below.in.

Section.2.2.2.

Studies.in.humans.who.abused.methamphetamine.and.possibly.other.substances.revealed.persistent.

reductions.in.striatal.dopamine.transporter.as.observed.by.imaging.techniques.(reviewed.in.(27, 68)).

and.deficits.in.striatal.dopamine,.tyrosine.hydroxylase.activity,.and.dopamine.transporters.during.

autopsy.(reviewed.in.(27))..The.effects.in.autopsy.subjects.were.described.as.likely.markers.of.damage.

to.the.striatal.dopaminergic.system,.but.it.was.noted.that.there.were.no.obvious.behavioral.symptoms..

Dopaminergic.effects.in.humans.receiving.therapeutic.doses.of.amphetamines.are.not.known..

2.2.2 Experimental Animal

Symptoms.of.acute.amphetamine.toxicity.in.rats.and.mice.include.hyperactivity,.piloerection,.salivation,.

and. hyperpnea. (reviewed. in.(24));. dilated. pupils. and. convulsions. have. also. been. reported.(69)..

Symptoms.of.acute.methamphetamine.toxicity.in.rodents.were.reported.as.excitement,.convulsions,.

and.changes.in.seizure.threshold.(70)..The.oral.LD50.for.d-amphetamine.in.rats.is.reported.at.96.8.mg/

kg.bw..LD50.values.for.d,l-amphetamine.and.methamphetamine.in.various.species.are.summarized.

in.Table.21.and.Table.22..

Appendix II

Table 21. LD50 Values for d,l-Amphetamine Species Exposure

Route LD50 (mg/kg bw)

Mouse

oral 24a

ip 13a

iv 31.8a

sc 7a

Rat

oral 55

ip 125

sc 160

Dog oral 23

iv 6

Guinea.pig ip 50

sc 105

Rabbit iv 22

Data.from.NIOSH.(69).for.all.routes.and.from.NTP.(24) for.oral.route.

a.The.Expert.Panel.questions.the.accuracy.of.the.mouse.

LD50.data,.as.explained.in.text.below.

[The Expert Panel questions the accuracy of mouse LD50 values reported for d,l-amphetamine (Table 21). It does not make sense that the oral LD50 would be less than the iv LD50, nor that the sc LD50 would be lowest of all. The discrepancies may be due to the use of animals of different ages. In addition, while the LD50 for oral administration of d,l-amphetamine in mice is listed as 24 mg/kg in Table 21, the NTP carcinogenicity studies (24, 71) described in Section 2.4.2 used an estimated 19 (female) and 30 (male) mg/kg bw/day dose for 103 weeks and had no differences in survival of treated groups.]

Table 22. LD50 Values for Methamphetamine Species Exposure

Route

LD50 (mg/kg bw) Mouse

ip 15.

iv 6.3

sc 7.56

Rat sc 10.93

Guinea.pig oral 90

Data.from.Registry.of.Toxic.Effects.of.Chemical.Substances.

(RTECS).database.(70).

Appendix II

Continuous.iv.infusion.of.rats.with.amphetamines.1.mg/kg.bw/hour.for.12.days.resulted.in.reduced.

brain.norepinephrine.and.cardiac.catecholamine.levels.and.increased.motor.activity.and.stereotypic.

behaviors,.manifested.as.grooming,.scratching,.rearing,.limb.flicks,.and.biting.(reviewed.in.(24))..

Behavioral.effects.were.reversed.upon.cessation.of.dosing..Amphetamine.effects.following.repeated.

oral. dosing. are. reported. below. in. the. description. of. an. NTP. study.. Repeated. parenteral. dosing.

of.rodents.with.methamphetamine.has.caused.excitement,.weight.loss.or.decreased.weight.gain,.

alteration.in.classical.conditioning,.changes.in.pancreas,.and.hemorrhage.(70)..Higher.doses.[not specified].of.amphetamines.were.reported.to.induce.brain.lesions.such.as.hyperemia,.hemorrhage,.

and.glial.proliferation.in.monkeys.and.enlarged.and.chromatolytic.medulla.oblongata.neurons.in.cats.

(reviewed.by.(71))..

A.review.by.Kita.et.al..(27).reported.that.parenteral.dosing.with.methamphetamine.or.amphetamine.

concentrations. exceeding. therapeutic. levels. has. resulted. in. persistent. regional. (mainly. striatal).

depletion.of.brain.dopamine.levels.in.rats,.mice,.cats,.guinea.pigs,.and.monkeys,.and.decreased.

tyrosine.hydroxylase.activity.in.rats.and.cats..Decreased.numbers.of.dopamine.transport.pumps.were.

reported.in.mice.and.rats..Catecholamine.turnover.was.found.to.be.increased.in.rats..Reductions.in.

brain.norepinephrine.levels.were.observed.in.monkeys.and.cats..Decreases.in.serotonin.concentration.

and.tryptophan.hydroxylase.activity.were.reported.in.rats.and.cats.and.reduced.numbers.of.serotonin.

transporter. pumps. were. reported. in. one. rat. study.. Some. recovery. of. neurotransmitter. levels. was.

observed.at.lower.doses.in.monkeys.(~2.0.mg/kg.bw).and.rats.(≤.12.5.mg/kg.bw),.but.at.higher.doses,.

the.effects.persisted.for.months..Studies.examining.effects.of.amphetamines.on.neurochemical.indices.

in.developing.animals.are.discussed.in.detail.in.Section.3.2.3..

Neuroanatomical.evidence.of.amphetamine-induced.toxicity.was.also.reported..Swollen.nerve.fibers.

and.terminals.were.observed.in.rats.and.mice.dosed.with.amphetamine.or.methamphetamine.(reviewed.

in.(27))..Methamphetamine.treatment.has.resulted.in.reductions.of.brain.dopaminergic.axons.and.axon.

terminals.in.rats.and.monkeys.and.serotonergic.axons.and.axon.terminals.in.rats.(reviewed.in.(72))..

Development.of.neurotoxicity.depends.on.dose,.number.of.exposures,.intervals.between.dosing,.and.

duration.of.neuron.exposure.(reviewed.in.(72))..It.has.been.reported.that.administration.of.reuptake.

blockers.with.amphetamines.prevents.neuronal.damage.(reviewed.in.(27, 72))..Apoptosis.was.reported.

as.a.possible.mechanism.of.neurotoxicity.in.mice.and.rats.(reviewed.in.(27))..

A.review.by.Kita.et.al..(27).discusses.the.animal.literature.and.modeling.that.supports.self-injurious.

behaviors.in.humans..Kita.et.al..state.“The.acute.appearance.of.self-injurious.behavior.associated.

with.administration.of.amphetamines.to.rodents.may.accurately.predict.the.later.neurotoxicity.and.at.

the.same.time.serve.as.a.model.for.the.study.of.this.disabling.symptom.in.humans.”.Animal.literature.

does.not.provide.a.neurochemical.basis.for.self-injurious.behavior.although.it.points.to.involvement.

of.central.dopamine.neurons..Reversal.of.some.self-injurious.behaviors.by.dopamine.antagonists.

provides.evidence.of.dopaminergic.involvement.

NTP.toxicity.studies.were.reviewed.in.detail.because.reproductive.organs.were.examined.in.a.subchronic.

and.a.carcinogenicity.study.and.growth.was.measured.in.the.subchronic.study..The.carcinogenicity.

study.is.described.in.Section.2.4.2.

Appendix II

sulfate. in. F344/N. rats. and. B6C3F1. mice.. Rats. and. mice. were. randomly. assigned. to. groups. and.

administered. USP. grade.d,l-amphetamine. sulfate. (99%. purity). through. feed.. Drug. stability. and.

concentration.in.feed.were.verified..Survival.data.were.analyzed.using.Kaplan.Meier,.Cox,.or.Tarone.

life.table.test.methods..Continuous.data.were.analyzed.using.Dunn,.Shirley,.or.Jonckheere.tests..

In.the.14-day.study,.7-week-old.rats.(5/sex/group).were.fed.diets.containing.0,.47,.94,.188,.375,.or.

750.ppm.d,l-amphetamine.sulfate..Nine-week-old.mice.(5/sex/group).were.fed.diets.with.0,.125,.250,.

500,.1000,.or.2000.ppm.d,l-amphetamine.sulfate..Animals.were.observed.daily.and.weighed.before,.

during,.and.after.the.study..Following.kill,.animals.were.necropsied.and.organ.weights.were.measured..

Major.organs.were.fixed.in.10%.neutral.buffered.formalin.for.a.histological.analysis..Included.among.

organs.analyzed.were.mammary.gland,.prostate,.testis,.seminal.vesicle,.ovary,.and.uterus..Doses.at.

which.histological.evaluation.was.conducted.in.each.species.are.discussed.below..

In.the.14-day.study,.all.rats.survived..Final.mean.body.weights.in.the.375.and.750.ppm.groups.were.

7.–.9%.lower.for.males.and.5.–.16%.lower.for.females.compared.to.controls..Reduction.in.final.body.

weight.was.statistically.significant.for.females.at.750.ppm..Feed.intake.was.reduced.in.groups.exposed.

to.≥94.ppm.during.the.first.week.of.the.study.and.was.marginally.reduced.in.males.from.the.750.ppm.

group.during.the.second.week.of.the.study..Hyperactivity.[determined by general observations, not standard measures].was.observed.in.rats.exposed.to.≥375.ppm..According.to.the.results.section,.

absolute.heart.weight.was.reduced.in.females.exposed.to.≥375.ppm..[The only organ weight effect data shown in Table J1 of the NTP study are for liver. According to that table, relative (to body weight) liver weights were increased in males exposed to 750 ppm and females exposed to ≥188 ppm.].Histopathologic.evaluation.was.conducted.on.animals.from.the.control.and.750.ppm.groups;.

no.lesions.were.observed.[data not shown].

Four.males.in.the.1000.ppm.group.and.1.male.in.the.2000.ppm.died.in.the.14-day.mouse.study..

According.to.study.authors,.the.deaths.were.not.clearly.related.to.treatment..Weight.loss.occurred.

in.males.exposed.to.≥500.ppm..Mean.final.body.weights.of.females.exposed.to.≥250.ppm.were.

significantly.lower.than.controls.by.12.–.13%..Feed.intake.was.similar.in.all.groups,.although.it.was.

noted.that.the.2000.ppm.males.scattered.their.feed..Mice.in.the.1000.ppm.group.were.either.hyperactive.

or.lethargic.and.hyporesponsive..According.to.the.results.section,.relative.liver.weights.were.increased.

in.males.exposed.to.≥.250.ppm.and.females.from.the.2000.ppm.group..Other.significant.organ.weight.

changes.listed.in.Table.J3.of.the.NTP.report.included.decreased.absolute.brain.and.thymus.weight.

and.increased.relative.kidney.weights.in.males.of.the.2000.ppm.group;.absolute.heart.weight.was.

increased.in.females.exposed.to.≥125.ppm..Histopathologic.evaluation.was.conducted.in.controls,.the.

2000.ppm.group,.and.males.in.the.1000.ppm.group..No.lesions.were.observed.[data not shown].

The.13-week.studies.were.conducted.according.to.FDA.Good.Laboratory.Practice.(GLP).procedures..

At.7.–.8.weeks.of.age,.10.rats/sex/dose.were.fed.diets.containing.0,.47,.94,.188,.375,.or.750.ppm.d,l-amphetamine.sulfate..At.8.–.9.weeks.of.age,.10.mice/sex/group.were.fed.diets.containing.0,.125,.250,.

500,.1000,.or.2000.ppm.d,l-amphetamine.sulfate..Doses.were.based.upon.results.observed.in.the.14-day.studies..Animals.were.observed.daily.and.weighed.before,.during,.and.after.the.study..Following.

kill,.animals.were.necropsied.and.organs.were.weighed..Major.organs.were.fixed.in.10%.neutral.

buffered.formalin.for.histological.analysis..Included.among.organs.analyzed.were.mammary.gland,.

prostate,.testis,.ovary,.and.uterus..Doses.at.which.histologic.evaluation.was.conducted.in.each.species.

Appendix II

are.discussed.below..Thymus.and.spleen.were.also.examined.in.some.rats.from.lower.dose.groups.

All.rats.survived.in.the.13-week.study..Final.body.weights.were.significantly.reduced.in.both.sexes.

of.all.treated.groups..Final.mean.body.weights.in.the.188,.375,.and.750.ppm.groups.were.11,.18,.and.

38%.lower.in.males.and.15,.26,.and.32%.lower.in.females..Feed.intake.by.the.750.ppm.males.was.20%.

lower.than.controls..Hyperactivity.was.observed.in.all.dose.groups.and.severity.increased.according.

to.dose..According.to.study.authors,.organ.weight.changes.were.due.to.body.weight.reductions..

[The study authors’ statement is confirmed by dose-related reductions in absolute weight and increases in relative organ weights observed in many organs. The exceptions that appeared to be dose-related were an increase in absolute brain weight (≥94 ppm females) and decreases in relative (to body weight) liver (750 ppm males) and thymus (≥94 ppm males, ≥375 ppm females) weights.].A.histopathological.examination.was.conducted.in.controls.and.the.750.ppm.group..No.

treatment-related.lesions.were.observed.[data not shown]..

In.the.13-week.mouse.study,.8.males.of.the.500.ppm.group.died,.3.males.of.the.1000.ppm.group.died,.

and.7.females.and.6.males.from.the.2000.ppm.group.died..Mean.final.body.weights.of.all.treated.

groups.were.lower.than.controls..At.doses.≥250.ppm,.body.weights.were.18.–.30%.lower.than.controls.

in.males.and.13.–.19%.lower.than.controls.in.females..All.treated.mice.were.hyperactive.and.severity.

increased.according.to.dose..Fighting.was.observed.in.males.exposed.to.≥250.ppm..According.to.study.

authors,.increases.in.relative.organ.weights.were.due.to.reduced.body.weights..[Decreases in absolute organs weights were also consistent with reduced body weights.] A.histological.evaluation.was.

conducted.in.the.control.and.2000.ppm.groups,.males.in.the.1000.ppm.group,.and.all.mice.that.died.

during.the.study..No.treatment-related.lesions.were.observed.[data not shown].

ドキュメント内 Amphetamins(原文) (ページ 59-63)