Re: haldol

[Guest guest]

Dear : Thank you! Now I'm really freaked out. We don't want

any of those problems. He already has some - like seizures,

tachycardia, etc. Oh, it looks like there is no good solution for

this problem.

Thanks for the help.

Cindy

>

> From Nurse's Drug Guide 2004 pub by Prentice Hall

>

> Tourette's Disorder

> Child: PO (oral) 0.05-0.75 mg/kg/d in 2-3 divided doses

>

> USES: Management of manifestation sof psychotic disorders and for

control of

> tics and vocal utterances of Gilles de la Tourette's dyndrome; for

treatment of

> agitated states in acute and chronic psychoses. Used for short-term

treatment

> of hyperactive children and for severe behaviorproblems in children

of

> combative, explosive hyperexcitability.

>

> CONTRAINDICATIONS: Parkinson's disease, parkinsonism, seizure

> disorders, coma; alcoholism; severe mental depression, CNS

depression,

> thyrotoxicosis. Safe for use during pregnancy (category C),

lactation or in

> children <3y is not established.

> CAUTIOUS USE: Older adult or debilitated patients, urinary

retention,

> glaucoma, severe cardiovascular disorders; patients receiving

> anticonvulsant, anticoagulant or lithium therapy.

[Guest guest]

Cindy,

I really don't think that Haldol would be a good idea for a child with

mito. It increases oxidative stress in the brain and inhibits Complex

I. Also have you ever tested glutathione levels? If glutathione

levels are not adequate there is more risk with Haldol.

Neurochem Int. 2001 Apr;38(5):425-35

Protein thiol oxidation by haloperidol results in

inhibition of mitochondrial complex I in brain regions: comparison with

atypical antipsychotics.

Balijepalli S, Kenchappa RS, Boyd MR, Ravindranath V.

Department of Neurochemistry, National Institute of Mental Health &

Neurosciences, Hosur Road, Bangalore 560 029, India.

Usage

of 'typical' but not 'atypical' antipsychotic drugs is associated with

severe side effects involving extrapyramidal tract (EPT). Single dose

of haloperidol caused selective inhibition of complex I in frontal

cortex, striatum and midbrain (41 and 26%, respectively) which was

abolished by pretreatment of mice with thiol antioxidants, alpha-lipoic

acid and glutathione isopropyl ester, and reversed, in vitro, by

disulfide reductant, dithiothreitol. Prolonged administration of

haloperidol to mice resulted in complex I loss in frontal cortex,

hippocampus, striatum and midbrain, while chronic dosing with clozapine

affected only hippocampus and frontal cortex. Risperidone caused

complex I loss in frontal cortex, hippocampus and striatum but not in

midbrain from which extrapyramidal tract emanates. Inhibition of the

electron transport chain component, complex I by haloperidol is

mediated through oxidation of essential thiol groups to disulfides, in

vivo. Further, loss of complex I in extrapyramidal brain regions by

anti-psychotics correlated with their known propensity to generate

side-effects involving extra-pyramidal tract.

Life Sci. 2000 Feb

25;66(14):1345-50

Mitochondrial ultrastructure and density in a

primate model of persistent tardive dyskinesia.

Eyles DW, Pond SM, Van der Schyf CJ, Halliday GM.

Queensland Centre for Schizophrenia Research, Wolston Park Hospital,

Brisbane, Qld, Australia. Eyles@...

The

use of neuroleptic drugs to treat schizophrenia is almost invariably

associated with extrapyramidal movement disorders. One of these

disorders, tardive dyskinesia (TD), can persist long after neuroleptic

withdrawal suggesting that permanent neurological damage is produced.

However, there appears to be no convincing pathology of TD and its

pathogenesis remains unknown. Findings that neuroleptics interfere

with

normal mitochondrial function and produce mitochondrial ultrastructural

changes in the basal ganglia of patients and animals suggest that

mitochondrial dysfunction plays a role in TD. We have established

a

model for persistent TD in baboons that appears to involve compromised

mitochondrial function. In this study, we evaluated two animals treated

for 41 weeks with a derivative of haloperidol and two treated with

vehicle only. Treatment was then withdrawn and the animals observed for

a further 17-18 weeks. Treated animals developed abnormal orofacial

signs that were consistent with TD. These symptoms persisted during the

drug-free period. The animals were euthanased, the brains

perfused-fixed then post-fixed in 4% paraformaldehyde and the caudate

and putamen prepared for electron microscopy. Regardless of whether

mitochondria were located in neural soma, excitatory terminals, glia or

in non-somal neuropil there was no consistent difference either in size

or number between treated and control animals. Thus, even if

mitochondria in striatal neurons undergo ultrastructural alterations

during neuroleptic therapy, these changes do not persist after drug

withdrawal.

Neuropharmacology.

1999 Apr;38(4):567-77

Inhibition of mitochondrial complex I by

haloperidol: the role of thiol oxidation.

Balijepalli S, Boyd MR, Ravindranath V.

Department of Neurochemistry, National Institute of Mental Health and

Neurosciences, Bangalore, India.

We

have examined the effects of a variety of classical and atypical

neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase

(complex I) activity. Sagittal slices of mouse brain incubated in vitro

with haloperidol (10 nM) showed time- and concentration-dependent

inhibition of complex I. Similar concentrations of the pyridinium

metabolite of haloperidol (HPP+) failed to inhibit complex I activity

in this model; indeed, comparable inhibition was obtained only at a

10000-fold higher concentration of HPP+ (100 microM). Treatment of

brain slices with haloperidol resulted in a loss of glutathione (GSH),

while pretreatment of slices with GSH and alpha-lipoic acid abolished

haloperidol-induced loss of complex I activity. Incubation of

mitochondria from haloperidol treated brain slices with the thiol

reductant, dithiothreitol, completely regenerated complex I activity

demonstrating thiol oxidation as a feasible mechanism of inhibition. In

a comparison of different neuroleptic drugs, haloperidol was the most

potent inhibitor of complex I, followed by chlorpromazine, fluphenazine

and risperidone while the atypical neuroleptic, clozapine (100 microM)

did not inhibit complex I activity in mouse brain slices. The present

studies support the view that classical neuroleptics such as

haloperidol inhibit mitochondrial complex I through oxidative

modification of the enzyme complex.

Neuroleptic medications inhibit complex I of the

electron transport chain.

Burkhardt C, JP, Lim YH, Filley CM, WD Jr.

Department of Neurology, University of Colorado School of Medicine,

Denver.

Neuroleptic

medications are prescribed to millions of patients, but their use is

limited by potentially irreversible extrapyramidal side effects.

Haloperidol shows striking structural similarities to the neurotoxin

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces

parkinsonism apparently through inhibition of NADH:ubiquinone

oxidoreductase (complex I) of the mitochondrial electron transport

chain. We now report that haloperidol, chlorpromazine, and

thiothixene

inhibit complex I in vitro in rat brain mitochondria. Clozapine, an

atypical antipsychotic reported to have little or no extrapyramidal

toxicity, also inhibits complex I, but at a significantly higher

concentration. Neuroleptic treated patients have significant

depression

of platelet complex I activity similar to that seen in idiopathic

Parkinson's disease. Complex I inhibition may be associated with the

extrapyramidal side effects of these drugs.

Induction of reactive oxygen species in neurons by

haloperidol.

Sagara Y.

The Salk Institute for Biological Studies, La Jolla, California, USA.

Haloperidol

(HP) is widely prescribed for schizophrenia and other affective

disorders but has severe side effects such as tardive dyskinesia.

Because oxidative stress has been implicated in the clinical side

effects of HP, rat primary cortical neurons and the mouse hippocampal

cell line HT-22 were used to characterize the generation of reactive

oxygen species (ROS) and other cellular alterations caused by HP.

Primary neurons and HT-22 cells are equally sensitive to HP with an

IC50 of 35 microM in the primary neurons and 45 microM in HT-22. HP

induces a sixfold increase in levels of ROS, which are generated from

mitochondria but not from the metabolism of catecholamines by monoamine

oxidases. Glutathione (GSH) is an important antioxidant for the

protection of cells against HP toxicity because (1) the intracellular

GSH decreases as the ROS production increases, (2) the exogenous

addition of antioxidants, such as beta-estradiol and vitamin E, lowers

the level of ROS and protects HT-22 cells from HP, and (3) treatments

that result in the reduction of the intracellular GSH potentiate HP

toxicity. The GSH decrease is followed by the increase in the

intracellular level of Ca2+, which immediately precedes cell death.

Therefore, HP causes a sequence of cellular alterations that lead to

cell death and the production of ROS is the integral part of this

cascade.