Pharmacokinetics of Galanthamine Hydrobromide after Single Subcutaneous and Oral Dosage in Humans

Mihailova, D.; Yamboliev, I.; Zhivkova, Zvetanka; Tencheva, Jasmina; Jovovich, V.

doi:10.1159/000138571

Cited by 44 publications

(15 citation statements)

References 3 publications

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“…5 A and B). Because the molecular weight of galantamine is 287.4, these findings suggest that the minimal plasma concentration of galantamine needed to prevent OP toxicity and lethality is Ϸ2.8 M. Doses of galantamine recommended for treatment of patients with Alzheimer's disease are between 8 and 24 mg͞day (14), and peak plasma concentrations of 0.2-3 M have been detected in healthy human subjects treated orally or s.c. with a single dose of 10 mg of galantamine (26,27). Thus, doses of galantamine needed to prevent OP toxicity generate peak plasma concentrations similar to those achieved with doses clinically used to treat Alzheimer's disease.…”

Section: Doses Of Galantamine That Effectively Prevent Op-induced Toxmentioning

confidence: 87%

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Albuquerque

Pereira

Aracava

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

137

126

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The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.galantamine ͉ guinea pig ͉ pyridostigmine ͉ soman ͉ sarin T he organophosphorus (OP) compounds soman, sarin, VX, and tabun, referred to as nerve agents, are among the most lethal chemical weapons ever developed (1). Some of them were used with catastrophic results in wars and also in terrorist attacks in Japan in the 1990s (2). The majority of insecticides are also OPs, and intoxication with these compounds represents a major public-health concern worldwide (3, 4). The possibility of further terrorist attacks with nerve agents and the escalating use of OP insecticides underscore the urgent need to develop effective and safe antidotes against OP poisoning.The acute toxicity of OPs results primarily from their action as irreversible inhibitors of acetylcholinesterase (AChE) (5). In the periphery, acetylcholine accumulation leads to persistent muscarinic receptor stimulation that triggers a syndrome whose symptoms include miosis, profuse secretions, bradycardia, bronchoconstriction, hypotension, and diarrhea. It also leads to overstimulation followed by desensitization of nicotinic receptors, causing severe skeletal muscle fasciculations and subsequent weakness. Central nervous system-related effects include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma.Current therapeutic strategies to decrease OP toxicity include atropine to reduce the muscarinic syndrome, oximes to reactivate OP-inhibited AChE, and benzodiazepines to control OPtriggered seizures (5). The limitations of these treatments are well recognized (4), and alternative therapies have been sought. Among these therapies are phosphotriesterases and butyrylcholinesterase (...

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Section: Doses Of Galantamine That Effectively Prevent Op-induced Toxmentioning

confidence: 87%

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Albuquerque

Pereira

Aracava

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

137

126

View full text Add to dashboard Cite

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“…Doses of galantamine recommended for AD treatment range from 8 to 24 mg/day. Peak plasma concentrations ranging from 0.2 to 3 M have been detected in healthy human subjects treated, orally or subcutaneously, with a single dose of 10 mg of galantamine (Mihailova et al, 1989;Jann et al, 2002). In rats treated with a dose of galantamine, sufficient to generate a peak plasma concentration of 2 M, brain concentrations of galantamine peak at around 913 ng/g (Bores et al, 1996) or 2.5 M (considering 80% brain weight as water and the molecular weight of galantamine as 278).…”

Section: Figmentioning

confidence: 99%

Competitive Antagonism between the Nicotinic Allosteric Potentiating Ligand Galantamine and Kynurenic Acid at α7* Nicotinic Receptors

Lopes

Pereira²,

Wu³

et al. 2007

J Pharmacol Exp Ther

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Galantamine, a drug used to treat Alzheimer's disease, is a nicotinic allosteric potentiating ligand, and kynurenic acid (KYNA), a neuroactive metabolite of the kynurenine pathway, is an endogenous noncompetitive inhibitor of ␣7* nicotinic receptors (nAChRs) [the asterisk next to the nAChR subunit is intended to indicate that the exact subunit composition of the receptor is not known (Pharmacol Rev 51:397-401, 1999)]. Here, possible interactions between KYNA and galantamine at ␣7* nAChRs were examined in vitro and in vivo. In the presence of tetrodotoxin (TTX), approximately 85% of cultured hippocampal neurons responded to choline (0.3-30 mM) with ␣7* nAChR-subserved whole-cell (type IA) currents. In the absence of TTX and in the presence of glutamate receptor antagonists, choline triggered inhibitory postsynaptic currents (IPSCs) by activating ␣7* nAChRs on GABAergic neurons synapsing onto the neurons under study. Galantamine (1-10 M) potentiated, whereas KYNA (10 nM-1 mM) inhibited, choline-triggered responses. Galantamine (1 M), applied before KYNA, shifted to the right the concentration-response relationship for KYNA to inhibit type IA currents, increasing the IC 50 of KYNA from 13.9 Ϯ 8.3 to 271 Ϯ 131 M. Galantamine, applied before or after KYNA, antagonized inhibition of choline-triggered IPSCs by KYNA. Local infusion of KYNA (100 nM) in the rat striatum reduced extracellular dopamine levels in vivo. This effect resulted from ␣7* nAChR inhibition and was blocked by coapplied galantamine (1-5 M). It is concluded that galantamine competitively antagonizes the actions of KYNA on ␣7* nAChRs. Reducing ␣7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased ␣7* nAChR activity in the brain.

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“…Although earlier studies have been published on the pharmacokinetic profile of galantamine in both animals (Mihailova et al, 1985;Mihailova and Yamboliev, 1986;Bickel et al, 1991a) and humans (Westra et al, 1986;Mihailova et al, 1989;Bickel et al, 1991b), advances in analytical techniques have made further elucidation of the metabolic profile of this compound possible. The studies presented here were therefore performed to elucidate the metabolic profile of galantamine after oral dosing and to compare the metabolism and excretion of galantamine in rats, dogs, and humans.…”

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confidence: 99%

The Metabolism and Excretion of Galantamine in Rats, Dogs, and Humans

Mannens¹,

Snel²,

Hendrickx³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered 3 H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, Odemethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine.

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Pharmacokinetics of Galanthamine Hydrobromide after Single Subcutaneous and Oral Dosage in Humans

Cited by 44 publications

References 3 publications

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Competitive Antagonism between the Nicotinic Allosteric Potentiating Ligand Galantamine and Kynurenic Acid at α7* Nicotinic Receptors

The Metabolism and Excretion of Galantamine in Rats, Dogs, and Humans

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