galantamine Dotaz Zobrazit nápovědu
Galantamin je dualisticky působící kognitivum nové generace. Mechanizmus účinku spočívá v inhibici acetylcholinesterázy a alosterické modulaci nikotinových receptorů. Kromě zvýšení koncentrace acetylcholinu dochází v neuronálních synapsích k uvolnění i dalších neurotransmiterů, neuroprotektivního prekurzoru amyloidního proteinu (APP) a expresi některých genů ve vztahu k nikotinovému receptoru. V 7 kontrolovaných studiích galantamin ovlivnil úspěšněji než placebo kognitivní a nekognitivní příznaky Alzheimerovy demence a terapeutický účinek přetrvával nejméně 1 rok. Při delším podávání bylo pozorováno zpomalení progrese choroby. Slibným je i pro terapii nonrespondérů k donepezilu a rivastigminu pro odlišný farmakologický profil. V kontrolované studii galantamin úspěšně léčil i smíšenou a vaskulární demenci. Jeho nevýhodou je nutnost počáteční titrace, podávání 2x denně a možné interakce s inhibitory P4502D6 a 3A4 a dalšími obdobně působícími léky.
Galantamine is a dual action cognitive enhancer of a new generation. Its mechanism of effect consists in the inhibition of acetylcholinesterase and alosteric modulation of nicotine receptors. Besides increasing the concentration of acetylcholine, galantamine causes the release of other neurotransmitters, the neuroprotective amyloid protein precursor (APP) and gene expression in neuronal synapses. In 7 controlled studies, galantamine was more effective than placebo in influencing both cognitive and non-cognitive symptoms (BPSD) of the Alzheimer's dementia while its therapeutic effect lasted for at least one year. It delayed the progression of the disease during the long-term administration. Due to its different pharmacological profile, galantamine also seems promising in the treatment of donepezil and rivastigmine non-responders. It proved successful even in treating mixed and vascular dementia in a controlled study. Its drawbacks are the slow initial titration, administration twice per day and possible interactions with P4502D6 and 3A4 inhibitors and other drugs with a similar mechanism of action.
Galantamin je duálním kognitivem, které zlepšuje cholinergní přenos v CNS zvýšením acetylcholinu a alosterickou modulací nikotinových receptorů a působí neuroprotektivně. Klinická účinnost galantaminu byla ověřena v 7 dvojitě slepých placebem kontrolovaných a v 1 jednoduše slepé donepezilem kontrolované studii u nemocných s Alzheimerovou demencí. Tyto studie byly otevřeně prodlouženy až na 48 měsíců terapie. Kognitivní funkce nemocných byly stabilizovány po dobu 12–18 měsíců a poté se postupně zhoršovaly. Prvých 12 měsíců léčby se stabilizovaly rovněž poruchy chování a psychotické příznaky (BPSD) a prvých 6 měsíců i denní aktivity nemocných. Galantamin byl rovněž klinicky úspěšný u vaskulárních a smíšených demencí, u kterých se kognitivní funkce stabilizovaly 21 příp. 12 měsíců. Galantamin byl dobře snášen a z nežádoucích účinků oproti placebu byly častější gastrointestinální obtíže, závratě a cefalgie.
Galantamine is a dual cognitive enhancer improving the cholinergic transmission in the CNS by increasing acetylcholine levels, enhancing alosteric modulation of nicotine receptors and by neuroprotective effect. The clinical efficacy of galantamine has been verified in 7 double-blind, placebo controlled trials and 1 single-blind donepezil-controlled trial involving patients with Alzheimer's dementia. The trials were extended openly up to 48 months of therapy. Patients' cognitive functions deteriorated gradually after initial 12–18 months of stabilization. Behavioural and psychological symptoms (BPSD) of the demented patients were stabilized for 12 initial months; their activities of daily living were stable for the 6 initial months. Galantamine was also therapeutically successful in the treatment of vascular and mixed dementia, with cognitive functions stabilization for 21 and 12 months respectively. The drug was well tolerated and from undesirable effects only gastrointestinal complaints, vertigo, and cephalalgia were more frequent compared to placebo.
- MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- demence farmakoterapie patologie MeSH
- dospělí MeSH
- galantamin farmakokinetika farmakologie terapeutické užití MeSH
- hodnocení léčiv MeSH
- lidé MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- klinické zkoušky MeSH
In a retrospective postmarketing study, 28 patients suffering from Alzheimer‘s disease were treated with galantamine (8–24 mg/day) for 3 (6 patients) or 6 months (22 patients) in routine psychiatric out-patient practice. In 22 patients (78,6%) the state of the pacients improved or remained without progression as measured with the Mini-Mental State examination (MMS). Generally, galantamine was well tolerated. Case report of 72 years old woman.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- ambulantní péče MeSH
- galantamin aplikace a dávkování MeSH
- lidé MeSH
- retrospektivní studie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Galantamin je alkaloid z některých druhů sněženek a narcisů, pro terapeutické využití je vyráběn synteticky. Je to inhibitor mozkových acetylcholinesteráz a navíc allosterický modulátor nikotinových receptorů, zvyšující jejich citlivost k acetylcholinu. Má také neuroprotektivní působení. Inhibitory mozkových cholinesteráz jsou užívány k léčbě Alzheimerovy choroby ve stadiu demence. Acetylcholinergní systém je první porušený neurotransmiterový systém u Alzheimerovy choroby. Jsou popsány i efekty galantaminu u jiných typů demencí.
Galantamine is the alkaloid from some kinds of snowdrops and daffodils; for therapeutical use it is produced synthetically. Galantamine is the inhibitor of brain acetylcholinesterases and moreover the allosteric modulator of nicotinic receptors, enhancing their sensitivity to acetylcholine. It has also a neuroprotective effect. The brain acetylcholinestrerase inhibitor are used in the therapy of Alzheimer's disease in the stadium of dementia. Acetylcholinergic system is the first disturbed neurotransmitter system in Alzheimer's disease. There are described also the effects of galantamine in some other types of dementia.
- MeSH
- Alzheimerova nemoc * etiologie farmakoterapie MeSH
- amyloidní plaky patofyziologie patologie MeSH
- cholinesterasové inhibitory * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- demence s Lewyho tělísky etiologie farmakoterapie MeSH
- fenylkarbamáty aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- galantamin antagonisté a inhibitory škodlivé účinky terapeutické užití MeSH
- indany aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- neurokognitivní poruchy * etiologie farmakoterapie MeSH
- piperidiny aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- statistika jako téma MeSH
- vaskulární demence etiologie farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Galantamine is a drug used for the treatment of Alzheimer's disease and some other cognitive disorders. It is an inhibitor of acetylcholinesterase; however, interaction with nicotinic acetylcholine receptors has also been reported. Owing to the significant role of cholinergic anti-inflammatory pathways in neuro-immunomodulation, we decided to examine the effect of galantamine on tularemia-infected BALB/c mice. METHODS: Animals were infected with Francisella tularensis LVS and treated with galantamine (0.1 mg/kg of body weight). Total mortality over the course of tularemia infection was assessed and interleukin 6 (IL-6) and interferon gamma (IFN-gamma) in plasma samples were measured by enzyme-linked immunosorbent assays. Apart from the cytokine assays, biochemical markers such as inorganic phosphate, uric acid, lactate dehydrogenase, gamma glutamyltransferase, creatinine phosphokinase and amylase were assayed. RESULTS: The modulation of immunity by galantamine depended on two opposing processes: up-regulation of IFN-gamma and down-regulation of IL-6. Tularemia infection resulted in significant nephropathy, as hyperphosphataemia and hyperuricaemia occurred in infected animals. In addition, galantamine resulted in the mitigation of nephropathy, and markers of kidney dysfunction were modulated. Alterations in mortality were also found in this study. CONCLUSIONS: Galantamine can significantly influence the immune response via the cholinergic anti-inflammatory pathway. Despite the decrease in IL-6 levels, galantamine treatment enhanced protection against the intracellular pathogen F. tularensis, resulting in the remission of some pathology and reduced mortality.
- MeSH
- analýza přežití MeSH
- Francisella tularensis účinky léků MeSH
- galantamin farmakologie terapeutické užití MeSH
- interferon gama krev MeSH
- interleukin-6 krev MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- tularemie krev farmakoterapie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Galantamine (GAL) is a selective, competitive and reversible acetylcholinesterase (AChE) inhibitor, which increases the activity of the cholinergic system and hence gives rise to an improvement of cognitive functions in patients suffering from dementia of Alzheimer type. L-Carnitine (CAR) is a natural component of the mammalian tissue and is known to increase penetration of some chemical compounds/groups across biological membranes. The aim of this study was to evaluate the influence of pretreatment with CAR on AChE inhibition caused by GAL in selected brain parts in rat (basal ganglia, septum, frontal cortex, hippocampus) and in hypophysis, which does not lay beyond the blood-brain-barrier. During the first stage of the study, GAL was administered i.m. in different doses ranging from 2.5 to 10 mg/kg. The highest degree of AChE dose dependent inhibition was observed in hypophysis, while that in CNS was lower and became apparent in frontal cortex and hippocampus only after the administration of the dose of 10 mg/kg i.m. In the second stage, CAR was administered daily during 3 consecutive days at a dose of 250 mg/kg p.o. prior to the administration of GAL (10 mg/kg i.m.). Pretreatment with CAR enhanced trend of AChE inhibition in all selected brain parts comparing with single GAL administration, however, significant difference was not observed. Comparing these results with control group, statistical significance was found in frontal cortex, hippocampus and hypophysis.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory farmakologie MeSH
- galantamin farmakologie MeSH
- karnitin farmakologie MeSH
- krysa rodu rattus MeSH
- mozek enzymologie MeSH
- potkani Wistar MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diisopropylfluorophosphate exerts its toxic effect by irreversibly inhibiting acetylcholinesterase. This results in over-stimulation of central and peripheral cholinergic activity. The aim of the present study was to evaluate the possible preventive effects of acute treatment with reversible acetylcholinesterase inhibitor galantamine against the signs of cholinergic toxic syndrome provoked by diisopropylfluorophosphate, such as hypothermia, muscular fasciculations, oral dyskinesia and decreased locomotor performance in a rat model of intoxication. The effects of these two anticholinesterases on acetylcholinesterase activity and on the expression of mRNA of the immediate early response gene c-fos in the brain were assessed by histochemical acetylcholinesterase staining and by in situ hybridization, respectively. Diisopropylfluorophosphate induced rapidly progressing hypothermia, muscular fasciculations, oral dyskinesia and decreased locomotor performance. The increased cholinergic cortical and hippocampal activity due to irreversible acetylcholinerase inhibition were indicated by the increased c-fos mRNA autoradiographic signal and by the inhibition of acetylcholinesterase staining, respectively. Galantamine by itself provoked transient and relatively weak inhibition of the acetylcholinesterase staining, while it did not induce increased c-fos mRNA expression or significant behavioural signs of cholinergic toxicity. Galantamine significantly reduced the rate of the onset, but not the maximal hypothermia induced by diisopropylfluorophosphate. Importantly, all the above-mentioned behavioural and neurochemical effects of diisopropylfluorophosphate were significantly reduced by galantamine. These results indicate that the acute pre-treatment with galantamine may have prophylactic effects against the intoxication by diisopropylfluorophosphate.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- fascikulace chemicky indukované genetika patologie patofyziologie MeSH
- galantamin farmakologie MeSH
- isofluorofát toxicita MeSH
- krysa rodu rattus MeSH
- messenger RNA genetika metabolismus MeSH
- mozek účinky léků enzymologie patologie patofyziologie MeSH
- neuroprotektivní látky farmakologie MeSH
- pohybová aktivita účinky léků MeSH
- pohybové poruchy genetika patologie patofyziologie MeSH
- potkani Wistar MeSH
- protoonkogenní proteiny c-fos genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- tělesná teplota účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: The alkaloid galantamine (GAL), which exhibits a combined anticholinesterase and direct parasympathomimetic mechanism of action, is employed in conjunction with therapeutic interventions in the stimulation of central cholinergic transfer in cognitive diseases. We attempted to achieve pharmacologically-induced enhancement of the parasympathomimetic activity of GAL in the key areas of rat brain, using an interactive combination of the alkaloid with the transmembrane enhancer L-carnitine (CAR). METHODS: We investigated activities of acetylcholinesterase (AChE) in brain areas (frontal cortex, basal ganglia, septum and hippocampus) and the hypophysis, and that of butyrylcholinesterase (BuChE) in plasma and liver. RESULTS: Following administration of the highest of the GAL doses used (2.5; 5; 10 mg/kg i.m.), AChE activity decreased mainly in the frontal cortex, hippocampus and hypophysis. In the interaction of GAL and CAR, AChE inhibition was stronger but without any statistical significance. The peripheral inhibition of BuChE was found to be dose-dependent. Premedication by CAR led to a slight change in the values of the activities monitored. CONCLUSIONS: CAR in terms of positive modulation of GAL targeting to the central nervous system had no statistically significant effect.
- MeSH
- acetylcholinesterasa krev metabolismus MeSH
- butyrylcholinesterasa krev metabolismus MeSH
- cholinesterasové inhibitory farmakologie MeSH
- galantamin * farmakologie MeSH
- hypofýza enzymologie účinky léků MeSH
- játra enzymologie účinky léků MeSH
- karnitin * farmakologie MeSH
- krysa rodu rattus MeSH
- mozek * enzymologie účinky léků MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Galantamine, an alkaloid isolated from the bulbs and flowers of Caucasian snowdrop (Galanthus woronowii, Amaryllidaceae) and related species, is employed in human medicine for the treatment of various neuromuscular and neurodegenerative diseases. After the administration, the products of oxidative biotransformation (O-desmethyl-galantamine, N-desmethyl-galantamine, galantamine-N-oxide) and chiral conversion (epigalantamine) are formed in various concentrations from parent compound. For the identification and determination of galantamine and its phase I metabolites in blood plasma and tissues, a new bioanalytical method based on a reversed-phase high-performance liquid chromatography with UV photodiode-array, fluorescence and mass spectrometric detection was developed, validated and applied to pharmacokinetic and biotransformation studies. Sample preparation included a homogenization of the rat tissues (liver, brain, hypophysis) in a phosphate buffer 0.05 mol/L pH 7.4. Plasma samples and tissue homogenates were purified using a mixed-mode solid-phase extraction (Waters Oasis MCX cartridges). Galantamine, its above-mentioned metabolites and the internal standard codeine were separated on a Discovery HS F5 column (Supelco, 150 mmx4.6 mm I.D., 5 microm) at flow rate of 1 mL/min using a linear gradient elution. UV photodiode-array and mass spectrometric detection were employed for the identification of individual galantamine metabolites in various biomatrices, the fluorescence detection (lambdaexcit=280 nm/lambdaemiss=310 nm) was chosen for the quantification of galantamine and its metabolites. The developed method was applicable in liver tissue in the range from 0.50 to 63.47 nmol/g of galantamine, from 0.32 to 41.42 nmol/g of O-desmethyl-galantamine, from 0.54 to 69.40 nmol/g of N-desmethyl-galantamine and from 0.70 to 89.03 nmol/g of epigalantamine. Limit of detection was found to be 0.04 nmol/g for galantamine, 0.19 nmol/g for O-desmethyl-galantamine, and 0.07 nmol/g for N-desmethyl-galantamine and epigalantamine.
- MeSH
- extrakce na pevné fázi metody MeSH
- financování organizované MeSH
- fluorescenční spektrometrie metody MeSH
- galantamin analýza chemie krev MeSH
- hmotnostní spektrometrie metody MeSH
- hypofýza chemie MeSH
- játra chemie MeSH
- krysa rodu rattus MeSH
- molekulární struktura MeSH
- mozek - chemie MeSH
- spektrofotometrie ultrafialová metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
