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DRUG INTERACTIONS |
From Johnson & Johnson Pharmaceutical Research & Development, LLC, Titusville, New Jersey (Dr Yao, Dr Raoufinia, Dr Gold, Dr Nye, Dr Zhao); SGS Biopharma S.A. Research Unit Stuivenberg, Antwerp, Belgium (Dr Ramael); Smith Hanley Consulting Group, Lake Mary, Florida (Mr Padmanabhan); Johnson & Johnson Pharmaceutical Research & Development, LLC, Beerse, Belgium (Dr Verhaeghe, Dr Walschap). Drs Yao, Gold, and Zhao are members of the American College of Clinical Pharmacology.
Address for reprints: Qinying Zhao, PhD, Johnson & Johnson Pharmaceutical Research & Development, LLC, 1125 Trenton-Harbourton Road, PO Box 200, Titusville, NJ 08560.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Alzheimer's disease • galantamine • memantine • drug interaction • pharmacokinetics
At present, the most commonly used pharmacological treatments for AD are acetylcholinesterase inhibitors (AChEIs), including galantamine, donepezil, and rivastigmine.5 These agents differ in their mechanisms of acetylcholinesterase (AChE) inhibition,4 in the selectivity of their enzyme inhibition,4 and in their elimination half-lives.4
Galantamine hydrobromide, a tertiary alkaloid originally derived from various plant species,6 is indicated for the treatment of mild to moderate dementia of the Alzheimer's type.7 Galantamine is both a reversible and a competitive inhibitor of AChE and an allosteric modulator of the 
4ß2 and 7 nicotinic receptor subtypes.8,9 This dual mechanism of action may result in better long-term efficacy in the treatment of AD than AChE inhibition alone.8-10
In 4 randomized, placebo-controlled trials with durations of 3 to 6 months and a total enrollment of 2653 patients with mild to moderate AD, treatment with galantamine at daily maintenance doses of 16 to 32 mg was associated with beneficial effects on cognition, activities of daily living, and behavior.11-14 In these studies, galantamine was shown to be safe and generally well tolerated.11-14 Galantamine is well absorbed after oral administration, with an absolute bioavailability of about 90%.7 The pharmacokinetics of galantamine are linear over the range of 8 to 32 mg/day. The terminal elimination half-life is about 7 hours in healthy subjects.7 In vitro studies have shown that cytochrome P450 (CYP) 2D6 and CYP3A4 are the major CYP isoenzymes involved in the metabolism of galantamine.7 Galantamine does not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6, and CYP2E1.7 The plasma protein binding of galantamine at therapeutically relevant concentrations is only 18%,7 indicating that the potential for replacement by other drugs in protein binding is low.
Memantine hydrochloride, which is indicated for the treatment of moderate to severe AD,15,16 represents a new approach to the treatment of AD.17 As a putative noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, memantine binds preferentially to NMDA receptor-operated cation channels in the central nervous system (CNS), thereby reducing activation of NMDA receptors by the excitatory amino acid glutamate.15 In pivotal clinical trials, memantine was administered either as monotherapy or as adjunctive therapy with donepezil.15,17 The recommended target dose of memantine is 10 mg bid.15 After administration of memantine at single oral doses of 10 to 40 mg, time to reach the maximum observed plasma concentration (tmax) ranges between 3 and 7 hours.15,16 Memantine has linear pharmacokinetics over the therapeutic dose range and has a terminal elimination half-life of 60 to 80 hours.15 The pharmacokinetics of memantine are not affected by food, age, or gender.15 Most of the administered dose (57%-82%) is excreted unchanged in urine.15,16 Memantine produces minimal inhibition of CYP enzymes and does not alter the metabolism of donepezil.15
Because combination therapy with memantine may help patients who are already on stable doses of galantamine, it is important to characterize the potential for a drug-drug interaction. Based on the pharmacokinetic properties of the individual agents, the addition of memantine to galantamine is unlikely to alter the pharmacokinetic or safety profile of either drug. An in vitro study found that reversible AChEIs, including galantamine, do not lose their therapeutic efficacy when combined with memantine.18 Thus, the primary objective of the present study was to evaluate the effect of multiple doses of memantine on the pharmacokinetics of galantamine. The secondary objective was to assess the safety and tolerability of galantamine and adjunctive memantine therapy.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects
Sixteen healthy subjects were enrolled in this study through screening of inclusion and exclusion criteria at the study site to ensure that 12 subjects completed the study.
Healthy male and female subjects between the ages of 18 and 55 years with a body mass index of 19.0 to 28.0 kg/m2 were eligible to participate. Female subjects of childbearing potential were required to use an effective method of birth control before entry and throughout the study and to have negative results from a serum human chorionic gonadotropin pregnancy test at screening and a negative urine pregnancy test at baseline. Male subjects were required to agree to avoid insemination. Subjects were required to be nonsmokers or to habitually have smoked no more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 6 months before screening. Subjects were deemed healthy on the basis of a prestudy physical examination, medical history, vital signs, 12-lead electrocardiogram (ECG), and the results of clinical laboratory tests performed within 3 weeks of the first dosing. They were to have signed an informed consent document indicating that they understood the purpose of and procedures required for the study and were willing to participate in the study.
Exclusion criteria included a history of or alcohol abuse within the past 5 years or positive results from a urine drug screening test for drugs that may be abused (eg, benzodiazepines, barbiturates, or tricyclic antide-pressants). Although use of prescription or nonprescription drugs was not allowed 14 days before the first dose or during the study, hormonal replacement drugs or contraceptives, thyroid replacement drugs, and acetaminophen were permitted. Subjects were excluded if they were known to demonstrate hypersensitivity to the active or excipient ingredients of galantamine or memantine; to cholinesterase inhibitors, choline agonists, or similar agents; and to bromide, lithium, or other components of the drugs under study.
Subjects also were ineligible if they had a history of disease that may be affected by cholinergic stimulation or worsened by memantine or if they had a history of significant cardiovascular, respiratory, hepatic, renal, neurologic, endocrine, immunologic, or thromboembolic disease. They were disqualified if they were pregnant, if they were breast-feeding, if they had any current physical condition that could interfere with the interpretation of the study results, or if they had positive results on a serology test for hepatitis B surface antigen, human immunodeficiency virus, or hepatitis C virus antibody. Presence of bradycardia of less than 50 beats per minute (bpm) (exceptions were granted for athletic individuals), any evidence of atrioventricular block, or a clinically significant abnormality on an ECG resulted in ineligibility, as did significant loss of or donation of blood or plasma (>500 mL) within 30 days before the start of the study. Subjects who had received an experimental drug or used an experimental medical device within 60 days before the planned start of treatment were excluded.
Except as previously noted, subjects were instructed to take no prescription drugs, over-the-counter medications, vitamins, or herbal supplements from 14 days before the first dosing of the study drug until after the last blood collection of week 4. They also were required to refrain from ingesting alcohol, grapefruit, grapefruit juice, oranges, orange juice, caffeine, and/or other methylxanthine-containing foods or beverages (including chocolate) from at least 24 hours before drug dosing up to 24 hours after the last morning drug dosing. Food containing poppy seeds was not allowed from 3 days before screening to the end of the study because it might cause positive results in the urine drug screen.
Blood Sample Collection
Multiple blood samples were collected for the determination of galantamine and memantine concentrations. Venous blood samples were obtained from an antecubital vein or via an indwelling cannula.
During week 1, blood samples were collected immediately before the first drug intake on day 1 (2 mL). During week 2, a blood sample (2 mL) was collected immediately before the first drug intake on day 6. On day 7 of week 2, blood samples (2 mL to obtain about 1 mL of plasma) were collected to determine plasma galantamine at predose (0 hours), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours after the galantamine dose.
During week 4, a blood sample (6 mL) was collected immediately before morning drug intake on day 6. Another blood sample (4 mL) was collected at 12 hours after the galantamine dose, immediately before the evening dose of memantine, to determine the memantine plasma concentration. On day 7 of week 4, blood samples totaling 6 mL were collected at predose (0 hours), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours after study drug administration to measure galantamine and memantine concentrations. An additional blood sample (6 mL) was taken 24 hours after morning drug intake on day 7 of week 4.
Bioanalytic Methods
Galantamine plasma levels were determined with liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) using an isotopically labeled internal standard. Details of this method are described elsewhere.19 Accuracy and precision of the method during sample analysis were assessed by analyzing quality control samples in duplicate at 3 concentrations: 3.00, 20.0, and 400 ng/mL. The interbatch accuracy ranged from 105.0% to 110.2%, and the interbatch precision ranged from 4.0% to 4.9% (expressed as percent coefficient of variation [%CV]).
Memantine levels were determined by AAI Deutschland GmbH & Co. in Neu-Ulm, Germany, with gas chromatography/mass spectrometry (GC/MS). Sample preparation was as in the following brief description: after spiking 25 ng of the internal standard to 1-mL aliquots of plasma, 1 mL of a 2M HCl solution and 1 mL of water were added and the samples incubated for 30 minutes at 70°C. After cooling, 0.5 mL of NaOH (35% solution) was added, and the samples were extracted with 0.75 mL of hexane. The organic phase was subsequently separated and derivatization was performed by adding 50 µL of an acylating agent and incubating for 30 minutes at 70°C. The resulting samples were evaporated at 35°C under nitrogen and the residue dissolved in 40 µL of ethylacetate/toluene (80/20; v/v). Then, 1 µL of this extract was injected into the GC/MS system at 170°C (splitless for 30 seconds). Chromatography was on an RTX-1701 15 m x 0.32 mm I.D. x 0.25 µL column (Restek Corp, Bellefonte, Pa) with helium as the carrier gas. The GC (HP 5890, Hewlett Packard, Palo Alto, Calif) temperature program started at 80°C, was held for 1 minute, then ramped at 20°C/min to 165°C and then at 25°C/min to 180°C, and held at 180°C for 2 minutes. Mass spectrometry detection was on a Trio 2000 (Micromass, Cheshire, UK), operated in the positive ion chemical ionization mode with ammonia as the reagent gas and an electron energy of 75 eV. Memantine and its internal standard were monitored at an m/z of 293 and 265, respectively. The method was validated in the range 0.500 to 500 ng/mL. The accuracy and precision of the method during sample analysis were determined from quality control samples at 3 levels: 1.50, 25.0, and 400 ng/mL. Inter-batch accuracy ranged from 88.8% to 103.4%, and interbatch precision ranged from 6.7% to 8.1% (expressed as %CV).
Pharmacokinetic Data Analysis
Based on the individual plasma concentration-time data, using the actual sampling times, steady-state pharmacokinetic parameters of galantamine (from data on day 7 of weeks 2 and 4) and of memantine (from data on day 7 of week 4) were observed. Parameters included maximum observed plasma concentration (Cmax), tmax, and trough plasma concentration (Ctrough) before dosing or at the end of the dosing interval of any dose other than the first dose. Area under the plasma concentration-time curve of galantamine from time 0 to 24 hours postdosing (AUC24 h) and area under the plasma concentration-time curve of memantine from time 0 to 12 hours postdosing (AUC12 h) both were calculated by linear trapezoidal summation using observed plasma concentration values. Average plasma concentration at steady state (Cavg,ss) was calculated by AUC24 h/24 for galantamine and by AUC12 h/12 for memantine. Oral clearance (CL/F) was calculated as dose/AUC24 h for galantamine and as dose/AUC12 h for memantine.
Predose plasma samples taken on the mornings of days 6 and 7 and 24 hours after the morning doses on day 7 of weeks 2 and 4 were used for evaluation of galantamine steady-state conditions by visual inspection. Predose plasma samples taken on the mornings of days 6 and 7 and 12 hours after the morning doses on days 6 and 7 of week 4 were used to evaluate memantine steady-state conditions by visual inspection.
Safety Assessment
Safety assessment data were summarized using descriptive statistics. Safety was evaluated by examining the incidence, the severity, the relationship to either galantamine or memantine, and the type of adverse events (AEs) and by assessing changes in the clinical laboratory results, the physical examination results, the 12-lead ECG (which was taken at screening, baseline, day 1 of week 2, predose on day 1 of week 3, day 1 of week 4, and at discharge), the vital sign measurements, and the concomitant medication and/or therapy required from prestudy to poststudy. An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to that product. Clinical laboratory tests included a hematology panel, a serum chemistry panel, urinalysis, and a serology test. Blood and urine samples for these tests were taken at screening, day 1 of week 3, and at the end of treatment (day 1 of week 5).
Statistical Analysis
Based on a previous study, the intrasubject CV for the area under the plasma concentration-time curve (AUC) and for the Cmax of galantamine was estimated to be less than or equal to 12% (data on file, J&JPRD, LLC). Using an intrasubject CV of 12%, a sample size of 12 subjects would be sufficient for the point estimate of the ratio of the mean of galantamine with and without coadministration of memantine to fall within 10% of its true value with 90% confidence. Sixteen subjects were enrolled to allow for 4 dropouts. Dropouts were to be replaced only if the number of active subjects fell below 12.
All estimated pharmacokinetic parameters were summarized with descriptive statistics. The primary parameters of interest for the statistical analysis were AUC24 h and Cmax of galantamine. The analysis was performed on log-transformed estimated pharmacokinetic parameters. Only the data from subjects who completed the study were included in the statistical analysis. Analysis of variance model was fit to the data with 1 of the estimated pharmacokinetic parameters of interest as the dependent variable, treatment (galantamine with memantine and galantamine alone) as a fixed effect, and subject as a random effect. The estimated least squares means and intrasubject variance from the above model were used to construct 90% confidence intervals (CI) for the difference in means on the log scale between the 2 treatments. The limits of the CIs were retransformed using antilogarithms to obtain 90% CIs for the ratio of the mean pharmacokinetic parameters of galantamine with and without coadministration of memantine.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics: Galantamine
The pharmacokinetic parameters of galantamine are summarized in Table I. The mean plasma concentration-time profiles of galantamine during the galantamine-alone (day 7 of week 2) and galantamine with memantine treatments (day 7 of week 4) are shown in Figure 1. The log-linear mean Ctrough-time profiles of galantamine are shown in Figure 2. The similar trough concentrations (Figure 2) at these time points indicate that galantamine steady-state plasma level was reached by the end of week 2 for galantamine alone and by the end of week 4 for galantamine and memantine administered together.
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The plasma concentration-time profiles of galantamine were comparable during the galantamine-alone and galantamine and memantine treatments. Mean galantamine peak plasma concentrations of 52.5 and 51.5 ng/mL were reached at a mean tmax of 4.63 and 5.67 hours after administration of 16 mg of galantamine during the galantamine-alone and galantamine and memantine treatments, respectively.
A summary of the treatment ratios of the primary pharmacokinetic parameters of galantamine is shown in Table II. For Cmax and AUC24 h parameters, the ratio of means and the 90% CI for the ratio of means from the galantamine and memantine treatment to that from the galantamine-alone treatment were within the 80% to 125% limits. This indicates that the galantamine-alone and galantamine and memantine treatments delivered similar overall exposure to galantamine at steady state. Memantine, administered at a dose of 10 mg bid every 12 hours, had no effect on the steady-state pharmacokinetics of galantamine administered at a dose of 16 mg qd.
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Pharmacokinetics: Memantine
The pharmacokinetic parameters of memantine are summarized in Table III. Mean plasma concentration-time profile of memantine during galantamine and memantine treatment (day 7 of week 4) is shown in Figure 3. The logarithmic-linear mean Ctrough-time profiles of memantine are shown in Figure 4 and indicate that steady-state memantine plasma concentration was achieved on day 7 of week 4.
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During the galantamine and memantine treatment, a mean memantine peak plasma concentration of 83.5 ng/mL was reached at a mean tmax of 5.62 hours after administration of a 10-mg dose of memantine in the morning.
Safety
All 16 subjects reported at least 1 AE (Table IV). The most commonly reported AEs were headache (11 subjects), dizziness (8), and fatigue (7). Dizziness was the most frequent AE during adjunctive memantine treatment (8 subjects), but it was reported in only 1 subject during the galantamine-alone treatment. Fatigue was slightly more frequent during adjunctive memantine treatment (5 subjects vs 1 and 3 subjects during treatment with galantamine alone, 8 and 16 mg, respectively). Syncope, which was reported in 1 subject for 5 minutes on the last day of week 2 while on treatment with galantamine 16 mg, was considered to be of moderate severity and not drug related. This patient had an increased heart rate of 46 bpm with a corresponding increase of 37 ms in QTcB on the ECG the following morning. Both ECG and vital signs normalized before the following morning's assessment.
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Ten of the 18 reported AEs were reported in only 1 subject. Most AEs were mild. One episode of headache during treatment with galantamine 16 mg and 1 episode of psychosis during add-on memantine treatment were considered severe. The subject with the severe episode of psychosis was the sole discontinuation of treatment (on day 3 of week 4). This reaction was considered doubtfully related to galantamine but possibly related to memantine by the investigator. There were no deaths or serious AEs during the study.
There were no clinically relevant changes in laboratory values during the study. Electrocardiography revealed that 4 subjects had heart rate values below the lower limit of normal (<55 bpm) at screening, and 3 continued to have low values at the end of the study. Compared with their values at screening, 3 subjects had QTc increases between 30 and 60 ms, and 1 of these subjects also had an increase in QTcB of 61 ms. At the end of the study, however, the increases were less than 30 ms above screening levels.
No clinically relevant changes in vital signs were observed. Compared with screening levels, pulse increased slightly at most time points. The maximum mean increase was 9.1 bpm on day 1 of week 3. Both supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased at each time point. The maximum mean decreases were -11.1 mm Hg for SBP on day 1 of week 2 and -3.1 mm Hg for DBP on day 1 of week 3.
There were no abnormalities in physical examination at screening. At the next physical examination, on day 1 of week 1, 1 subject had painful lymph nodes in the throat that normalized after he discontinued treatment. These painful lymph nodes may have been associated with a viral illness. It is also possible that the rhinitis, headache, hypertonia, and fever reported during the study resulted from a viral illness that spread through the subjects who were exposed to each other at various times during the study. The 5 subjects with rhinitis also had headache.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The current study design also allows an evaluation of the pharmacokinetic parameters of memantine in the galantamine and memantine combination treatment. The drug exposure (AUC) of memantine in the current study agrees reasonably well with the single memantine treatment data in the memantine bioequivalence study publication.16 In the 12 healthy subjects in this publication, the value of AUC0-
of a single-dose 20-mg tablet was 1870 ± 352 ng•h/mL. Given the linear pharmacokinetics of memantine, this value is consistent with the value of AUC12 h (800 ± 150 ng•h/mL) at steady state following 10-mg bid treatment in the current study. The memantine pharmacokinetic data in this study are comparable with previous memantine data from 2 multiple-dose studies in healthy elderly volunteers with the same dose regimen (AUC24 h = 1803-1848 ng•h/mL and Cmax = 85.8-91.3 ng/mL).15
Galantamine, an AChEI and an allosteric modulator of nicotinic neurotransmission, has been shown to be safe and effective in the treatment of mild to moderate AD.11-14 As demonstrated in an in vitro study, memantine does not attenuate the inhibition of AChE produced by galantamine and other reversible AChEI inhibitors.18 It is possible that the addition of memantine, an NMDA receptor antagonist, to galantamine might complement the therapeutic benefits of galantamine in patients with AD.18
Although a demonstration of complementary therapeutic effects was beyond the scope of the present study, the results indicate that concomitant treatment with galantamine and adjunctive memantine is generally safe and well tolerated. Although many subjects experienced mild AEs in the present study, this rate of AEs may not be relevant to patients who are initiating galantamine and then adding adjunctive memantine according to the recommended dosing. This study used a rapid escalation of galantamine dosage and a rapid introduction of memantine. In clinical practice, however, the recommended starting dose of galantamine IR is 8 mg/day.7 The dose should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should only be attempted after an additional minimum of 4 weeks. The AEs associated with galantamine are seen mainly during titration7 and typically last for 5 to 11 days (data on file, J&JPRD, LLC). In clinical use, the dose of galantamine will most likely be stabilized for a substantial period of time before the introduction of adjunctive memantine.
Product labeling for memantine also advises gradual titration.15 From a recommended starting dose of 5 mg qd, the dose should be increased in 5-mg increments to 10 mg/day (5 mg bid), 15 mg/day (5 mg and 10 mg as separate doses), and the recommended target dose of 20 mg/day (10 mg bid). The minimum recommended interval between dose increments is 1 week.
Despite the rapid dose escalation used in this study, it is noteworthy that most AEs were mild, with no deaths or serious AEs. One subject discontinued treatment during week 4 due to a psychotic reaction consisting of anxiety, dysphoria, and depersonalization. The investigator noted that dysphoric mood changes and hallucinations are seen frequently with NMDA receptor antagonists such as memantine and, therefore, deemed the reaction possibly related to memantine. This subject had had a prior adverse reaction to a selective serotonin reuptake inhibitor.
Although 1 subject had borderline QTc values at screening and at several time points during the study, and another had a borderline QTc value at screening and a prolonged value on day 1 of week 4, both had normal values at the end of the study. No clinically relevant changes in laboratory values or vital signs were observed.
This study demonstrates that the pharmacokinetic profile and parameters of 16 mg/day of galantamine were not affected by the addition of memantine at a dose of 10 mg bid. Furthermore, galantamine 16 mg qd with adjunctive memantine 10-mg bid treatment was relatively well tolerated. Overall, based on the lack of change in pharmacokinetics, it is concluded that no dose adjustment for either memantine or galantamine is necessary when these 2 drugs are coadministered in the dose range studied.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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