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PHARMACOKINETICS |
From FORENAP, Rouffach, France (Demazières, Monreal, Cisterni, Metzger, Luthringer) and TARGACEPT, Winston-Salem, North Carolina (Dunbar, Kuchibhatla).
Address for reprints: A. Demazières, FORENAP, 27 rue du 4° RSM, 68250 Rouffach, France; e-mail: agnes.demazieres{at}forenap.asso.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSION REFERENCES |
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4ß2 nicotine acetylcholine receptor partial agonist, has shown memory-enhancing properties in rodents and a good tolerability profile. The safety and the full pharmacokinetic profile of TC-1734 and its N-desalkylated metabolite, TC-1784, were investigated in 2 phase I studies, and results are reported in this article. Study A used a double-blind, placebo-controlled, crossover design with a rising single-dose scheme (2-320 mg). Study B used a double-blind, placebo-controlled, parallel-group design with a rising multiple-dose scheme (doses: 50, 100, and 200 mg, once daily, x 10 days). Cmax of TC-1734 was reached around 1 to 2 hours postdose, and mean terminal half-life (t
) ranged from 3 to 5.3 hours (single doses) and from 2.7 to 8.8 hours (repeated doses). No accumulation of TC-1734 was observed after 10 days. Renal clearance appeared to be a minor method of elimination of TC-1734 and TC-1784. A high interindividual variability was noted for all parameters. Across the dose ranges explored, TC-1734 was safe and well tolerated. No changes of clinical significance were seen on laboratory and cardiovascular parameters. Adverse events were generally of mild to moderate intensity, with dizziness and headache being reported most frequently.
Key Words: Alzheimer • ispronicline • nicotine acetylcholine receptor (nAChR) • phase I
4ß2 subtype are of particular interest because high densities of these receptors are found in brain regions involved in memory processes and AD.4,7-10 Moreover, mice lacking high-affinity ß2 binding sites for nicotine showed impaired spatial learning,11 and hippocampal infusion of an 4ß2 antagonist induced working memory impairment, which was reversed by nicotine.12 TC-1734 is a new nAChR partial agonist with a high affinity and selectivity for the 4ß2 receptor. The hemigalactarate (TC173412) and the di-toluoyltartrate salts (TC1734-112) (Figure 1) were used in preclinical investigations. TC-1734 displayed neuroprotective and cognitive-enhancing properties without safety concerns that would preclude its administration in human (see Gatto et al13 and Obinu et al14 for review). Pharmacokinetic studies conducted in rats and dogs after oral administration of TC-1734-112 indicated a rapid plasma elimination of the compound with mean terminal half-lives around 1 hour in both species. Although TC-1734 was subject to a wide and extensive metabolism, it remained the major compound in the plasma.13 CYP 2D6 was shown to participate in the metabolism of TC-1734, but possible involvement of other enzymes needs to be determined. It was suggested that the cognitive-enhancing effects observed at low doses in rats, despite very low plasma and brain levels, might be due to the combined pharmacological activity of TC-1734 and some of its metabolites. Because the desalkylated metabolite (TC-1784) is the only one detected in plasma that displays a certain affinity for the 4ß2 site,13 it may participate in the pharmacological activity of oral TC-1734. This article reports the pharmacokinetic and safety results of single and repeated oral doses of TC-1734-112 (referred as TC1734 thereafter) from the first 2 phase I dose escalation trials conducted in healthy young male subjects.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSION REFERENCES |
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Participants
Nonsmoking men aged between 18 and 45 years, with a body mass index between 18 and 28 kg/m2, were enrolled based on inclusion/exclusion criteria for healthy volunteers, after giving written informed consent. Subjects could not be included if they had any disease or condition that could lead to misinterpretation of the study results.
Study Design and Treatments
Both studies were conducted in a randomized, double-blind, placebo-controlled fashion according to a 2-period crossover design (study A) and a parallel-group design (study B).
Study A consisted of 8 dose cohorts of 6 subjects each to test ascending single oral doses of TC-1734 (2, 4, 10, 20, 40, 80, 160, and 320 mg). The first doses were chosen on the basis of safety and pharmacological data obtained from animal studies (see Gatto et al13 for more details). Each subject received 1 dose of TC-1734 and its matching placebo 1 day apart in the order determined by their assigned randomized sequence.
Study B consisted of 3 dose cohorts to test repeated oral doses of TC-1734 (50, 100, and 200 mg) administered once daily for 10 days. In each dose cohort, 6 subjects were randomized to receive TC-1734 and 2 subjects to receive placebo. This design provided equal group sizes (n =6) for placebo and each dose level.
Capsules containing TC-1734 or its placebo were swallowed with a glass of water around 9:00 AM in fasting conditions.
For both studies, escalation from 1 dose to the next was performed only if safety, tolerability, and exposure of TC-1734 from the previous dose level were satisfactory.
Blood and Urine Sample Collection
For both studies, venous blood samples (5 mL) were collected into tubes containing lithium heparinate. Then, each sample was immediately refrigerated on ice and centrifuged within 15 minutes (3000 rpm, +4°C, x 10 min) to separate plasma. Urinary samples were fractionated into several consecutive periods, and the total urinary volume was recorded for each fraction. All samples were immediately stored at -20°C until analysis.
Study A. For the dose groups up to 80 mg, blood samples were collected prior to drug administration and 5 minutes, 10 minutes, 20 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours postdosing in each treatment period. For the 2 highest tested doses (160 and 320 mg), blood samples were collected prior to drug administration and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours postdosing of each period. Urine samples were collected in epochs of 6 hours from drug administration up to 24 hours.
Study B. Blood samples were collected on the first and last day of dosing (day 1 and day 10), prior to drug administration and at different times thereafter (0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours). Blood samples were also drawn before dosing (trough concentrations) from day 2 to day 9 for evaluation of pharmacokinetic steady state. Additional blood samples were collected 24 and 36 hours (day 11) and 48 hours (day 12) after the last dose. Urine samples were collected on day 1 and day 10, at baseline (within 2 hours prior to dosing), and postdosing (from 0 to 2, 2 to 4, 4 to 6, 6 to 12, and 12 to 24 hours).
Analytical Procedures
A high-performance liquid chromatography (HPLC) assay method using tandem mass spectrometry detection (LC/MS/MS; Sciex API 365) was developed by Biotec (Orleans, France) to quantify TC-1734 and its desalkylated metabolite, TC-1784, in human plasma and urine.
Extraction Procedures
After addition of the internal standard (TC-2559) to the plasma or urine sample, TC-1734 and TC-1784 were extracted by a liquid/liquid extraction using methylene chloride in basic conditions. The organic phase was treated by acidic methanol and evaporated under a nitrogen stream. Then the residue was dissolved in the mobile phase before injection onto the HPLC column.
Chromatographic Procedures and Assay Performances
The chromatographic separation was performed on a 33 x 4.6-mm 3-µm LC-8-DB reversed-phase SUPELCOSILTM HPLC column operating at room temperature. The mobile phase was a mixture of 100 mM ammonium formate and acetonitrile in a 15/85 volume/volume ratio. The flow rate was set to 0.3 mL/min. A triple quadrupole mass spectrometer (MS/MS) was used for this assay method. The ion source was operating at an atmospheric pressure electrospray ionization mode. The detection was performed in the multiple-reaction monitoring mode. The following ion transitions mass-to-charge ratios were monitored: 235 to 162 (TC-1734), 221 to 136 (TC-1784), and 207 to 146 (internal standard). The plasma concentrations corresponding to the lower limit of quantification (LLOQ) and the upper limit of quantification (ULOQ) were 0.1 ng/mL and 50 ng/mL, respectively, for both TC-1734 and TC-1784. The urine concentrations corresponding to the LLOQ and the ULOQ were 1 ng/mL and 500 ng/mL, respectively, for both TC-1734 and TC-1784. The calibration curves were linear over these concentration ranges. For plasma, interassay accuracy was between 103% and 112% and between 84.7% and 94.9%, and precision (expressed as percentage of coefficient of variation) was always better than 9.7% and 9.9% for TC-1734 and TC-1784, respectively. For urine, interassay accuracy was between 99% and 110% and between 88.8% and 104%, and precision was always better that 6.7% and 9.9% for TC-1734 and TC-1784, respectively. All assays were performed by Biotec Centre.
Pharmacokinetic Evaluations
For both studies, the pharmacokinetic parameters of TC-1734 and its metabolite were estimated by standard noncompartmental methods (WinNonlin V4 software). The maximum plasma concentration (Cmax) and the time of its occurrence (tmax) were directly obtained from the visual inspection of the individual plasma concentration-time curves. The elimination rate constant (
z) was calculated by fitting the individual data from the terminal phase of the plasma concentration-time plots to log-linear regression using the method of least squares. The apparent terminal elimination half-life (t) of TC-1734 and TC-1784 was calculated as ln2/z. The area under the plasma concentration-time curves (AUClast) was calculated from measured data points from the time of administration to the time of the last quantifiable concentration (Clast) by the linear trapezoidal rules. Extrapolation to time infinity was determined by Clast/z, and AUC
was calculated as AUClast + Ct/. The area under the plasma concentration-time curves to 24 hours in study A (AUC0-24) or during the dosing interval in study B (AUC
) was also calculated. The apparent oral clearance (Cl/F) of TC-1734 was calculated as the ratio of the dose to AUC. The amount of the compound excreted in the urine over the time interval from 0 to 24 hours (Ae) was directly derived from visual inspection of the urinary concentration-time curves. The percentage of the dose administered excreted in urine was calculated according to the following formula: Ae/Dose·100. Renal clearance (Clr) was calculated by the ratio Ae/AUC over the same time interval from 0 to 24 hours.
Additional parameters were calculated in study B: the trough concentration measured at the end of the dosing interval, that is, immediately before the next administration (Cmin) from day 2 to day 10; the linearity factor of pharmacokinetics after repeated administration (LF) was calculated by dividing AUC on day 10 by AUC on day 1.
Statistical Analyses
Pharmacokinetic parameters of TC-1734 and its metabolite, TC-1784, obtained for each dose level were summarized as means, standard deviations, and coefficients of variation (CV).
In study A, log-transformed values of AUClast and Cmax were plotted against log-transformed doses to test dose proportionality. Statistical comparisons were performed by an analysis of variance (ANOVA). Ninety percent confidence intervals for differences from the lowest detectable dose were calculated from the residual variance. The estimates were back-transformed to obtain estimates and 90% confidence intervals for the ratios compared to the lowest detectable dose.
In the multiple-dose study, dose proportionality of AUCs and Cmax for TC-1734 was tested separately after a single dose and after 10 days of administration by a linear regression power model assessing the relationship between logAUCs or logCmax and logDose.15
Safety Evaluations
Vital signs (blood pressure, heart rate, supine respiratory frequency, and oral body temperature), 12-lead electrocardiogram (ECG), and physical examination were monitored at screening, regularly during the study, and at the follow-up visit (except body temperature). Continuous cardiac monitoring was performed at screening, on the days of drug administration (study A), and on the first and last days of administrations (study B). Laboratory safety evaluations (hematology, blood and urine chemistry) were assessed at screening, admission, and at the follow-up visit. Additional laboratory evaluations were performed 24 hours postdosing (study A) and on day 5 as well as 48 hours after the last dose administration (study B).
Adverse events (AEs) were captured throughout the study by solicited and spontaneous subject reports. For each subject presenting with an adverse event, time of onset, duration, intensity, outcome, and relationship to treatment were recorded. Safety results were reviewed at the end of each dose level by the physician and the medical monitor before progression to the next higher dose.
All the subjects who took at least 1 dose of the investigational compounds (TC-1734 or placebo) were included in the safety analyses. Only descriptive analyses were performed on safety data.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSION REFERENCES |
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Mean age varied from 25.3 to 33.5 years (range, 18-45 years) and BMI from 22.22 to 24.85 kg/m2 (range, 18.4-28.4 kg/m2) across the dose groups from both studies.
Pharmacokinetic Results
Study A
TC-1734. TC-1734 was undetectable in most subjects after a 2-mg dose, and TC-1734 plasma levels dropped rapidly below the LLOQ after a 4-mg dose. Consequently, pharmacokinetic parameters could not be determined with accuracy at these low doses, and these doses were not taken into account in the statistical analyses. At higher doses, plasma levels of TC-1734 were detected in all subjects, from 1 to 8 hours or 12 hours postdose at the 10-mg dose and from 0.5 up to 24 hours in most of the subjects at doses between 40 and 160 mg or even longer after a dose of 320 mg. Mean plasma concentration-time curves of TC-1734 at each dose level are shown in Figure 2A, and corresponding pharmacokinetic parameters of TC-1734 are depicted in Table I. Plasma levels of TC-1734 reached a peak around 1 to 2 hours postdose and then declined, with a mean t varying from 3 to 5.3 hours across doses. Although the range of doses rose by a factor 32 (10-320 mg), Cmax and AUCs increased by a factor around 100 and 70-80, respectively. Comparison of dose-normalized Cmax revealed statistically significant differences for doses of 160 mg and 320 mg compared to the 10-mg dose (P < .001 for 160 mg vs 10 mg; P = .05 for 320 mg vs 10 mg), suggesting a lack of dose proportionality between low doses (10-80 mg) and high doses (160-320 mg). No statistical differences were detected for dose-normalized AUCs. The oral clearance values (Cl/F) appeared to be lower for doses of 160 and 320 mg than within the dose range 10 to 40 mg but with a large interindividual variability for all doses (Table I). The renal clearance was around 10 L/h across doses, except for the highest dose, with this difference being likely due to a high intersubject variability (CV = 59%) (Table I). The percentage of the dose administered excreted in the urine (Ae%) was low and comparable across doses (around 1%) (Table I).
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TC-1784. TC-1784 was not detected in plasma of any subjects who received 2 mg TC-1734 and in only 2 subjects who received 4 mg TC-1734. Thus, plasma pharmacokinetic parameters could not be calculated for these low doses. At higher doses, TC-1784 was detected in the plasma shortly after the detection of the parent compound (about 30 minutes) and persisted in the plasma for a similar interval, as was seen for TC-1734 in most subjects. Mean plasma concentration-time curves of TC-1784 at each dose level are shown in Figure 2B, and corresponding pharmacokinetic parameters are depicted in Table II. Plasma levels of TC-1784 reached a peak around 3 hours for all doses and then declined with t ranging from 4.3 hours (320 mg) to 6.2 hours (10 mg). Cmax and AUCs were lower for the metabolite than the parent compound, and the percentage of TC-1734 administered excreted in the urine as TC-1784 was below 0.5% at all doses (Table II). As with TC-1734, high interindividual variability was observed for the different pharmacokinetic parameters of TC-1784 at all dose levels. Contrary to TC-1734, Cmax and AUCs of TC-1784 increased in a dose-dependent manner (see Table II).
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Study B
TC-1734. Mean plasma concentration-time curves of TC-1734 at each dose level of study B are shown in Figure 3. After oral daily doses of 50, 100, or 200 mg, TC-1734 was detected in the plasma as early as the first postdose sample (+0.5 hours) on day 1 and day 10 in most of the subjects; it was still detectable up to 12 hours after the lowest dose and up to 24 hours after the highest dose. Plasma and urinary pharmacokinetic parameters are depicted in Table I. Cmax was achieved around 2 hours postdosing both on day 1 and day 10. Although the range of tested doses rose by a factor of 4 (50-200 mg), Cmax and AUC showed an increase higher than 10 times both on day 1 and day 10. The regression power model did not detect a nonlinear Cmax increase with dose, whereas a nonlinear AUC increase was detected but only on day 10 (see Figure 4). Elimination of TC-1734 from the plasma was similar after day 10 and day 1 for a daily dose of 50 mg (t = 2.91 and 2.68 h) but appeared slower after day 10, for daily doses of 100 and 200 mg, as indicated by longer t values (6.6 to 8.8 hours vs 4.7 hours). Renal clearance (Clr) of TC-1734 was comparable on day 1 and day 10 for a same dose level but appeared higher after the 50-mg dose than after the 2 highest doses. Cmin values were below the LLOQ in 5 out of 6 subjects for the 50-mg dose, and median Cmin values varied from 0 to 1 ng/mL for the tested dose range (50-200 mg).
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TC-1784. Plasma and urinary pharmacokinetic parameters of TC-1784 in study B are depicted in Table II. TC-1784 was detected in the plasma within 0.5 hours after the detection of the parent compound in most of the subjects, and it was eliminated from the plasma with a mean t ranging from 4.03 to 5.91 hours on day 1 and from 3.82 to 8.98 hours on day 10 (Table II). Mean Cmax was reached between 2 and 3.5 hours on day 1 and between 2.5 and 3 hours on day 10 (ie, within 0 to 2 hours of the Cmax observed for the parent compound). As with TC-1734, Cmax and AUC values increased with the dose. Mean Cmax values of TC-1784 were about 3- to 4-fold and 7- to 10-fold higher after administration of TC-1734 at the dose of 100 mg and 200 mg than after the dose of 50 mg. The cumulative urinary excretion (Ae) of TC-1784 was lower after the 50-mg dose than after the 2 highest doses, whereas the renal clearance (Clr) tended to decrease with dose. As with TC-1734, high interindividual variability was observed for the different pharmacokinetic parameters of TC-1784 at all dose levels. The subjects with high TC-1734 levels also displayed the highest TC-1784 levels.
Safety Results
A summary of treatment-emergent adverse events (AEs) reported during the 2 phase I studies is presented in Table III. TC-1734 was well tolerated up to a daily dose of 200 mg for 10 days. No serious AEs were reported during these 2 trials. The most frequently reported AE during the single-dose study was headache of mild to moderate intensity, reported both on placebo and TC-1734 from 20 to 320 mg. The most frequently reported AE during the repeated-dose study was postural hypotension of mild intensity reported with the dose of 200 mg. These AEs were considered as possibly related to the study drug. Most of the other AEs were of mild or moderate intensity and recovered spontaneously. Only 4 AEs were considered severe (1 episode of asthenia, 1 episode of muscular weakness, 2 episodes of light-headedness coded as syncope). They occurred with the highest single tested dose of 320 mg and were considered as probably related to TC-1734. The rate of AEs was comparable between placebo and doses of TC-1734 up to a single dose of 160 mg (study A) and up to a repeated daily dose of 100 mg. A higher incidence of AEs was reported with the single dose of 320 mg and the repeated dose of 200 mg. No clinically significant modifications of hematology and biochemistry parameters were observed in these studies. No subjects were discontinued prematurely because of an AE, except 1 subject who experienced asymptomatic ventricular extrasystoles of mild intensity approximately 17 hours after receiving a single dose of 20 mg of TC-1734. This AE was possibly related to TC-1734 and recovered spontaneously. Except for this case, no clinically relevant changes in cardiac parameters were recorded by the 12-lead ECG or the 24-hour Holter ECG.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSION REFERENCES |
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4ß2 receptor subtype.13 TC-1734 is currently under clinical development for AD and other dementia disorders based on its memory-enhancing properties and its low toxicity observed in animals.13 In this article, the pharmacokinetics, safety, and tolerability of rising single and multiple doses of TC-1734 were studied for the first time in humans. Pharmacokinetic characteristics of its N-desalkylated metabolite, TC-1784, were also explored. Indeed, preclinical findings indicate appreciable affinity of TC-1784 for the nAChR of the 4ß2 subtype, although 40 to 100 times lower than the affinity of the parent compound.13 In the present study, plasma levels of this metabolite were 10-fold less than the parent drug. Given the relative receptor affinity and plasma concentrations, TC-1784 would not be expected to be involved in any pharmacodynamic effect seen after oral administration of TC-1734.
According to the very first single-dose study (study A), no AEs were observed with doses of TC-1734 as low as 2 and 4 mg, which did not produce detectable plasma levels in most subjects. The rate of occurrence of AEs remained low and comparable for doses from 20 to 160 mg but increased at the 320-mg dose level, which was considered as close to the maximal well-tolerated dose. These clinical safety findings, along with the findings of prolonged improvement of memory up to at least 18 hours after a single oral dose in mice despite a very short t,13 led to the choice of a once-daily regimen of doses from 50 to 200 mg in the next multiple-dose study (study B).
In both the single- and multiple-dose trials, TC-1734 was found to be rapidly absorbed and rapidly converted to TC-1784. TC-1734 and TC-1784 were rapidly eliminated from the plasma with a mean plasma t value between 3 and 6 hours after single doses and between 3 and 9 hours after repeated doses (see Tables I and II). Such results are in agreement with animal studies, in which a rapid elimination of TC-1734 was also found (t around 1 hour in rats and dogs).13 According to the low percentage of TC-1734 and TC-1784 excreted in urine, renal excretion appeared to play a minor role in the elimination of TC-1734 and TC-1784 in humans. TC-1734 plasma levels (Cmax and AUC) rose faster than predicted by the dose increase. Dose proportionality was observed for single oral doses in the range of 10 to 80 mg. On the contrary, disproportionately higher Cmax was obtained at high single doses (160-320 mg), and disproportionately higher AUC was obtained after repeated doses in the range of 50 to 200 mg/d. A lack of dose proportionality in TC-1734 exposure was also reported in the rat at doses of 10 and 20 mg/kg compared to the dose of 1 mg/kg (data from the investigator's brochure). The linearity factor was close to 1 at all doses (50-200 mg/day), suggesting pharmacokinetic linearity with time after daily administrations for 10 days. Mean AUC and mean Cmax appeared higher on day 10 than on day 1, but these differences were due to the very high intersubject variability in the degree of exposure to TC-1734 and its metabolite (CV = 100%). Furthermore, the lack of a decrease in TC-1734 plasma levels (Cmax, AUC) on day 10 compared to day 1 does not support pharmacokinetic data in rats suggesting that TC-1734 could induce its own metabolism.13 The large interindividual variability in drug exposure may also explain the lack of dose proportionality in Cmax (study A) and AUC (study B) observed in these exploratory studies involving only a small number of subjects per dose. Administration of various doses in a same subject would be necessary to clearly identify a possible nonlinear pharmacokinetic profile with dose. Two major sources of pharmacokinetic variability and nonlinearity are suspect. First, findings in rats showed that the drug was subject to a high firstpass effect that could be saturated at high doses. Second, 1 enzymatic system involved in TC-1734 metabolism is CYP2D6, which is known to be subject to a genetic polymorphism, leading to high individual differences in the drug metabolic capacities. A genotyping/phenotyping study has just been completed and seems to confirm this hypothesis. Based on preclinical data, Cmax ranging between 5 and 25 ng/mL is expected to be associated with efficacy in humans. This Cmax range was reached in most of the subjects receiving a 50-mg daily dose, whereas Cmax values largely above 25 ng/mL were obtained in most of the subjects receiving the 200-mg daily dose. Intermediate results were obtained with the intermediate daily dose. Cmin values were very low at all doses, as could be expected by using a dosing interval quite longer than the plasma elimination half-life of the drug. However, animal studies have shown persistent memory-enhancing properties beyond the plasma lifetime of the compound after a single dose (cognitive effects lasting for 18-25 hours vs plasma t around 1 hour).13 Consequently, daily doses of 50 to 150 mg are expected to provide adequate cognitive effects in humans despite low Cmin values. This is currently under investigation in phase II trials. Moreover, TC-1734 showed good tolerability up to daily doses of 200 mg. No clinically laboratory abnormalities were observed. No cardiovascular alterations were recorded, except mild asymptomatic ventricular extrasystoles in 1 subject (study A) and symptomatic orthostatic hypotension in 2 subjects (studies A + B). The lack of cardiac as well as musculoskeletal effects of TC-1734 was in agreement with its lack of stimulation at ganglion-type and muscle-type nAChRs10 and was different from nicotine, which causes cardiac changes due to stimulation of sympathetic ganglia and adrenal medulla.6 Interestingly, gastrointestinal effects (nausea, vomiting, diarrhea) usually observed with other selective brain nicotinic agonists16 appeared rather uncommon with TC-1734, at least up to 200 mg/d. Adverse events were seen mainly in the nervous system and may be explained by the central pharmacological properties of the compound. For example, dizziness is a well-known side effect of nicotine and was reported with other selective brain nicotinic agonists.16
The present data suggest that daily doses up to 200 mg can be used safely in humans.
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CONCLUSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSION REFERENCES |
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Financial support for these studies was provided by Targacept Inc.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSION REFERENCES |
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