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Single-Dose Pharmacokinetics of Varenicline, a Selective Nicotinic Receptor Partial Agonist, in Healthy Smokers and Nonsmokers

From the Departments of Clinical Pharmacokinetics and Pharmacodynamics (Dr Faessel, Dr Gibbs), Pharmacokinetics, Pharmacodynamics, and Metabolism (Dr Smith, Mr Gobey), and Medical and Developmental Sciences (Dr Faessel, Dr Gibbs, Dr Clark, Dr Burstein), Pfizer Global Research and Development, Groton, Connecticut.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Varenicline is a novel and selective 4ß2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline.

Key Words: Varenicline • single-dose pharmacokinetics • food effect • evening dosing

Varenicline (CP-526,555) is a novel and selective nicotinic receptor partial agonist that binds specifically at the 4ß2 receptor and is FDA approved for smoking cessation.⁶ Because of its mixed agonist-antagonist effects, varenicline is expected to reduce the psychogenic reward associated with smoking while also relieving nicotine craving and withdrawal symptoms in abstinent subjects.

The primary objectives of this study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
In total, 102 subjects were enrolled in the study. Sixty-eight healthy, male (n = 64) or female (n = 4), cigarette smokers (10 cigarettes smoked per day, confirmed by urine cotinine levels >500 ng/mL) and nonsmokers (confirmed by cotinine levels) between the ages of 18 and 45 years, inclusive, received varenicline. Women must have been of nonchildbearing potential, that is, surgically sterilized or at least 2 years postmenopausal, and not breast-feeding. Smokers ranged in age from 21 to 43 years, in height from 154.0 to 196.0 cm, and in body weight from 51.5 to 91.0 kg. The nonsmokers ranged in age from 19 to 44 years, in height from 159.0 to 190.0 cm, and in body weight from 58.0 to 83.9 kg. Smokers must have had a Fagerström Nicotine Dependence Rating of 6 or higher. There was no restriction on smoking during the study, except for the group of smokers in which the effect of smoking restriction (smoking was not allowed from 8 hours before dosing until 4 hours after dosing) was explored. Nonsmokers must not have smoked any form of nicotine, including but not limited to cigarettes, cigars, and pipes, for at least 3 months prior to participation in the study. Nonsmokers must not have been on any nicotine replacement therapy for the same duration. Nonsmokers could not have smoked during the entire study period. The study was conducted at 2 clinical sites. The study was approved by VanTx Research AG Muttenz, St Jakobsstrasse 41-43, Mutenz, CH-4132, Switzerland; and by PPD Development Clinic Independent Ethics Committee, 72 Hospital Close, Evington, Leicester, LE5 4WW, United Kingdom. All subjects gave written informed consent to participate prior to undergoing any study procedures. Alcohol, caffeine, and grapefruit juice were not permitted, beginning 48 hours prior to the start of the study through the completion of the study.

Study Design
This was a phase 1, double-blind, placebo-controlled, single-dose, dose-escalation study, with subject groups for fed/fasted dosing comparisons and with subject groups for morning/evening dosing comparisons. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. The subjects only received one single oral administration of varenicline or placebo. Six dose levels (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers, and 7 dose levels were investigated in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Additional subject groups were studied in pilot evaluations of the effect of food, smoking restriction, and evening dosing on the bioavailability of varenicline. All subjects, with the exception of the smokers receiving 3 mg under fed conditions in the evening (n = 4) and the corresponding placebo subjects (n = 2), were studied at VanTx Research AG Muttenz.

Test Drugs and Administration
Dosage and administration. Study drug (varenicline succinate or placebo) was supplied as oral powder for constitution and administered as a solution. A total volume of 240 mL, including the volume of dosing solution, was consumed with the dose. The sponsor provided specific dosing instructions to the site. All blinded doses were prepared by an unblinded member of the Clinical Research Unit staff with appropriate training and experience and who was not responsible for other aspects of the study.

Dosing under fasting conditions in the morning. Subjects were dosed at approximately 8 AM following an overnight fast of at least 8 hours. To standardize experimental conditions, all subjects were required to refrain from lying down (except for vital sign and electrocardiogram [ECG] measurements), eating, and drinking beverages other than water during the first 4 hours after drug administration.

Dosing under fed conditions in the morning. Varenicline was administered under fed conditions in a 3-mg dose group in smokers and a 1-mg dose group in nonsmokers. Subjects fasted for at least 8 hours prior to consuming a standard Food and Drug Administration (FDA) high-fat breakfast that was completely ingested over a 20-minute period. This standardized breakfast consisted of 2 eggs fried in butter, 2 strips of bacon, 2 oz hash brown potatoes, 2 slices toast with 2 pats butter, and 8 oz whole milk (compositio 25% carbohydrate, 60% fat, and 15% protein). Subjects were dosed at approximately 8 AM, immediately after the meal. Subjects were required to refrain from lying down except for vital sign measurements and from eating during the first 4 hours after drug administration to standardize experimental conditions.

Dosing under fed conditions (standard, non-high-fat meal) in the evening. A single-dose group of smokers was administered 3 mg varenicline under fed conditions in the evening. The group fasted for at least 2 hours prior to eating a standard, non-high-fat meal. The daily nutritional composition was 50% carbohydrate, 35% fat, and 15% protein. The meal was completely ingested over a 20-minute period. Varenicline was then to be administered at approximately 9 PM, immediately after the meal.

To standardize experimental conditions, all subjects were required to refrain from eating and drinking beverages other than water during the first 4 hours after drug administration.

Analytical Methods
Blood sufficient to provide a minimum of 3 mL plasma for varenicline pharmacokinetics was collected in heparinized tubes at the following times: 0 (just before dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours after drug administration. For the evening dosing portion of the study, blood samples for the measurement of varenicline concentrations were drawn at 0 (just before dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 84, and 108 hours after drug administration. Blood samples were processed to obtain plasma and stored frozen prior to analysis.

To plasma samples (1 mL) was added CP-533,633 as an internal standard followed by alkalinization (1M NaOH; 0.5 mL) and extraction with methyl tertbutyl ether (MTBE). The organic phase was evaporated to dryness and reconstituted in 100 µL of a 1:1 mixture of acetonitrile (ACN) and 10 mM ammonium acetate (NH₄OAc). Analysis was conducted by highperformance liquid chromatography-mass spectrometry (HPLC-MS). Reconstituted extracts were injected (0.04 or 0.05 mL) onto a BDS Hypersil Cyano column (100 x 2 mm, 5µ particle size) equilibrated in 10 mM ammonium acetate in 78% acetonitrile at a flow of 1 mL/min. Elution was isocratic, and the retention times for varenicline and internal standard were both at approximately 1 minute.

The effluent was introduced into an atmospheric pressure chemical ionization source on a PE SCIEX API 3000 triple quadrupole mass spectrometer operated in the positive ion mode. Optimal ionization occurred at a temperature of 400°C, a needle current (DI) of 5.0 µamps, an auxiliary gas flow of 1000 mL/min, and nebulizing gas pressure 60 pounds per square inch of N₂. Nitrogen nebulizer gas was set at a nominal value of 10, and curtain gas was set at a nominal value of 10. Analysis was performed by multiple reaction monitoring after collision induced dissociation of drug and internal standard in the mass spectrometer collision cell, at a collision energy of 45 eV and a collision gas nominal value of 10. The mass spectrometer was adjusted to monitor parent-to-product ion transitions of mass-to-charge ratio (m/z) 212.1 to 168.0 for drug (varenicline), and m/z 240.1 to 198.0 for internal standard (CP-533,633). The dynamic range of the assay was from 0.100 to 50.0 ng/mL. Assay selectivity was evaluated by extracting several different lots of human plasma, and no interferences were observed. For independently prepared quality control samples, the interassay precision was 8%, and determined concentrations were accurate to within 4%. The stability of quality control samples was evaluated. Accuracy was within 6.2% after 3 freeze-thaw cycles and within 0.8% after 25 hours at room temperature.

Pharmacokinetic Evaluation
All pharmacokinetic parameters were estimated using standard noncompartmental methods (WinNonlin Version 2.1, Pharsight Corp, Mountain View, Calif). The following pharmacokinetic parameters that were reported for each subject included maximum plasma concentrations (C_max), the time of occurrence of C_max (t_max), terminal phase half-life (t), and area under the plasma concentration versus time curve from t = 0 to infinity using linear trapezoid approximation (AUC_0-).

Mean plasma concentrations were determined only when individual values were above the lower limit of quantification (0.100 ng/mL) in 50% of the subjects receiving a given dose. For concentration values below the lower limit of quantification, a value of zero was used in the calculation of summary statistics. For plasma concentrations and pharmacokinetic parameters, the values are reported as arithmetic means ± standard deviations.

Safety
All subjects were evaluated for safety, which was assessed by clinical observation, physical examinations, vital signs, ECGs, and clinical laboratory measurements. For the nonsmokers, vital signs were measured at screening, the night before dosing (approximately 12 hours prior to dosing), 0 (just prior to dosing), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 120 hours postdose. For the smokers dosed in the morning, vitals signs were measured at screening, the night before dosing (approximately 12 hours prior to dosing), upon awakening (day 1 only), after first cigarette (day 1 only), 0 (just prior to dosing), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 120 hours postdose. Subjects dosed in the evening had vital signs measured at screening, 0 (just prior to dosing), and at 2, 12, 48, and 108 hours postdose. A 12-lead ECG was obtained in nonsmokers at screening, the night before dosing (approximately 12 hours prior to dosing), 0 (just prior to dosing), 1, 2, 3, 4, 8, 12, 24, 36, 48, and 120 hours postdose. For the smokers dosed in the morning, a 12-lead ECG was obtained at screening, the night before dosing (approximately 12 hours prior to dosing), upon awakening (day 1 only), after first cigarette (day 1 only), 0 (just prior to dosing), 1, 2, 3, 4, 8, 12, 24, 36, 48, and 120 hours postdose. Subjects dosed in the evening had ECGs obtained at screening, 0 (just prior to dosing), and at 2, 12, 48, and 108 hours postdose. Laboratory tests were performed at screening, 0 (just prior to dosing), 24, 48, 72, and 120 hours postdose for subjects dosed in the morning and at screening, 0 (just prior to dosing), 24, 48, 60, and 108 hours postdose for subjects dosed in the evening.

Statistics
No specific statistical hypothesis tests were planned. Pharmacokinetic and safety data were summarized through appropriate data tabulations, descriptive statistics, and graphical presentations.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Pharmacokinetics in Smokers
Plasma concentrations of varenicline at the 0.01-mg dose were below the lower limit of quantification of 0.100 ng/mL. In the group that received 0.03 mg varenicline, plasma concentrations could be measured in most subjects up to 8 hours postdose. Mean C_max and t_max values were 0.165 ng/mL and 0.75 hour, respectively. Terminal half-life could not be calculated in the 0.03-mg dose group. After single oral administration of 0.1 mg and 0.3 mg, plasma concentrations of varenicline for most subjects were quantifiable up to 24 hours and 72 hours, respectively, after dosing. When oral doses of varenicline from 1.0 mg to 10.0 mg were given to smokers, all subjects had quantifiable plasma levels of varenicline up to 120 hours postdose. Over this dose range, plasma concentrations peaked within 1.5 mg to 4.25 hours postdose. Overall, the mean terminal half-life of the decay phase ranged from 14.4 hours to 19.5 hours over the dose range from 0.1 mg to 10 mg. Systemic exposure to varenicline was assessed by C_max and AUC_0-. Approximate dose proportional increases in C_max and AUC_0- occurred from 0.1 mg to 3.0 mg. There was no further increase in C_max and AUC_0- with dose when comparing the 3.0-mg and 10.0-mg dose groups. However, all 4 subjects at the 10.0-mg dose vomited shortly after dosing, which may have affected C_max and AUC_0- estimates. The pharmacokinetic parameters and plasma concentration–time profiles for smokers are presented in Table I and Figure 1.

View larger version (19K): [in this window] [in a new window]   Figure 1. Mean plasma concentration versus time plot of varenicline after single oral administration of different doses of varenicline under fasted conditions in healthy smokers (N = 4; except N = 1 in 1-mg group) on a linear scale (A) and on a semilogarithmical scale (B).

Three additional pilot studies were conducted in the smoking subjects. The first evaluated the pharmacokinetics of a single oral 3.0-mg dose of varenicline immediately following a standard FDA high-fat breakfast. These results showed that the plasma concentrations and derived pharmacokinetic parameters were nearly identical to a previous group of smokers who had been orally dosed with 3.0 mg varenicline in the fasted state (Table I, Figure 1). Thus, there was no apparent effect of food on the pharmacokinetics of a single 3.0-mg dose of varenicline. A second group was evaluated to assess whether smoking influences the pharmacokinetic and adverse event profiles of a 3.0-mg dose of varenicline in smokers. Smoking restriction produced no detectable change in the pharmacokinetic profile of varenicline (Table I, Figure 2). Finally, 4 smokers received a single oral dose of 3.0 mg in the evening. Mean C_max and AUC_0- were approximately 40% and 17% lower, respectively, than previously observed values in the subject groups given 3.0 mg under conditions of fasting, fed, or smoking restriction (Table I). There were, however, no notable differences in individual t_max and t values.

View larger version (16K): [in this window] [in a new window]   Figure 2. Mean plasma concentration versus time plot of varenicline under fasted and fed conditions after 1-mg dose of varenicline in healthy adult nonsmokers (N = 4) and 3-mg dose in healthy adult smokers (N = 4).

Pharmacokinetics in Nonsmokers
Plasma concentrations of varenicline at the 0.01-mg dose were below the lower limit of quantification of 0.100 ng/mL. In the group that received 0.03 mg varenicline, plasma concentrations could be measured in several plasma samples from each subject, with the measurements being at or slightly above 0.1 ng/mL. The mean C_max and t_max values were 0.135 ng/mL and 2.0 hours, respectively. Terminal half-life could not be calculated in the 0.03-mg dose group.

When oral doses of varenicline from 0.1 mg to 3.0 mg were given to subjects, a complete oral plasma concentration versus time profile could be characterized. On average, C_max occurred from 1.75 hours to 3.13 hours postdose. The mean terminal half-life of the decay phase ranged from 11.1 hours to 20.5 hours over the dose range from 0.1 mg to 3.0 mg. Systemic exposure to varenicline increased approximately linearly with dose from 0.1-mg to 1-mg doses. When comparing nonsmokers who received 1.0 mg or 3.0 mg of varenicline, however, the observed increases in mean C_max and AUC_0- were slightly less (approximately 2-fold) than dose-proportional. Two of 4 subjects at the 3.0-mg dose vomited shortly after dosing, which may have affected C_max and AUC_0- estimates. The pharmacokinetic parameters and plasma concentration time profiles for nonsmokers are presented in Table II and Figure 3.

View larger version (17K): [in this window] [in a new window]   Figure 3. Mean plasma concentration versus time plot of varenicline after single oral administration of different doses of varenicline under fasted conditions in healthy nonsmokers (N = 4) on a linear scale (A) and on a semilogarithmical scale (B).

In addition, in one group of nonsmokers, the pharmacokinetics of a single oral 1.0-mg dose of varenicline given immediately after a standard FDA high-fat breakfast was evaluated. These results showed that the plasma concentrations and the derived pharmacokinetic parameters were nearly identical to a previous group of nonsmoker subjects that had been orally dosed with 1.0 mg varenicline in the fasted state (Table II, Figure 2). Thus, there appeared to be no apparent effect of food on the pharmacokinetics of a single 1.0-mg dose of varenicline in nonsmoker subjects.

Safety
There were no deaths, serious adverse events, or withdrawals due to adverse events. More than 1 adverse event was experienced by 57% of subjects receiving varenicline and 50% of subjects receiving placebo. All adverse events were mild to moderate in severity and resolved without sequelae. The most frequent, dose-related adverse events were nausea and vomiting. Subjects who were smokers appeared to demonstrate improved tolerability relative to nonsmokers, as the frequency of these events (nausea and/or vomiting) appeared to increase at a dose of 3.0 mg in fasted nonsmokers and restricted smokers and at a dose of 10.0 mg in smokers. In addition, in this small data set, administration with food suggested improved tolerability regarding the incidence of nausea. Two of 4 smokers administered 3.0 mg under fasted conditions experienced nausea compared to 0 of 4 smokers administered 3.0 mg under fed conditions. Overall, there was no apparent effect of varenicline on clinical laboratory assessments, vital signs (blood pressure and heart rate), QTc, or ECG morphology.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The current study is the first to report on the safety, tolerability, and pharmacokinetics of the selective 4ß2 nicotinic receptor partial agonist, varenicline. Overall, varenicline was well tolerated after single doses up to 1.0 mg in nonsmokers and 3.0 mg in smokers. At doses of 3.0 mg and 10.0 mg in nonsmokers and smokers under fasting conditions, respectively, nausea and vomiting occurred. The underlying mechanisms responsible for the dose-related toleration findings and side effects are unclear at this time but are consistent with the pharmacologic actions of other nicotinic agents.^7-9 One cannot rule out the involvement of other nicotinic subtypes or second messengers. Also, it is not known whether peripheral or central mechanisms are involved. The differential tolerance to the nausea and vomiting in smokers relative to nonsmokers is consistent with proposed chronic pharmacodynamic tolerance to nicotine. This phenomenon has been previously demonstrated with nicotine replacement therapies including the nicotine patch⁷ and spray.^8,9 There was an apparent improvement in tolerability in subjects who were smokers and in those who were dosed in the fed state.

There was no apparent effect of varenicline on laboratory assessments, vital signs, or QTc. This is consistent with in vitro data that show varenicline had no effect on the isolated dog Purkinje fiber resting membrane potential, and produced 6% inhibition of the human ether-a-go-go-related gene (HERG) channel at varenicline concentrations >1000 ng/mL which is 75-fold greater than total concentrations achieved in this study (A. Davis et al, unpublished data, May 2002; J. Zhou, F. Matos, unpublished data, June 2002).

Varenicline single-dose pharmacokinetics was found to be similar in smokers and nonsmokers. Systemic exposure to varenicline increased approximately proportionately with dose over the range of 0.1 mg to 3.0 mg in smokers and of 0.1 mg to 1.0 mg in nonsmokers. Less than dose-proportional increases in C_max and AUC_0- estimates were, however, observed at the highest studied dose of 10.0 mg in smokers and 3.0 mg in nonsmokers, whereby subjects vomited shortly after dosing. The overall mean t_max was about 2.9 hours (range in individuals, 0.5-8 hours) in smokers and 2.6 hours (range in individuals, 0.5-8 hours) in nonsmokers. Plasma varenicline concentrations declined with a terminal elimination phase that ranged from 10.1 hours to 25.6 hours (overall mean, 16.6 hours) in smokers and from 8.1 hours to 30.2 hours (overall mean, 14.2 hours) in nonsmokers. A pilot arm was included in the smoker groups to investigate the effect of evening dosing on varenicline bioavailability. C_max was found to be somewhat lower in subjects dosed in the evening, whereas AUC and t_max values were similar to the morning-administration groups.

In addition, smoking restriction did not affect the pharmacokinetics of varenicline in smokers. The metabolism of varenicline has been studied in vivo in 3 preclinical species (rat, monkey, and mouse). In all species, the majority of drug-related material was excreted in the urine. In rat, monkey, and mouse, respectively, 95%, 88%, and 95% of recovered [¹⁴C]-varenicline was unchanged drug, indicating varenicline is eliminated primarily by renal elimination in preclinical species.¹⁰ In concert with the preclinical in vivo findings, in vitro human liver microsomal studies indicate varenicline is not a substrate for the cytochrome P450 (CYP) family of metabolizing enzymes (B. J. S. et al, unpublished data, October 1998). The polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of CYP1A1, CYP1A2, and possibly CYP2E1.¹¹ Hence, cigarette smoking has resulted in clinically significant drug interactions of many well-known drugs including theophylline, caffeine, imipramine, haloperidol, and propranolol.¹¹ Furthermore, nicotine is primarily metabolized in the liver by CYP2A6. It has been proposed that nicotine induces its own clearance; however, smokers have a lower clearance of nicotine compared to nonsmokers.¹² Although CYP1A2 and possibly CYP2A6 are induced in the smoking population, results from this study would indicate that because there were no apparent differences in the pharmacokinetics of varenicline between smokers and nonsmokers, these isozymes do not contribute to the metabolism of varenicline in smokers. This finding would also be consistent with the importance of renal clearance as the elimination route of varenicline observed in preclinical species.¹⁰

Food did not affect varenicline pharmacokinetics in healthy smokers and nonsmokers. The plasma exposure obtained after oral dosing of varenicline to smokers and nonsmokers suggests that varenicline can be classified as a low clearance drug. After oral drug administration, and assuming absorption is complete, oral clearance is equal to intrinsic clearance times the fraction unbound in blood. Thus, one would not expect blood flow changes (eg, induced by food) to affect the clearance of varenicline.¹³ Food can affect bioavailability parameters such as solubility, gastric pH, and gastrointestinal transit time.¹⁴ In vitro, varenicline has high solubility and high permeability (data on file). These physiochemical properties are similar to that of the class I compounds of the Biopharmaceutics Classification System. Class I compounds are highly soluble across a wide range of pH values.¹⁵ For these compounds, food is not expected to alter the extent of absorption.¹⁵ Thus, the lack of food effect observed in this study is consistent with in vitro data describing the pharmacokinetic characteristics of varenicline.

In conclusion, varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. No safety concerns were identified. After single-dose oral administration, systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Administration of varenicline with food had no effect on the oral bioavailability of varenicline in both smokers and nonsmokers. Smoking restriction and time-of-day dosing had no obvious effect on the single-dose pharmacokinetics of varenicline in smokers treated with the 3.0-mg dose.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors thank Dr Masako Nakano-Morris, the principal investigators Dr Radoslav Jovic and Dr Pius Hildebrand at VanTx Research AG (Muttenz, Switzerland), and Dr Salvatore Febbraro and Dr Boyd Mudenda at the PPD Development Clinic (Leicester, United Kingdom) for the conduct of this trial. We are grateful to Dr R. Scott Obach and Dr Tanya Russell for their useful comments on the article.

DOI: 10.1177/0091270006290669

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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