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Keywords:

  • miconazole;
  • mucoadhesive buccal tablet;
  • oral candidiasis;
  • head and neck cancer;
  • radiation therapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

Topical antifungal treatments are recommended but rarely used as first-line therapy for oropharyngeal candidiasis (OPC) in patients with cancer. Miconazole Lauriad 50-mg mucoadhesive buccal tablet (MBT) Loramyc reportedly delivered rapid and prolonged, effective concentrations of miconazole in the mouth. The objective of the current study was to compare MBT with miconazole 500-mg oral gel (MOG) in patients with head and neck cancer.

METHODS.

Two hundred eighty-two patients with head and neck cancer received a 14-day treatment of either single-dose MBT or MOG administered in 4 divided doses. The primary endpoint was clinical success at Day 14, and secondary endpoints included clinical success at Day 7, clinical cure, improvement in clinical symptoms, mycologic cure, recurrence rate, and safety.

RESULTS.

The success rate was statistically not inferior (P < .0001) in the MBT population to the rate observed in the MOG group (56% vs 49%, respectively; P < .0001). After adjustment for the extent of lesions and salivary secretions, a trend toward superiority was observed in favor of MBT (P = .13), particularly among patients with multiple lesions (P = .013). Results for secondary endpoints were comparable to those observed for the primary endpoint. Compliance with MBT was excellent, and >80% of patients completed treatment. Both treatments were safe.

CONCLUSIONS.

The success rate of MBT Loramyc was significantly not inferior to that of MOG in the treatment of cancer patients with OPC; and, after adjusting for prognostic variables, it was more effective than MOG. MBT was well tolerated and, thus, may be recommended as first-line treatment in cancer patients who have OPC as an alternative to systemic antifungal agents. Cancer 2008. © 2007 American Cancer Society.

Candida is present in the oral cavity in 40% to 60% of healthy individuals and is not harmful. In immunocompromised patients, it can become aggressive, induce oropharyngeal candidiasis (OPC), invade the digestive tract and even lead to systemic infections.1

OPC is the most common oral fungal infection in cancer patients,2–5 with a mean incidence between 30% and 70%.6 Its occurrence is favored by chemotherapy- and/or radiation therapy-induced xerostomia and mucositis.7 In cancer patients, it results in oral discomfort and marked reduction in food and liquid consumption, it contributes to poor nutritional status, and it strongly deteriorates quality of life.6

Patients with head and neck cancer are particularly susceptible to OPC, because they usually suffer from both markedly reduced salivary secretion and radiation therapy-induced mucositis.8–13 The occurrence of OPC in these patients further deteriorates the oral mucosa; increases pain, dysphagia, and anorexia; alters taste; and contributes toward worsening nutritional and general status. Recurrence occurs in approximately 33% of patients.13

The objectives of the treatment of OPC are to eliminate signs and symptoms of the disease and to prevent recurrence. The Infectious Disease Society of America recommends treating initial episodes of OPC with topical treatments and reserving systemic treatments for frequently recurrent episodes of OPC and for esophageal dissemination.14 In practice, these recommendations are not followed mainly because of the need for 4 to 6 daily dosing and the poor taste acceptance of topical agents, which compromise patient compliance and may lead to poor/moderate efficacy. Consequently, despite their risk for drug-drug interactions and liver toxicity, once-daily dosing azole agents that improve patient compliance progressively have replaced topical drugs.

The large use of fluconazole recently has been implicated in the selection and development of resistant strains of Candida and in the increase in the incidence of nonalbicans species.15, 16 Thus, there is need for a topical agent that is as effective as systemic agents, well tolerated, administered once daily, and does not increase the risk of emergence of resistance.

Miconazole has a broad-spectrum antifungal activity against the most frequent Candida observed in OPC, including C. glabrata, C. krusei, and C. tropicalis.17, 18 It is worth noting that no initial resistance has been described, and resistance in chronically treated patients rarely is reported. Topical miconazole is used infrequently in patients with OPC because of the multiple daily dosing and bad taste.19 A new, 50-mg miconazole mucoadhesive buccal tablet (MBT) Lauriad reportedly demonstrated the ability to deliver high and prolonged salivary miconazole concentrations without significant plasma exposure.20 Salivary concentrations were >10 times higher than those of miconazole gel and persisted over the minimum inhibitory concentration (MIC) (1 μg/mL) for >12 hours after a single 50-mg gingival application. Moreover, the reduction in drug dose precluded the risk of systemic exposure, drug-drug interactions, and liver toxicity. Finally, 17 of 18 volunteers preferred the gingival mucoadhesive tablet, which was well tolerated.21

The objective of the current clinical trial was to comparing the clinical efficacy of a once-daily administration of miconazole (Loramyc, BioAlliance Pharma, Paris, France) 50-mg MBT with that of miconazole oral gel (MOG) administered in 4 equal daily doses of 125 mg. Both treatments were administered for 14 days to patients with head and neck cancer who had OPC. MOG was chosen as a comparator at the request of drug agencies to evaluate the intrinsic effects of this new targeted formulation and to control for drug variability.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Selection

Men and women aged >18 years who underwent radiation therapy for head and neck cancer with clinical signs and symptoms of OPC who had either a first episode or a recurrence of OPC were eligible for the study. OPC had to be confirmed by direct mycologic examination and positive fungal culture with >100 colonies.

Patients were excluded if they had systemic or disseminated candidiasis outside the oropharyngeal cavity, if they had received systemic antifungal treatment within the last 14 days, if they were receiving concomitant treatments that could interfere with miconazole (anticoagulants, hypoglycemic sulfonylureas), if they had liver failure (defined as aspartate and/or alanine transferase levels >5 times the upper limit of the normal values and/or reduced prothrombin time [<80%]), or if they were unable to understand or follow the study procedures. Exclusion criteria also included poor general condition (an Eastern Cooperative Oncology Group performance status >2), recent participation in another trial, and women of childbearing age with no acceptable contraception methods or treatment.

The study was approved by independent ethics committees and was performed in accordance with Good Clinical Practice, Guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and the Declaration of Helsinki. All patients signed a written informed-consent form before participation in the study.

Eligible patients were randomized to receive either miconazole Lauriad 50-mg MBT (Loramyc, BioAlliance Pharma) once daily or MOG 500 mg (Daktarin; Janssen-Cilag) daily in 4 125-mg divided doses for 14 days. Patients were instructed to apply the MBT on the gum once daily in the morning. MOG was to be kept in the mouth as long as possible before swallowing.

Study Procedures

Baseline assessments were performed on Day 1, efficacy assessments were conducted on Days 7 and 14, and recurrence assessments were conducted on Days 30 and 60. At all visits, the Murray Scoring Scale was used to evaluate the extent of the oral candidiasis lesions (0, none; 1, single localized; 2, multiple localized; 3, extensive or confluent). Candidiasis symptoms (odynophagia, burning/soreness) were evaluated by using a rating scale from 0 to 3 in which 0 indicated the absence of symptoms, 1 indicated mild symptoms, 2 indicated moderate symptoms, and 3 indicated severe symptoms. Direct microscopic examination of yeasts and fungal cultures were undertaken at Days 0 and 14, at Day 7 in patients who had a complete clinical response, and during follow-up in the event of recurrence. The duration of tablet adhesion and local safety were self-evaluated daily by questionnaire for patients who were randomized to the MBT group. At each visit, any clinical adverse event that was reported spontaneously by patients and/or observed by investigators or any biologic adverse events were reported and graded according to the National Cancer Institute-Common Toxicity Criteria.

Endpoints

The primary endpoint was the success rate at Day 14, which was defined as complete or partial clinical response. A complete clinical response was defined as the complete disappearance of OPC lesions, and a partial clinical response was defined as improvement by ≥2 points of the Murray Scoring Scale compared with the score at baseline. All other responses were considered failures. An amendment introduced a blind assessment of the primary criterion performed in each investigational center by an independent healthcare member who was unaware of the study drug allocated to each patient. It was implemented after the inclusion of 59 patients.

Secondary endpoints were the success rate at Day 7, the percentage of complete responses at Days 7 and 14, the percentage of clinical cures (sign- and symptom-free patients), improvement in candidiasis symptoms (defined as a decrease of ≥1 point in the score coding for the severity of symptoms compared with the score at baseline), the percentage of mycologic cures (defined as complete eradication of Candida or <10 colonies per plate), the recurrence rate in responders, and the progression rate in nonresponders. The time to recurrence was calculated. Finally, biologic, local, and general safety was compared between treatments.

Statistical analyses were performed in modified intent-to-treat (mITT) (all randomized patients who received at least 1 treatment dose and had 1 efficacy evaluation after randomization) and per-protocol populations. Safety analyses included all patients who received at least 1 dose of study medication.

A noninferiority statistical approach was used; a clinical margin of 20% was chosen taking into account that severe local oral conditions could impede the correct adhesion of MBT to the gum. In the absence of data on the efficacy of MOG in patients with head and neck cancer who underwent radiation therapy, a 50% efficacy rate was assumed. A sample size of 103 patients per treatment arm was required to obtain a 90% power to demonstrate the noninferiority of MBT to MOG (α level, 5%; β level, 20%; both 1-sided). To compensate for a potential 10% dropout rate and for the 59 patients who were included before implementation of the abovementioned amendment, the number of patients to be enrolled was increased to 286. Continuous data were compared using either the Student t test or the Mann-Whitney nonparametric test. For binary data, the 2 treatment groups were compared using the chi-square test or the Fisher exact test. The Mantel-Haenszel test was used to evaluate ordinal quantitative data.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

In total, 306 patients were enrolled in the study from May 2002 to June 2004; 282 patients (141 per treatment group) were included in the mITT population, and 294 patients (147 per treatment group) were included in the safety population (Fig. 1). The baseline characteristics for the mITT population are presented Table 1. Patient demographics, characteristics, and disease histories were not different between the 2 treatment groups. However, the percentage of patients with reduced or absent salivary secretion and with multiple or confluent oral lesions were marginally higher in the MBT group (21% and 71%, respectively) compared with the percentages observed in the MOG group (13% and 58%, respectively; P = .09 and P = .06, respectively). Pretreatment samples determined that C. albicans was the only causative organism in 63% of patients, whereas C. nonalbicans was the only species in 25% of patients.

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Figure 1. Patient disposition.

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Table 1. Baseline Characteristics of 282 Modified Intent-to-treat Patients Who Underwent Radiation Therapy for Head and Neck Cancer and Had Oral Candidiasis
CharacteristicMiconazole 50 mg MBT (n = 141), %Miconazole 500 mg MOG (n = 141), %
  • MBT indicates mucoadhesive buccal tablet; MOG, miconazole oral gel; ECOG, Eastern Cooperative Oncology Group.

  • *

    P = .09 between groups.

  • P = .06 between groups.

Sex
 Men7377
 Women2723
Median age (range), y53 (17–83)54 (17–83)
ECOG performance status
 063.167.4
 133.327.6
 23.55
Localization
 Cavum46.144
 Oropharynx7.89.2
 Larynx6.49.2
 Not specified39.737.6
Treatment
 Surgery31.937.6
 Chemotherapy6667.4
 Radiotherapy100100
  Mean delay, m13.511.5
  Range, m0.47–2011.40–161
Oropharyngeal candidiasis characteristics 
 History of antifungal treatment50.349.6
  Local33.334.7
  Systemic1714.9
 Salivary secretion*
  Absent21.313.5
  Partial74.582.3
  Normal4.34.3
 Extent of lesion
  Unique localized34.840.4
  Multiple localized53.245.4
  Spread or confluent12.114.2
 Burning/soreness50.451.1
 Odynophagia36.939
 Inflammation72.373
 Erythema73.878.8
 Mucositis53.956
  Mild39.738.3
  Moderate13.415.6
  Severe0.72.1
 Concomitant treatments and disease 
 Diabetes02.8
 Corticosteroids2.84.2
 Antibiotics5.67

After 14 days of treatment, the success rate in the MBT group was statistically not inferior to (P < .0001) or and numerically higher than the success rate in the MOG group (56% vs 49%, respectively; P < .0001). The noninferiority margin was 4.8%. Per protocol, and sensitivity analyses confirmed the robustness of data. Complete responders accounted for almost all of the success rate (Table 2).

Table 2. Clinical Efficacy Results After 14 Days of Treatment With Either Miconazole 50 mg Mucoadhesive Buccal Tablet or Miconazole Oral Gel
mITT (n = 282)Treatment group, %Difference in %95% CIP
Miconazole 50 mg MBTMiconazole 500 mg MOG
  1. mITT indicates modified intent-to-treat; MBT, mucoadhesive buccal tablet; MOG, miconazole oral gel; 95% CI indicates 95% confidence interval; CR, complete response; PR, partial response.

CR plus PR5648.97.1−19, +4.8<.0001
CR52.545.47.1−18.7, +4.5<.0001

Because patients were distributed unevenly in terms of the extent of lesions and severely impaired salivary secretions, a complementary statistical analysis adjusting for these parameters was performed. The results from that analysis indicated a strong trend toward superiority in favor of MBT (P = .13) (Table 3). After adjustment, the success rate at Day 14 in patients who had multiple lesions was 58.7% in the MBT group versus 37.5% in the MOG group (57% increase; P = .013). Likewise, in patients without impaired saliva secretion at the time of their inclusion, the success rate at Day 14 was 100% in the MBT group versus 40% in the MOG group (150% increase; P = .034) (Table 3). Clinical success at Day 7 was achieved in 14% of the MBT group and in 20% of the MOG group (noninferiority; P = .0016; 95% confidence interval, −2.8% to 15.2%).

Table 3. Clinical Efficacy Results After 14 Days of Treatment Adjusted for Unbalanced Baseline Parameters (Salivary Secretion and Extent of Lesions)
ParameterNo. of patients/Total No. (%)Difference in %P
Miconazole 50 mg MBT*Miconazole 500 mg MOG*
  • MBT indicates mucoadhesive buccal; MOG, miconazole oral gel.

  • *

    P = .13 between groups after adjustment for lesion extent and saliva secretion (unbalanced at baseline).

Lesions
 Unique localized28/49 (57.1)33/57 (57.9)−1.4.94
 Multiple localized44/75 (58.7)24/64 (37.5)56.6.013
 Spread or confluent7/17 (41.2)11/19 (57.9)−28.8.32
Saliva
 Normal6/6 (100)2/5 (40)150.034
 Partial59/105 (56.2)60/116 (51.7)8.7.50
 Absent14/30 (46.7)6/19 (31.6)47.8.30

Clinical symptoms improved in 70.3% and 76.5% of patients in the MBT and MOG groups, respectively (P value nonsignificant [NS]). Among patients who had burning/soreness at inclusion, 63.5% and 56% were symptom-free in the MBT and MOG groups, respectively (P value NS), and 57.6% and 50% of patients were odynophagia-free, respectively, among those who reported odynophagia at baseline (P value NS). Likewise, erythema and inflammation disappeared in >50% of patients in both groups, and mucositis disappeared in 43.6% of patients in the MBT group (vs 57.6% in the MOG group; P value NS). At the end of treatment, 39.1% of patients in both treatment groups were free of signs and symptoms (clinical cure; P value NS).

Fourteen days after the end of treatment, recurrence occurred in 19% and 12.5% of complete responders in the MBT and MOG groups, respectively. Forty-five days after the end of treatment, the recurrence rates were 21.5% and 17%, respectively. On average, the time to recurrence was 18.75 days and 20.60 days posttreatment for the MBT and MOG groups, respectively. There was no clinical extension of oral lesion to the esophagus and no systemic spread in either group. The progression rate in nonresponders at Day 60 was low: 4.3% in the MBT group versus 3.9% in the MOG group.

Despite critical local conditions, MBT adhesion was very good; 92.2% and 61.6% of tablets adhered for 6 hours and 12 hours, respectively. Approximately 50% of tablets still adhered to the gum at bedtime. Only 9 (6%) of patients applied <11 tablets during the study period and were considered noncompliant. Only 6% of tablets were swallowed without occurrence of adverse events. Adhesion for >6 hours was slightly less frequent in the first 2 days of treatment (85% of patients) than later (92-100% of patients).

In total, 130 adverse events (69 events in the MBT group and 61 events in the MOG group) were reported spontaneously. There were no differences in safety profile between the MBT and MOG groups. The incidence of adverse events (29.3% vs 27.2%, respectively) was similar between the 2 treatment groups. There were no age or sex effects in either treatment group, and no differences were observed in the severity of adverse events between groups (data not shown). Fewer serious adverse events were reported in the MBT group (0.7% vs 4.7% in the MOG group).

Adverse events that occurred with an incidence >1% are listed in Table 4. Nausea and vomiting were associated more frequently with MOG, and dysgeusia was associated more frequently with MBT. However, this latter event was reported exclusively in only 1 investigational center and likely was related to radiation therapy.

Table 4. Overall Safety Data*
AENo. of patients (%)
Miconazole 50 mg MBT (n = 147)Miconazole 500 mg MOG (n = 147)Total (n = 294)
  • AE indicates adverse event; MBT, mucoadhesive buccal tablet; MOG, miconazole oral gel.

  • *

    This table shows the number and prevalence of AEs that occurred during 14 days of treatment with miconazole as a 50-mg mucoadhesive buccal tablet or miconazole, 500 mg oral gel.

Patients with ≥1 AE43 (29.2)40 (27.2)83 (28.2)
Serious AEs1 (0.7)7 (4.7)8 (2.7)
Study discontinuation because of AEs3 (2)6 (4)9 (3.06)
Deaths0 (0)3 (2.04)3 (1.02)
Dysgeusia9 (6.1)0 (0)9 (3.4)
Abdominal pain5 (3.4)4 (2)9 (3.40)
Oral discomfort4 (2.7)5 (3.4)9 (3.4)
Pruritus3 (2)1 (0.7) 
Influenza3 (2)3 (2) 
Dyspepsia235
Nausea1 (0.7)4 (2.7) 
Vomiting1 (0.7)3 (2)4 (1.4)
Infusion site burning2 (1.4)2 (1.4) 
Neck pain2 (1.4)1 (0.7) 
Bronchitis1 (0.7)3 (2) 
Glossodynia0 (0)3 (2)3 (1)
Toothache1 (0.7)2 (1.4) 
Dysphagia1 (0.7)2 (1.4) 
Urinary tract infection2 (1.4)0 (0)2 (0.7)
Asthenia2 (1.4)0 (0) 
Nasopharyngeal disorder1 (0.7)0 (0)1 (0.35)
Parotidis0 (0)1 (0.7) 

Local tolerability, which was assessed only in the MBT group using a self-administered questionnaire, was satisfactory. Overall discomfort (5.3%), burning (7.2%), bad taste (7.2%), and pain (1.8%) were reported in few patients. Patients did not report any adverse events specifically related to the MBT formulation or to the duration of tablet adhesion to the gum.

A significant increase in alanine aminotransferase (ALT) was reported in 3 patients in the MOG group. There were no reports increased in ALT in the MBT group.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Radiation therapy for head and neck cancer substantially affects the condition of the oral cavity, including mucositis, deteriorated functioning of salivary glands, and risk of fungal infection. These potentially may cause pain while eating, possibly leading to a temporary suspension of radiation therapy for up to 15 days.22 These effects are aggravated if radiation therapy is combined with chemotherapy.22 OPC is the most frequent infection in these patients.13 The incidence of Candida colonization reaches 93%; and the incidence of oral candidiasis varies widely from 17% to >29% Candida colonization in patients with head and neck cancer, peaks 6 months after radiation therapy, and slowly declines to above normal values after 18 months.23 Patients, especially when they suffer from associated radiation-induced mucositis, remain at risk of OPC during this period. The occurrence of OPC increases the risk of treatment-induced complications, delays cancer treatment, and further worsens the local and general patient status. Therefore, OPC must be treated.

The results of the current multicenter, comparative, single-blind, randomized study demonstrated that mucosal administration of miconazole 50 mg MBT is an efficacious and safe alternative to systemic oral antifungal agents for the treatment of OPC. Indeed, in this trial, miconazole 50 mg MBT administered once daily provided clinical success (complete or partial disappearance of oral lesions) in >55% of patients with head and neck cancer, and a strong trend toward superiority over miconazole 500 mg gel (MOG) administered in 4 divided doses was observed when the statistical analysis was adjusted for baseline salivary secretions and extent of candidiasis lesions, factors that were unbalanced between the groups at baseline particularly in this population with multiple lesions. Clinical cure was observed in approximately 40% of patients. These results can be compared with those reported with oral fluconazole administered at a dose of 50 mg per day for 14 days, which induced a clinical response in 53% of patients, although a clinical cure was obtained in only 21% of patients.24

In patients with xerostomia, the efficacy of oral antifungal agents is likely to be low, because they are not excreted into saliva. Topical treatments are suited better for treating such patients. Our data indicated that, even if success rates with MBT were lower in these patients (46.7%) than in patients who had normal (100%) or reduced salivary secretion (56.2%), they remained clinically meaningful and largely superior to the rates observed with MOG (31.6%). This suggests that miconazole is released adequately from MBT and diffuses correctly in the xerostomic mouth.

There was no relation in the current study between clinical success or clinical cure and mycologic cure. This was expected, because Candida is a commensal host of oral mucosa, and most patients who are treated for head and neck cancer continue to harbor Candida long after they achieve a clinical cure. In fact, mycologic eradication is not an objective of antifungal treatment and rarely is achieved, even with systemic agents, with which 40% to 70% eradication rates were observed, depending on the population treated and the treatment received.25

Recurrence rates after antifungal treatment have not been reported in patients who have head and neck cancer with OPC. The rates observed with both MBT and MOG were low and were maintained for at least 60 days. The majority of recurrences occurred within 1 month after the end of treatment. No predictive factors for recurrences have been identified. There was no correlation between recurrence and the persistence of Candida at the end of treatment. Furthermore, no correlations have been identified between treatment failure or recurrence and the occurrence of new Candida species or the emergence of resistant yeasts at the end of the treatment period.

The efficacy of MBT was achieved with a 10-fold lower miconazole dose than that of the topical gel (50 mg vs 500 mg) using a once-daily administration schedule instead of a 4-times-daily administration. Rapid, high, and sustained salivary concentrations were obtained with mucoadhesive tablets.20 Along with good compliance, the MBT may contribute to a decreased risk of emergence or selection of resistant strains.

Overall, miconazole 50 mg MBT was tolerated well, and the nature and severity of the adverse events with MBT were in accordance with the pharmacologic properties of miconazole. There were no differences in the safety profile between miconazole MBT and gel formulations. Miconazole MBT did not induce increases in liver enzymes that may be deleterious in patients who are receiving multiple toxic treatments for their cancer and are at risk of liver metastases.

Miconazole MBT displayed excellent local tolerability: Only a small proportion of patients reported local adverse events, and the acceptability of this new treatment was good, as demonstrated by the very high compliance rate for a topical treatment. Tablet adhesion to the mucous membrane was excellent, with >90% and >60% of tablets adhering to the gum for at least 6 hours and 12 hours, respectively. Effective adhesion ensures a continuous release of miconazole and may contribute to the very good patient compliance and favorable efficacy rate obtained in patients with head and neck cancer. Unfortunately, it was not possible to adequately evaluate compliance in the MOG group to verify this assumption.

Lefebvre et al. reported that fluconazole suspension was a useful and well suited therapeutic alternative in patients who were treated for head and neck cancer, because it is administered once daily, well absorbed, and easy to swallow.24 MBT shares the same advantages and may be suited even better for these patients, because it provides an efficacy rate similar to that reported with oral agents, and it may prevent the emergence of resistant strains that have been described with fluconazole.26, 27 Therefore, in clinical practice, miconazole MBT may facilitate compliance with Infectious Diseases Society of America recommendations to treat OPC with topical agents.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Mrs. Aurelie Quemener and Sandra Boiziau for their strong support and comments and Dr. Dominique Moyse for his useful statistical assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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