Roderic.uv.es
J Clin Exp Dent. 2011;3(5):e424-9.
Non surgical management of chronic periodontitis.
Journal section: Periodontology
Publication Types: Research
Non-surgical management of chronic periodontitis
with two local drug delivery agents- A comparative study.
Jaspreet Singh Gill 1, Vipin Bharti 2, Harinder Gupta 3, Sharanjeet Gill 4
1 BDS, MDS. Senior Lecturer, Department of Periodontics and Implantology, SGT Dental College, Hospital and Research Institu-
te, Gurgaon, Haryana, India.
2 BDS, MDS. Prof & HOD, Department of Periodontics , Government Dental College, Patiala, Punjab, India.
3 BDS, MDS. Prof & HOD, Department of Periodontics , Government Dental College, Amritsar, Punjab, India.
4 BDS, MDS. Senior Lecturer, Department of Oral Pathology, Manav Rachna Dental College, Faridabad, Haryana, India.
Correspondence:
Department of Periodontics,
SGT Dental College,
Hospital and Research institute, gurgaon. Haryana.
E-mail address: [email protected]
Gill JS, Bharti V, Gupta H, Gill S. Non-surgical management of chronic
periodontitis with two local drug delivery agents- A comparative study. J
Clin Exp Dent. 2011;3(5):e424-9.
Received: 18/01/2011
Accepted: 10/07/2011
Article Number: 50490 http://www.medicinaoral.com/odo/indice.htm
Medicina Oral S. L. C.I.F. B 96689336 - eISSN: 1989-5488
Abstract
Background: The selective removal or inhibition of pathogenic microbes with locally delivered antimicrobials
when combined with scaling and root planing is often an effective approach for the managment of chronic perio-
Aim: To compare the clinical efficacy of tetracycline fibers and a xanthan based chlorhexidine gel in the treatment
of chronic periodontitis.
Methods and materials: Thirty systemically healthy patients in the age group of 30-50 years suffering from genera-
lized chronic moderate periodontitis were selected. For each subject, two experimental sites were chosen that had
probing depth >5mm and were located in symmetric quadrants and the sites were randomized at split mouth level
with one receiving tetracycline fibers and the other chlorhexidine gel. Plaque score, bleeding score, probing pocket
depth and relative attachment level gain was recorded on day 0 and at the end of 3 months.
Results and conclusion: In both groups, there was statistically highly significant reduction in all the clinical para-
meters i.e. plaque score, bleeding score and probing pocket depth and relative attachment level gain was seen at di-
fferent time intervals. Local delivery of tetracycline and chlorhexidine is a safe, easy and efficacious method along
with scaling and root planing in the treatment of chronic periodontitis. Inter-comparison of both local drug delivery
agents with respect to clinical changes shows that tetracycline fibers are better than chlorhexidine gel for treatment
of chronic periodontitis. Nevertheless, long term studies with more samples are suggested to further evaluate and
compare the efficacy of both materials.
Key Words: local delivery, periodontitis, tetracycline fibers, chlorhexidine gel.
J Clin Exp Dent. 2011;3(5):e424-9.
Non surgical management of chronic periodontitis.
cal drug delivery in various formulations such as mouth
Periodontal diseases represent a group of localized mi-
rinses, gels, sprays, varnishes, chips and subgingival
crobial induced infections involving gingiva and suppor-
irrigation devices (13-15).Chlorhexidine in form of gel
ting tissues of the teeth. The role of microorganisms in
has been used in varying concentrations such as 0.2%,
the etiology and progression of periodontitis is now well
1% and 2% (13-15). In the present study, xanthan based
documented (1). Periodontal diseases are routinely trea-
1.5% chlorhexidine gel was used as an adjunct to scaling
ted by mechanical procedures which include meticulous
and root planing .The aim of the present study was to
scaling and root planing in conjunction with patient's
compare the efficacy of tetracycline fibers (Periodontal
proper plaque control. Although mechanical therapy
Plus AB®) and chlorhexidine gel (Chlosite®) when used
may provide long term stability for many patients, but
as an adjunct to scaling and root planing in the manage-
it fails to eliminate the pathogenic bacteria completely
ment of chronic periodontitis.
and may not always result in complete elimination of
the disease (2).
Material and Methods
Local delivery of antimicrobial agents into periodontal
Thirty systemically healthy patients in the age group of 30-
pocket has been extensively developed and investiga-
50 years (both male and female) suffering from generali-
ted since late 1970's (3). Local delivery of antimicro-
zed chronic moderate periodontitis were selected amongst
bial agents includes oral rinses, subgingival irrigation
the patients visiting the Department of Periodontics, Govt.
and controlled release delivery systems (4). Controlled
Dental College and Hospital, Patiala (Punjab). Patients
release systems have received great interest and appear
did not receive any surgical or non surgical periodontal
to hold some promise in periodontal therapy. They have
therapy in past 6 months and were not on any antibiotic
been evaluated in several forms such as gels, strips, fi-
therapy since past 3 months. Written informed consent
bers, chips, ointments etc and using different antimicro-
was taken from each patient who participated in the stu-
bial agents such as tetracycline, doxycycline, metronida-
dy and ethical clearance was obtained from the institutio-
zole, minocycline and chlorhexidine (5-10). Pioneering
nal committee. For each subject, two experimental sites
work by Goodson introduced the use of tetracycline as
were chosen that had probing depth >5mm and were lo-
a local drug delivery agent for the treatment of perio-
cated in symmetric quadrants and after scaling and root
dontal diseases (11). He and his coworkers developed a
planing, the two sites were randomized at split mouth
local drug delivery system consisting of a polymer and
level by flip of a coin and divided into two groups:
ethylene vinyl acetate impregnated with 25% tetracycli-
Group I: Tetracycline fibers (Periodontal Plus AB®)
ne hydrochloride. One such local drug delivery system
were inserted into the periodontal pocket until pocket
is available in the form of resorbable tetracycline fibers
was filled. Coe pak® was then applied for 10 days. (Fi-
(Periodontal Plus AB®)
Chlorhexidine is also a highly effective antimicrobial
Group II: After washing the selected site with distilled
agent that has been extensively studied and shown to be
water and drying it, chlorhexidine gel (Chlosite®) was
effective as a mouthrinse against supragingival plaque
applied directly from the syringe into the pocket. Coe
bacteria in prevention of gingivitis and as a treatment
pak® was then applied for 10 days. (Figure 2)
for gingivitis (12) .Chlorhexidine has been used for lo-
Recording of various clinical parameters was carried on
Fig. 1. Showing Periodontal Plus AB® fibers and insertion of fibres into the periodontal pocket
J Clin Exp Dent. 2011;3(5):e424-9.
Non surgical management of chronic periodontitis.
Fig. 2. Showing Chlosite® gel and insertion of gel into the periodontal pocket
day 0 (baseline) and subsequently recording of plaque
chlorhexidine dihydrochloride. Xanthan is an optimum
score and bleeding score was made at the end of 1 month
substrate for the formation of a stable gel that is easily
and 3 months, while probing pocket depth and relative
extruded from a syringe needle.
attachment level was recorded on day 0 and at the end
# Periodontal Plus AB®: Advanced Bio Tech Products
of 3 months. The course of the study was of 3 months
(Ltd), * Chlosite®: Ghimas,Italy
duration. The significance of the differences in plaque
index, bleeding score, probing pocket depth and relati-
ve attachment level for both the groups at different time
Mean plaque score of both group I (Periodontal Plus
intervals was assessed using paired t-test, while the in-
AB®) and group II (Chlosite®) score at baseline (day
ter-comparison of both the groups was carried out using
0) and at the end of 1 month and 3 months was highly
unpaired t-test.
significant (p <0.001). On comparison of reduction in
mean plaque score of group I (Periodontal Plus AB®)
Clinical Parameters
and group II (Chlosite®) at different time intervals it was
1. Plaque Index (Quigley - Hein Plaque Index).
found that reduction in plaque score after 1 month and
2. Probing pocket depth (using Williams's calibrated
3 months from baseline (day 0) was non-significant (p>
periodontal probe)
3. Bleeding Index (PBI modified by Muhlemann HR)
Mean papillary bleeding score of group I (Periodontal
4. Relative Attachment Level (Measurement using
Plus AB®) and group II (Chlosite®) at day 0 and at the
customized acrylic stent)
end of 1 month and 3 months was highly significant (p<
0.001).On comparison , reduction in mean papillary
bleeding score between the two groups was significant
Tetracycline Fibers (Periodontal Plus AB®) #: Resorba-
(p< 0.05).(Table 2)
ble collagen fibers 25mg, impregnated with tetracycline
Mean probing pocket depth of group I (Periodontal Plus
hydrochloride containing approximately 1.7 ± 0.25mg
AB®) and group II (Chlosite®) at day 0 and at the end of
3 months was highly significant (p <0.001). On compa-
Chlorhexidine gel (Chlosite®)*: Xanthan based 1.5%
rison, reduction in mean probing pocket depth of group
chlorhexidine gel containing 0.5% fast releasing chlor-
I (Periodontal Plus AB®) and group II (Chlosite®) after
hexidine digluconate and 1% in form of slow releasing
3 months from baseline was significant (p< 0.05).(Table
After 1 month from baseline
After 3 months from baseline
# t-value calculated using unpaired t-test and p value used to determine the statistical significance
Table 1. Comparison of reduction in mean plaque score of group I (periodontal plus ab®) and group II (Chlosite®) at 1 month and 3 months
from baseline (day 0)
J Clin Exp Dent. 2011;3(5):e424-9.
Non surgical management of chronic periodontitis.
After 1 month from baseline
After 3 months from baseline
# t-value calculated using unpaired t-test and p value used to determine the statistical significance
Table 2. Comparison of reduction in mean papillary bleeding score of group I (Periodontal Plus AB®) and group II (Chlosite®) at 1 month and 3
months from baseline (day 0)
3months from baseline
# t-value calculated using unpaired t-test and p value used to determine the statistical significance
Table 3. Comparison of reduction in mean probing pocket depth (mm) of group I (Periodontal Plus AB®)
and group II (Chlosite®) after 3 months from baseline (day 0).
reach the site of action in adequate concentrations and
Mean relative attachment level of group I (Periodontal
the inability to localize and sustain at disease active sites
Plus AB®) and group II (Chlosite®) at day 0 and at the
(17) . Recently, advances in local delivery technology
end of 3 months was highly significant (p< 0.001). On
have resulted in control release of drugs that are suc-
comparison of relative attachment level gain of group I
cessful in maintaining effective drug concentration at a
(Periodontal Plus AB®) and group II (Chlosite®) after 3
lower dosage in the periodontal pocket.
months was significant (p< 0.05) (Table 4).
It was observed in the present study, in both group I
(tetracycline fibers) and group II (chlorhexidine gel),
a reduction in mean plaque score that was statistically
Scaling and root planing in conjunction with proper
highly significant at both time intervals. Similar obser-
plaque control results in alteration of the subgingi-
vations were made by Jeong et al (18), Friesen et al (19),
val environment that is sufficient, in most instances to
Oosterwaal et al (20), Vinholis et al (12). This reduc-
improve periodontal health and arrest further loss of
tion in supragingival plaque score could be attributed to
attachment(6). Nevertheless, scaling and root planing
chemical control of subgingival plaque by tetracycline
alone may not predictably lead to complete elimination
fibers which could also have an inhibitory effect on su-
of the disease (6). Poor access to the bottom of deep poc-
pragingival plaque (21). Moreover, good oral hygiene
kets and anatomical complexities may occasionally limit
practiced by patients during the entire study period could
the efficacy of root planing (3). Moreover, some bacte-
have also increased the reduction in plaque. However
ria have been shown to invade deep periodontal tissues,
on comparison of mean plaque scores between group
making mechanical therapy alone sometimes ineffective
I and group II, statistically non-significant differences
(16) and repopulation of scaled teeth from bacterial re-
were recorded and the findings are in accordance with
servoirs in dentinal tubules may also be responsible for
the study conducted by Unsal et al (15) who evaluated
recurrence of the disease (3).
the effects of subgingivally placed 2% chlorhexidine gel
Various antimicrobial agents have been administe-
and 10% tetracycline paste in periodontal pockets along
red systemically as well as locally/topically by means
with scaling and root planing.
of mouth rinses or irrigation solutions as an adjunct to
Bleeding on probing is an objective sign of inflamma-
scaling and root planing (14). However systemic admi-
tion. Research suggests that bleeding on probing often
nistration of antibiotics have been associated with side
is the first sign of gingival inflammation. Reduction in
effects, while effectiveness of local delivery of antimi-
mean bleeding score in both groups was highly signifi-
crobial agents in form of mouth rinses and subgingival
cant at both time intervals and the results are in accor-
irrigation has been limited due to inability of the drug to
dance with studies conducted by Minabe et al (22). In
3months from baseline
# t-value calculated using unpaired t-test and p value used to determine the statistical significance
Table 4. Comparison of gain in mean Relative attachment level (mm) of group I (Periodontal Plus AB®)
and group II (Chlosite®) after 3 months from baseline (day 0)
J Clin Exp Dent. 2011;3(5):e424-9.
Non surgical management of chronic periodontitis.
the present study reduction in bleeding is due to resolu-
riodontal pocket depth in group II (Chlosite®) at the end
tion of gingival inflammation after scaling and root pla-
of 3 months from baseline (day 0), however reduction
ning and well known antimicrobial effect of tetracycline
was lower when compared to group I (Periodontal Plus
(15, 23).Moreover, average gingival fluid concentration
AB®) at the end of 3 months. This could be attributed to
of 1500 µg/ml tetracycline has been observed during
the fact that chlorhexidine offers a low subgingival subs-
the first 10 days treatment period with Periodontal Plus
tantivity and there is poor adsorption of the drug in the
AB®. Tetracycline is released in almost linear fashion for
subgingival environment when compared to tetracycline
7-10 days. Similar findings were noted by Aimetti et al
(23). In a systematic review on the effects of subgingival
(6) and Heijl et al (25). On comparison of bleeding sco-
chlorhexidine gel adminstration in treatment of chronic
res between the two groups, reduction in mean papillary
periodontitis, it was concluded that the limited data cu-
bleeding score was significant at both 1 and 3 months
rrently available on the effects of subgingival chlorhexi-
(p< 0.05). There was more reduction in the tetracycline
dine gel application do not justify its use in the treatment
group, which can be attributed to the fact that tetracycli-
of chronic periodontitis (28) .However in a more recent
ne offers better substantivity (23) and good binding and/
randomized multicenter trial, xanthan based chlorhexi-
or penetration into the root surfaces (24) when compared
dine gel promoted greater pocket reductions and clinical
to chlorhexidine and thereby maintaining antimicrobial
attachment gains with better microbiologic and bioche-
effect for a longer time period.
mical outcomes compared with scaling and root planing
Periodontal probing is one of the most widely used diag-
alone (29). Moreover addition of chlorhexidine to xan-
nostic tools for clinical assessment of connective tissue
than gum seem to improve the bioadhesive properties of
destruction and periodontal pocket depth in periodontal
this material and the cationic charges of chlorhexidine
disease. In both groups the reduction in mean probing
can interact with the anionic charges of the xanthan gum
pocket depth was highly significant and a similar result
polymer, enhancing its gel structure and substantivity
was recorded by Goodson (11), Heijl et al (25), Rad-
(30).This in concordance with our findings as xanthan
var et al (3), Friesen et al (19) and Stabholz et al (23),
based chlorhexidine gel was effective in reducing pocket
Jeffcoat et al (14) and Vinholis et al (12). However, on
probing depth and there was gain of attachment.
comparison, mean probing pocket depth reduction bet-
ween group I and II was significant (p <0.05) at the end
of 3 months, with better results in group I. Reduction in
Both tetracycline fibers and chlorhexidine gel are an
probing pocket depth in both the groups (Group I and II)
effective means of non-surgical treatment modality for
is due to resolution of gingival inflammation after sca-
the management of chronic periodontitis. The adjuncti-
ling and root planing and to well known antimicrobial
ve use of both the agents along with scaling and root
effects of both locally delivered drugs. Unsal et al (15)
planing resulted in a significant improvement in all the
and Stabholz et al (23).
clinical parameters. Although tetracycline fibers resulted
Pocket depth might change from time to time even in un-
in better improvement in probing pocket depth reduction
treated periodontal disease because of changes in gingi-
and relative attachment level gain than chlorhexidine
val margin, while changes in the level of attachment can
gel, more studies with a large sample size are required to
be caused only by gain or loss of attachment and thus
further assess the comparative clinical efficacy of both
provide a better indication of the degree of periodontal
the local drug delivery agents.
destruction. There was highly significant gain (p <0.001)
in both group I (tetracycline fibers) group II (chlorhexi-
References
dine gel) at the end of 3 months from baseline. Similar
1. Socransky SS, Haffajee AD. The bacterial etiology of destructi-
findings were recorded by Goodson (11), Heijl et al (25),
ve periodontal diseases, current concepts. J Periodontol. 1992;
Radvar et al (3), Friesen et al (19) and Stabholz et al
2. Van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotics in pe-
(23), Jeffcoat et al (14), Vinholis et al (12).
riodontics. Periodontology 2000. 1996; 10:45-78.
On comparison, mean gain of attachment between
3. Radvar M, Pourtaghi N, Kinane DF. Comparison of 3 periodontal
group I and II was significant (p <0.05) at the end of
local antibiotic therapies in persistent periodontal pockets. J Perio-
3 months. There was more gain in relative attachment
4. Bonito AJ, Lux L , Lohr KN. Impact of local adjuncts to scaling
level in group I (tetracycline fibers), which may be due
and root planing in periodontal disease therapy: a systematic re-
to substantivity of tetracycline for a longer period(23),
view. J Periodontal 2005; 76:1227-36.
collagenase inhibition property(26), anti-inflammatory
5. Hanes PJ, Purvis JP. Local anti-infective therapy: pharmacological
effects and inhibition of bone resorption by tetracycline
agents. A systematic review. Ann Periodontol.2003; 8:79-98.
6. Aimetti M, Romano F, Torta I, Cirillo D, Caposio P, Romagnoli R.
and their property to promote attachment of fibroblasts
Debridement and local application of tetracycline-loaded fibres in
to root surface (27). Alveolar bone remineralization may
the management of persistent periodontitis: results after 12 months.
also be triggered by elimination of infection by tetracy-
J Clin Periodontol 2004; 31:166-72.
cline (6). There was highly significant reduction in pe-
7. Walker CB, Godowski KC, Borden L, Lennon J, Nango S, Stone C
et al. The effects of sustained release doxycycline on the anaerobic
J Clin Exp Dent. 2011;3(5):e424-9.
Non surgical management of chronic periodontitis.
flora and antibiotic-resistant patterns in subgingival plaque and sa-
in vitro release study. J Periodontol.1990; 61:393-8.
liva. J Periodontol.2000; 71:768-74.
RA, Heasman PA. Tetracyclines in the management of
8. Ainamo J, Lie T, Ellingsen BH, Hansen BF, Johansson LA, Ka-
periodontal diseases .A review. J Clin Periodontol. 1995; 22:22-
rring T et al. Clinical responses to subgingival application of a me-
tronidazole 25% gel compared to the effect of subgingival scaling
J, Sabzevar MM. A systematic review on the effects of
in adult periodontitis. J Clin Periodontol 1992; 19:723-29.
subgingival chlorhexidine gel administration in the treatment of
9. Renvert S, Lessem J, Dahlen G, Lindahl C, Svensson M. Topi-
chronic periodontitis.J Periodontol.2005; 76:1805-13.
cal minocycline microspheres versus topical chlorhexidine gel as
M, D Ercole S, Pilloni A, DArchivio D, Lisanti L Gra-
an adjunct to mechanical debridement of incipient peri-implant
ziani F et al. Clinical, microbiologic, and biochemical effects of
infections: a randomized clinical trial. J Clin Periodontol. 2006;
subgingival administration of a Xanthan-based chlorhexidine gel
in the treatment of periodontitis: A randomized multicenter trial. J
R, Pandit N, Aggarwal S, Verma A. Comparative evaluation
of subgingivally delivered 10% doxycycline hyclate and xanthan-
IG, Smales FC, Martin GP. An investigation of bioad-
based chlorhexidine gels in the treatment of chronic periodontitis.
hesive or periodontal and oral mucosal drug delivery .J Clin Perio-
J Contemp Dent Pract. 2008; 9:25-32.
dontol.1997; 24:394-400.
JM, Hogan PE, Dunham SL. Clinical responses following
periodontal treatment by local drug delivery. J Periodontol.1985;
inholis AH, Figueiredo LC, Marcantonio Junior E, Marcantonio
RA, Salvador SL, Goissis G. Subgingival utilization of a 1% chlor-
hexidine collagen gel for the treatment of periodontal pockets. A
clinical and microbiologic study.Braz Dent J. 2001; 12:209-13.
G. Effects of subgingival irrigation on periodontal sta-
tus. J Periodontol.1987; 58:822-34.
fcoat MK, Bray KS, Ciancio SG, Dentino AR, Fine DH, Gor-
don JM et al. Adjunctive use of a subgingival controlled release
chlorhexidine chip reduces probing depth and improves attachment
level compared with scaling and root planing alone. J Periodon-
Akkaya M, Walsh TF. Influence of a single application of
subgingival chlorhexidine gel or tetracycline paste on the clinical
parameters of adult periodontitis patients. J Clin Periodontol.1994;
R, Newman MG, Carranza FA Jr, Pattison GL. Bacterial
invasion of gingiva in advanced periodontitis in humans. J Perio-
JM, Offenbacher S, Farr DH, Hogan PE. Periodontal di-
sease treatment by local drug delivery. J Periodontol.1985; 56:265-
SN, Han SB, Lee SW,Manusson I. Effects of tetracycline-
containing gel and a mixture of tetracycline and citric acid contai-
ning gel on non surgical periodontal therapy. J Periodontol.1994;
LR, Williams KB, Krause LS, Killoy WJ. Controlled local
delivery of tetracycline with polymer strips in the treatment of pe-
riodontitis. J Periodontol.2002; 73:13-9.
PJM, Mikx FH, van't Hof MA, Renggli HH. Compa-
rison of the antimicrobial effect of the application of chlorhexidine
gel, amine fluoride gel and stannous fluoride gel in debrided perio-
dontal pockets. J Clin Periodontol.1991; 18:245-51.
amagami H, Takomori A, Sakamoto T, Okada H. Intrapocket
chemotherapy in adult periodontitis using a new controlled-release
insert containing ofloxacin (PT-01). J Periodontol.1992; 63:2-6.
M, Takeuchi K, Tomomatsu E, Hori T , Umemoto T. Clini-
cal effects of local application of collagen film-immobilized tetra-
cycline. J Clin Periodontol. 1989; 16:291-4.
A, Kettering J, Aprecio R, Zimmerman G, Baker PJ,
Wikesjo UM. Retention of antimicrobial activity by human root
surfaces after in situ subgingival irrigation with tetracycline HCl or
chlorhexidine. J Periodontol.1993; 64:137-41.
JM, Walker CB, Murphy JC, Goodson JM, Socransky SS.
Concentration of tetracycline in human gingival fluid after single
doses. J Clin Periodontol.1981; 8:117-21.
L, Dahlen G, Sundin Y, Wenander A, Goodson JM. A 4-qua-
drant comparative study of periodontal treatment using tetracycli-
ne containing drug delivery fibres and scaling. J Clin Periodon-
tol.1991; 18:111-6.
g D, Friedman M, Soskolne A, Sela MN. A new degrada-
ble controlled release device for treatment of periodontal disease:
Source: http://roderic.uv.es/bitstream/handle/10550/54229/424-429.pdf?sequence=1&isAllowed=y
A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors in vivo
International Journal of Cancer A mixture of amino acids and other small molecules presentin the serum suppresses the growth of murine and humantumors in vivo ´ kos Schulcz2 and Tamas Cz€omp€oly1 1 Immunal Ltd., Cancer Research and Product Development Laboratory, H-7630 Pecs, Finn u. 1/1., Hungary2 Department of Experimental Pharmacology, National Institute of Oncology, H-1122 Budapest, Rath Gy€orgy u. 7-9., Hungary
Microsoft word - prospectus_spanishtranslation.doc
Si tiene usted alguna duda sobre el contenido del presente Folleto, los riesgos derivados de invertir en la Sociedad o la idoneidad para usted de invertir en la misma, debe consultar a su agente de bolsa, gestor bancario, abogado, contable o a otro asesor financiero independiente. Los Administradores de la Sociedad, cuyos nombres aparecen bajo el epígrafe "Gestión y Administración" del presente Folleto, asumen la responsabilidad correspondiente a la información contenida en el mismo. Según el leal saber y entender de los Administradores, quienes han actuado con toda la diligencia razonable para asegurarse de que ello sea así, la información contenida en el Folleto se ajusta a los hechos y no omite nada que pudiera afectar a la importancia de la misma. Los Administradores asumen la responsabilidad correspondiente.