Comparison of New Topical Treatment ( Curcumine viscous solution 30 % ) For Recurrent Herpes

Aims: To determine the therapeutic effect of viscaus solution of curcumine 30% , as a topical treatment of RHL in comparison with the traditional antiviral agent " acyclovir ". Materials and methods: A total of 120 patients (100 female, 20 male) with RHL divided into four groups: Group I: Fifty patients used viscous solution of curcumine 30% topically. Group II: Thirty patients used viramed "acyclovir" cream topically. Group III: Twenty five patients used glycerol topically "control positive group". Group IV: Fifteen patients without treatment "control negative group". Results: Female were more affected than male with RHL (83.3% female, 16.3% male) with high percentage of association between highly stressed events and RHL. The results also showed significant differences between size of lesion, duration of healing and pain in patients using viscous curcumine solution topically and patients received viramed cream and patient received no treatment. The patients group which received glycerol "control positive" showed a significant differences in duration of healing compared with group I and group II. While, patients group which received viramed topically showed no significant differences compared with group III and IV in related to duration of pain and show significant difference with group I, III and IV in relation to duration of healing. Conclusions: Topical application of viscaus carcumine solution 30% showed a good effective response on RHL compared with other antiviral agent with the lower percentage of adverse effect, and further study for its effect on other oral lesion may be recommended.

The mechanism by which the virus is reactivated is not known (3) .However, it is likely that cellular and host signals, (in response to stress) reactivate the virus (4) .
The stages of cold sore out breaks are (5) : Stage (0) prodrome: It is characterized by tingling, burning, itching sensation.The duration from 1-24 hrs.Stage (1) erythema: It appears as redness of skin due to dilation and congestion of the capillaries.The duration from 1-2 days Stage (2) papule oedema: It appears as solid, raised lesion with inflammation.Duration from 1-2 days .Stage (3) vesicle / pustule : It appears as blister -like skin elevation in which fluid is vesible through the outer layer of skin.Duration from 1-3 days .Stage (4) ulcer / soft crust blister or has collapsed or burst duration 1-3 days .Stage (5) hard crust: drying of ulcer ,amber colored crust develops duration 4-14 days .Stage (6) Re-epithelialization: crust is lost, residual redness inflammation duration 4-14 days .Stage ( Normal skin, complete disappearance of all signs of disease. Systemic therapy with acyclovir, valaciclovir or famciclovir can suppress or shorten the duration of attack although the cost of these agent restrict their availability (6) .

Comparison of New Topical Treatment (Curcumine viscous solution 30% ) For Recurrent Herpes Labialis (RHL)
Topical therapy with acyclovir is popular ,although studies assessing the effects of treatment have yielded in consistent results (7) .Acyclovir is the prototypic antiherpetic therapentic agent, it incorporates into replicating viral DNA causing chain termination, its the main adverse effect is local irritation (8) .The efficacy of many preparation for topical use in herpes infection have remained rather disappointing.The development of new antiviral drugs, especially herbal preparation, thus remain desirable (9) .
Curumine is the main yellow phenolic material present in the rhizomes of turmeric (curcuma langa L.) and is widely use as food coloring agent (10) .
The structure of curcumine (C 21 H 20 O 6 ) was first describe in 1910 by Lamp and Milobedeska and it is shown to be diferuloyl methane (11) .
Curcumine exhibit anti-inflammatory and antiviral effect, and it is also considered as a potent scavenger of reactive oxygen and nitrogens species (12) .In addition the wound healing and detoxifying properties of curcumine have also received considerable attention.
This study aimed to compare between the efficacy of curcumine viscous solution "herbal extract", and acyclovir cream in the treatment of recurrent herpes labialis "RHL".

MATERIALS AND METHODS
Study Population: A pool of eligible subjects was identified, the study was explained, subject were required to have a history of perioral HSV occurring 6 or more time per year and to be 18 years of age or older.
Exclusion criteria included antiviral therapy in the previous month, longterm steroid therapy, immune compromised status , pregnancy or known allergy to drugs used. (6)his study was carried out over period of 8 month at private dental clinic in Mosul City from September 2007 to May 2008 .it included a total of 120 patients (100 females, 20 males ) participated ,the patients were divided into four groups : Group I: It included 50 patients ,with RHL and treated by viscous curcumine solution 30% Group II: It included 30 patients with RHL and treated by viramed (acyclovir) cream .
Group III: included 25 patients with RHL and treated by glycerin vehicle "control positive".
Group IV : included 15 patients with RHL without treatment "control negative " Preparation of Solution and Procedure: For group I viscous curcumine solution prepared by dissolving curcumine which rhizome portion of the plant used medically and its usually boiled ,cleaned and dried "30 gm of grinded curcumine in 100 ml of glycerin" (14) .
For group II, the patients received viramed (Acyclovir) dermic cream 20 gm from Medico labs.Homs-Syria each 1 gm contains 50 mg Acyclovir .
For group I, II and III, patients were instructed to start applying the solution, cream, vehicle respectively as soon as possible after onset of first prodromal symptom of attack and to continue treatment five times per day for five days (15) .They were seen in the clinic as soon as possible after the start of the attack and subsequent attempt were made to see them daily for assessments.All patients were seen at least three times during each attack (16) .
The patients were instructed to apply topical therapy of a RHL in the prodrom or erythema stage.If lesion was in papule, vesicle or ulcer stage.Therapy was not to be applied and patient were instructed to wait and attempt early treatment of subsequent episode (17) .
Evaluation of effectiveness of treatment based on (18) : 1. Lesion area: (by measuring the diameters of lesion in square millimeter mm 2 ). 2. The time of healing: time from first vesicle or ulcer to loss of crust (in hours).

The duration of pain (days).
For each patient information were recorded by a special case sheet for this study (Figure 1) .
The patient did not record any side effect of drugs.

Data Analysis:
The data obtained from this study were subjected to the statistical analysis include descriptive and analytic methods.
For descriptive way the mean of variance were used, while one way Analysis of variance and Duncan's Test for (intra -group comparison) and for the (intergroup) matching with 5% level of significance.

RESULTS
A total of 120 patients participated in this study.Most of them were females (83.3% females, 16.7% males), Table (1).
The mean age of samples was 22.5 ± 6.68 years for female and 30.5 ± 3.5 years for male (Table 2).
The association between RHL and occurrence of stressful situation had been shown in Table no.3 The effectiveness of drug used are shown in Table (4).This result showed that smaller lesion area "mean 34.8 ± 3.89" and shorter period of healing "mean 91.8 ± 31.9" and duration of pain "mean 1.5 ± 0.54" were seen in group (gp) I patients which received curcumine viscous solution followed by gp II which received viramed cream "mean lesion area 65.6 and duration of pain 3.9 day respectively".Then gp III "control positive group" "mean lesion area 71.0 ± 16.58 and duration of pain 4 days respectively followed by gp IV " control negative group", which showed larger lesion area "mean 75.0 ± 16.58" healing time "mean 181.3 ± 21.9 hr" and duration of pain "mean 4.0 ± 2.0" respectively , except that gp III which show less duration of healing "mean 153.2 ± 24.1 hr" compared with gp II and gp IV.
The one way analysis of variance (ANOVA) showed a highly significant difference p<0.05 "p=0.00" between and within groups.
Table ( 4) also showed the Duncan analysis of variance in relation to the mean lesion area which showed that gp I is high-ly significant different than group II, III and gp IV also gp II is highly significant different than group IV also group II was highly significant different than group IV while, there was no significant difference between group II , III and group IV .
Table (4) showed Duncan analyses of variance in relation to the mean healing time and it showed that group I had significant difference in related to group II, III and IV (p<0.01), also group II showed a significant difference in related to group I , III and IV While group III showed no significant difference in related to group IV Table (4) showed Duncan analyses of variance in relation to the duration of pain which clarify that group I significantly difference in related to group II, III and IV while there was no significant differences among other groups.
The minor adverse effect were reported and that shown in Table (5) which revealed that viscous solution of curcumin report a lower percentage of adverse effect 18.6% compared with viramed cream .

DISCUSSION
A large number of individuals suffer from RHL and seek treatment.A variety of treatment modalities have been used (19) .It includes (5) : 1. Non-prescriptive treatment like skin protectant "glycerin", external analgesic with possible antiviral activity "zinc-Heparin" and viral entry blocking agent "Docosanol" 2. Prescriptive treatment which include Acyclovir, penciclovir and famciclovir.
According to this study , females were more susceptible to RHL than males, this is due to factor which is triggers of recurrent infection which include internal (unpreventable) stress like menstruation, fever illness, and external (preventable) stress like sunburn, emotional stress, dental treatment are more common in female than male (20) .This was in agreement with the study of Shaws et al., (16) and Bernstein et al (18) .
This study showed that RHL are closely associated with different highly stressed situations which considered to be important factors known to activate the recurrent Herpes infection (21) this was in agreement with the study of Spruance (22) .
According to the results of this study viscous solution of curcumine is the most effective treatment for RHL than other treatment groups which demonstrated by smaller lesion size, less duration of healing and pain "with higher significant difference" when comparing with other groups.This was due to the fact that the sign and symptom of RHL were in part due to the inflammatory response following viral reactivation accordingly combination therapy with a drug which have anti inflamematory, and antiviral properties may have a beneficial effects compared to the use of antiviral drug alone (23) .
Curcumine has a potent anti inflammatory effects (12,24,25) which may attributed to its ability to inhibit pro-inflammatory arachidonic acid as well as neutrophil function during inflammatory state (24) , also it inhibit Cox activity result in decrease in the yield of infections viral progeny (26) .
Curcumine has been shown to have antiviral activity by inhibiting viral replication (27) .
According to this study viramed showed significant differences only in the reduction of area of inflammation compared with control negative groups and group I, this was in agreement with the study of Shaw et al. (16) , Mark et al. (28) , and Spruance et al. (17) , Which showed that there is no clinical benefit from treatment with ac-yclovir compared with placebo cream but it was disagreement with the study of Fiddia et al. (15) , who showed that acyclovir modify the course of sever RHL when therapy initiated by patient during prodrome.
According to this study glycerin "control positive group" showed a significant differences only in a reduce of duration of healing compared with the group I and group II; this was because glycerin kept the cold sores moist to discourage cracking of the skin, cracks increase discomfort, and increase the chance for secondary bacterial infections and prolong healing time glycerin also forms a protective barrier over the lesion which often improve the symptoms and aid healing (22) .
In related to minor adverse effects associated with the drug used stinging, flak-ing of skin, and discoloration, viramed caused the main adverse effect followed by curcumine solution, that cause temporally staining of skin only which in agreement with the study of Shaw et al (16) .

CONCLUSIONS
The viscous solution of curcumine 30% (herbal preparation) proved to be more effective than topical acyclovir cream in reducing size of lesion area, duration of healing and reducing pain of Recurrent Herpes labials compared with control positive "which receive glycerin only" and control negative "which receive no treatment" with minimum adverse effects which potentiat it use in the treatment of RHL due to it safety, effectiveness and low cost compared with other rotinal antiviral

Mean lesion area (mm 2 ) Healing time hr Duration of pain(days)
All values are shown as mean ± standard deviation; Different letter mean significant differences.

Table ( 5
): Minor adverse effect of drug used.