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International Journal of Ozone Therapy 8: 000-000, 2008 Safety of Topical Oleozon® in the Treatment
of Tinea Pedis: Phase IV Clinical Trial
S. MENÉNDEZ*, L. RE**, L. FALCÓN***, M.B. ARGOTE***, I. MÉNDEZ* D. FERNÁNDEZ****, B. ELÍAS-CALLE*****, M. VALERO**** * Ozone Research Center; Havana, Cuba** Molecular Pharmacology, Ancona University; Ancona, Italy*** Dr. Carlos J. Finlay, Hospital; Havana, Cuba**** FINE, Military Hospital; Cárdenas, Matanzas, Cuba***** Dr. Agostinho Neto, General Hospital; Guantánamo, Cuba Key words: ozonized vegetable oils, phase IV clinical trial, safety, tinea pedis, adverse drug reactions, Oleozon®
SUMMARY - The efficacy of topical OLEOZON® against tinea pedis has already been demonstrated.
The aim of the present study was to assess the adverse reactions associated with topical OLEOZON® in pa-tients with tinea pedis. A multicenter, open, phase IV clinical trial was carried out. An adverse drug reaction report form specifying the reactions most commonly associated with topical OLEOZON® was designed. This study lasted three years. Patients were treated with topical OLEOZON® twice a day for six weeks. Of the total of 2596 patients admitted to the study, 2165 (83.4%) patients finished the treatment. The main cause of drop out of the 431 patients (16.6 %), was the scant attendance at the clinical evaluation. Six pa-tients (0.3%) showed adverse reactions. The most frequently reported adverse reactions were skin burning sensation, pruritus and erythema of mild intensity. Skin burning sensation was considered, according to the causal relationship, as definite; pruritus and erythema were considered probable. Taking into account the number of patients that finished the treatment, an efficacy of 92.7% (2007 patients cured) was achieved. The favourable safety profile achieved with topical OLEOZON® in this study, together with its demonstrated ef-ficacy and its low cost justify the extension of this treatment in clinical practice for patients with tinea pedis, particularly in developing countries. Introduction
number of patients. Therefore, taking into account the characteristics of OLEOZON® and the need Tinea pedis is a very common and often chronic to find effective, low-cost safe antimycotic drugs, foot infection caused by fungi of the genera the aim of this study was to perform a multicenter Trichophyton, Microsporum or Epidermophyton open phase IV clinical assay to evaluate the true 1-3. Topical and oral OLEOZON® (ozonized sun- picture of adverse drug reactions (ADRs) and the flower oil) is a medication produced in Cuba which drug’s effectiveness in routine clinical practice.
has been evaluated previously in different clinical trials 4-7. It is already registered for the treatment of tinea pedis, impetigo and giardiasis. Its remarkable Patients and Methods
germicidal action has been well documented 8-10, as well as its lack of toxicity and low cost 11-13.
A multicenter, open, phase IV clinical assay was Topical OLEOZON® was evaluated in a control- carried out aimed at evaluating the possible ADRs led randomized phase III assay, using ketoconazole during the treatment of patients with tinea pedis (Nizoral®) as the comparing group 4. The results using topical OLEOZON®. An ADR report form, demonstrated that no significant differences were specifying the reactions most commonly associated found between the two medications, nor were any with OLEOZON® was designed. This study lasted side-effects or bacterial superinfection observed in three years. Four hospitals from different prov- inces of Cuba participated. All the patients were Adequate safety profiles for tinea pedis treat- clinically (presence of maceration, desquamation, ment were observed in different clinical trials fissures, erythema, vesicles and/or pruritus) and 14-16, as for topical OLEOZON® 4, but it was not mycologically (positive culture of skin scrapings of known whether a similar profile would be found the affected areas in Sabouraud glucose agar-chlo- in routine clinical practice conditions using a large ramphenicol) diagnosed as suffering from tinea Safety of Topical Oleozon® in the Treatment of Tinea Pedis: Phase IV Clinical Trial pedis. They were aged over 15 years, of either gen- der and any race and without previous treatment or with more than five days without any topical As a second aspect of this clinical assay, the effi- or systemic medication. From the study were cacy of topical OLEOZON® was measured in all excluded patients with decompensated diseases, the patients studied, and also with respect to the hypersensitivity to the medication and those being different clinical forms present in tinea pedis. The treated with antibiotics, corticoids, cytostatics or efficacy was evaluated as clinical cure (disappear- ance of all lesions, for that reason no mycological diagnosis was needed) before or in six weeks. If a patient was clinically cured before six weeks of treatment, the medication was continued until six weeks. If a clinical cure was not achieved at the end Patients were treated with topical OLEOZON® of the treatment, this was considered a failure.
(each 100 ml contains 8-12 % hydroxyperoxides Patients were submitted to clinical and ADR of unsaturated triglycerides as active oxygen 17,18), evaluation every two weeks and at the end of the study (six weeks). If any side-effects appeared in the meantime, patients would immediately inform the physician to classify the severity of ADR and to determine the causal relationship. After finish-ing the treatment, all patients had a follow-up at An ADR is defined as any noxious and unde- sired effect to a drug observed at doses usually The study was approved by the Scientific administered therapeutically in humans. The sever- Committee of the Ozone Research Center. As the ity of ADR was classified in four levels: study only involved the usual medical procedures 1) Mild, when the side-effect did not significantly (this is a medication already registered in Cuba interfere with the normal functions of the patient, for the treatment of tinea pedis, with its license to use it) and confidentiality of the subjects was 2) Moderate, when the side-effect produced an maintained, ethics approval and patient informed impairment of the normal functions of the patient, without being a risk to his/her health, but needed specific treatment;3) Severe, when the side-effect produced a sig- nificant impairment of the normal functions of the patient, without being a risk to his/her life, but Univariate analyses were performed to iden- tify the variables that could influence ADRs. The 4) Very severe, if a reaction was potentially life- analysis was assessed by χ2 test or Fisher’s exact threatening or contributed to the patient’s death.
test, depending on the minimum expected values. A qualitative assessment was used to classify the For the efficacy evaluation, data were analyzed by causal relationship as definite, probable, possible one-way analysis of variance (ANOVA) followed or doubtful 19. According to this method, a reac- tion was classified as definite if it (A) followed a reasonable temporal sequence after drug adminis-tration; (B) followed a known pattern of response to the suspected drug; (C) could not be explained by concurrent disease or other drugs; and (D) was In this study, the mean value of the evolution confirmed by improvement upon removal of the time of the disease was 60 months with five relaps- drug and by reappearance on rechallenge. It was es per year. The mean age was 35 years, 85% were considered probable if it had the criteria (A), (B), male and 55% were white. Interdigital lesions were (C) and was confirmed on suspension of the drug the most common symptom in more than 90%; but not on rechallenge. A reaction was defined as the plantar lesion was present in less than 50% of possible if it followed a reasonable time sequence to the application of the drug, but could also be A total of 2596 patients suffering from tinea explained by concurrent disease or other drugs. pedis were included in this study, but only 2165 Finally, a reaction that was more likely related to patients (83.4%) finished the treatment because factors other than the suspected drug was classi- 431 (16.6%) dropped out due to scant attendance at the clinical evaluation (every 2 weeks). Taking into account the number of patients that finished International Journal of Ozone Therapy 8: 000-000, 2008 Figure 1 General results of tinea pedis treatment with topical OLEOZON®.
Table 1 Classification of ADRs and their qualitative assessment in this study
In brackets is the number of patients that presented ADRs. One patient presented skin burning sensation and pruritus and another one presented skin burning sensation and erythema.
Table 2 Behavior of the patients that finished the topical OLEOZON® treatment in relation to the different clinical forms of tinea pedis
and their evaluation.
Different letters signify statistical differences (p<0.05).
the topical OLEOZON® treatment, an efficacy of 92.7% (2007 patients cured) was achieved and reappearance or not of the ADRs on rechallenge. only 7.3% (158 patients) were not cured (figure 1). Skin burning sensation was considered definite However, if we consider as failure the number of according to the causal relationship; pruritus and patients that abandoned the treatment the effec- erythema were considered probable. No causal tiveness decreases to 77.3% (analysis by inten- relationship considered as possible or doubtful was tion to treat). Only six patients (0.3%) presented ADRs. The most frequently reported ADRs were Considering the number of patients that finished skin burning sensation, pruritus and erythema of the treatment, a major incidence (50.1%) of the mild intensity. Four patients presented skin burn- scaly form of tinea pedia, followed by the macer- ing sensation, one patient presented skin burning ated form (31.9%), were present in this study. The sensation and pruritus and the other one also had scaly and macerated forms demonstrated a high skin burning sensation but with erythema. Once percentage of cured patients, with 97.9 and 94.9%, the ADRs appeared in these six patients, the treat- ment was suspended for 24h. Patients were evalu- No relapses were found in six months of follow- ated during this period to confirm their improve- Safety of Topical Oleozon® in the Treatment of Tinea Pedis: Phase IV Clinical Trial Discussion
to take into account, since in daily practice patients sometimes interrupt treatment, this result being a The results of this study suggest that topical truer figure of medication efficacy. The incidence OLEOZON® is a safe drug with an excellent post- in respect to the different clinical forms, is similar marketing safety profile. Post-marketing monitor- to that already reported 2, where the scaly form ing is an important procedure to detect reactions occupied the first on the list. Also, the scaly form that can become apparent only when the drug responds best to different treatments.
is used in a large and varied population. Indeed, Another aspect to highlight is that topical those observed in clinical trials for tinea pedis 14-16 OLEOZON® exhibits an antifungal and antibac- do not reflect the true behaviour of ADRs due to terial activity 4,5,8-10 as well as an anti-inflamma- tory property 21-22. Normally, the severity of tinea Active surveillance provides a vital service to pedis infection determines the course of treatment the healthcare system by identifying and assessing required. Mild infections may be resolved using a early warning signals, and when appropriate, tak- topical agent, but are commonly associated with ing preventive action to minimize the deleterious high relapse rates. However, more severe cases (eg, effects of drugs. In Cuba this has a special relevance dermatophytosis complex) may require oral and because the information generated in clinical trials topical treatment that eliminates the bacterial and can be limited by the patients’ recruitment rate.
fungal infection and sometimes if inflammation The most frequent ADRs associated with topical is present an agent with a known anti-inflamma- OLEOZON® therapy were skin-burning sensation, tory action may be needed. All these drugs can pruritus and erythema. These ADRs had also been be accompanied by side-effects such as gastroin- reported in the treatment of impetigo with topical testinal distress, headache, and hepatic toxicity, OLEOZON® 5 in a phase III clinical trial carried among others. In our study, the mean value of the out in 136 children. However, some contradictions evolution time of the disease was 60 months with are present with respect to ADRs. In the study five relapses per year, then, we can consider that 20, no ADRs were reported with the use of topi- we are studying chronic patients. This six weeks cal OLEOZON® in adults with different diseases topical OLEOZON® treatment guaranteed the (tinea pedis, pyoderma, onycomycosis, simplex absence of relapses (at least in the six months of herpes). Also, another study (unpublished obser- follow-up), and the presence of superinfection due vations) carried out in 80 children with impetigo to bacteria and the associated inflammation. In reported no ADRs. In this study only 0.3% of this case OLEOZON® will be the best choice due to its germicidal and anti-inflammatory properties, Skin burning sensation could be a consequence its low cost, safety and tolerability (favourable of topical OLEOZON® application, due to the active metabolites that are formed 17,18 (aldehydes, acids, ozonides and hydroperoxides) in the reac-tion of the ozone with the sunflower oil and the Conclusions
patient’s sensitivity. For that reason, skin burning sensation can be classified as definite, according The favourable safety profile achieved with to the causal relationship, however, erythema and topical OLEOZON® in this study together with pruritus were in the group of probable ADRs its demonstrated efficacy and low cost justify the (confirmed on suspension of the drug but not on extension of this treatment in clinical practice for patients with tinea pedis, particularly in developing A high efficacy (92.7%) was obtained when all the patients that finished the treatment are con-sidered. However, with respect to the analysis by intention to treat, where all the patients included Acknowledgements
in the study are considered, the effectiveness decreased to 77.3%, similar to that obtained in the This study was sponsored by the Ozone Research phase III clinical trial 4. This is an important point Center and the Health Ministry of Cuba. References
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