A comparative ex vivo permeation evaluation of a novel 5-Fluorocuracil nanoemulsion-gel by topically applied in the different excised rat, goat, and cow skin
Authors: Hussain Salman AlHomoud
Niyaz Ahmad
Hassan Ali Al-Nasif
Md Sarafroz
Rizwan Ahmad
Taysser Mohammed Buheazaha
Journal: Saudi Journal of Biological Sciences (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: 5-FU, 5-Fluorouracil; 5-FU-NE-Gel, 5-Fluorouracil Nanoemulsion Gel; 5-Fluorouracil; ANOVA, Analysis of variance; BCS, Biopharmaceutical Classification System
Affiliations: Department of Pharmaceutics, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia., Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia., Department of Natural Products and Alternative Medicine, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

Abstract:  Aim of the study: 5-Fluorouracil (5-FU) can't be given orally because of very low bioavailability and produces serious adverse effects. Therefore, the main objective of this research is to develop, evaluate, and comparative effects by different nanoformulations of topical application on chemoprevention of skin cancer in different types of skin. Material and methods: Castor oil (oil), Transcutol HP (surfactant), and Polyethylene glycol (PEG)-400 (co-surfactant) have taken on the basis of nonionic property and highest nanoemulsion (NE)-region. Aqueous micro titration method with ultra-sonication method (based on high energy) was used for the preparation of 5-FU-NE. Optimized-5-FU-NE was stable thermodynamically, and their characterizations was performed on the basis of globule size, zeta potential, refractive index, and viscosity. Optimized-NE has been converted into 5-FU-NE-Gel with the help of Carbopol® 934 and also performed their permeation studies in the different skins (cow, goat, and rat, ex vivo) using Logan transdermal diffusion cell (DHC-6T). Optimized-5-FU-NE and 5-FU-NE-Gel were evaluated cytotoxic studies (in vitro) on the melanoma cell lines. Results: The permeation of 5-FU from 5-FU-NE-Gel nanoformulation for rat skin model was 1.56 times higher than the 5-FU-NE and 12.51 times higher than the 5-FU-S for the cow and goat skin model. The values of steady state flux and permeability coefficient for 5-FU-NE-Gel of rat skin were higher i.e. 12.0244 ± 1.12 µgcm-2h-1 and 1.2024 ± 0.073 × 10-2 µg cm-2h-1, respectively. Optimized-5-FU-NE and 5-FU-NE-Gel nanoformulation were found to be physically stable. SK-MEL-5 cancer cells have showed the results based on cytotoxicity studies (in vitro) that 5-FU as Optimized-5-FU-NE-Gel is much more efficacious than 5-FU-NE followed by free 5-FU. Localization of 5-FU from 5-FU-NE-Gel was higher with higher permeation in rat skin. Conclusion: 5-FU-NE-Gel is found to be for the better to treatment of cutaneous malignancies. It can be developed 5-FU-NE-Gel could be a promising vehicle for the skin cancer chemoprevention. 

Retracted: No

PubPeer comments:
 From the comments section: https: doi.org 10.7326 M20-1334 Dinesh Ranjan retired transplant surgeon 5 April 2020 Premature conclusion and misquotation in  what every clinician should know about HCQ use in Covid-19 I have read with interest the review u201cUse of Hydroxychloroquine and Chloroquineu2026u201d by Drs. Yazdany and Kim (1). They make a good point about not relying on incomplete science to guide medical practice (in Covid-19 pandemic), especially if it begins to impact another segment of patient population (patients with connective tissue disorder). They are correct in stating that the frenzy started with publication of a poorly controlled study from France (2) by Gautret et al. However, they have gone further and stated that an earlier double- blinded and randomized trial (of hydroxychloroquine) by Paton et al in patients with influenza failed to show efficacy of this drug (3). To most clinicians, lack of efficacy of a drug in a double-blinded randomized trial confirms inefficacy u2013 and most will stop using the drug. Since the authorsu2019 discussion is on the scientific merit of information regarding HCQu2019s effectivity in Covid-19; it is only appropriate to review the evidence Dr Yazdany had cited. As we compare the Paton study with Gautret study, an obvious revelation is that this comparison is the proverbial u201capple to orangeu201d comparison: as in the Paton study they were not even using HCQ but its ancestor Chloroquine (CQ). That too in a preventative (not treatment) trial for prophylaxis against influenza u2013 where the study arm participants were given 500 mg of CQ day for a week followed by 500mg once a week for a total of 12 weeks. This dose scheme mimics malaria prophylaxis, a microbe vastly different from viruses (4). The difference between these two studies is striking: CQ is not HCQ, a preventative trial is different from a treatment trial and doses used are vastly different. So, why did the authors with seemingly impeccable credentials stoop to misquoting a published paper to support their conclusion? Perhaps the answer lies in the subsequent paragraphs in the review where the authors correctly describe increasing scarcity of HCQ for scientifically proven use in patients with connective tissue disorder and the authorsu2019 own clinical affiliations (Rheumatology). Authors are correct in stating that public figures should refrain from promoting unproven therapies, but then academic clinicians should also refrain from using unsound academic methodology in reaching premature conclusions and publishing them in highly respected journals. 1. Yazdany J, Kim AHJ. Use of hydroxychloroquine and Chloroquine during the Covid-19 pandemic: what every clinician should know. Ann Intern Med 2020 Mar 31. Doi: 10.7326 M20-1334 2. Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. PMID:32205204 3. Paton NI, Lee L, Xu Y et al. Chloroquine for influenza prevention: a randomized, double blind, placebo controlled trial. Lancet Infect Dis. 2011;11:677-683 4. Medicines for the prevention of malaria while traveling. https: www.cdc.gov ,