*2.2.2 Clinical observation-based drug repurposing*

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

In disease-centered paradigm, the observation and analysis of data from phenotypic assays, clinical trials, and literature could be an important resource for drug repositioning, as previously mentioned, this type of repositioning is oriented toward the clinical outcomes rather than the exact molecular mechanism behind the drug switch; from other angle, the researcher aims to find certain fingerprint on the genetic or proteomic level to support the repositioning hypothesis; for example, the transcriptomic analysis of different types of autoimmune diseases could reveal similar pattern of gene expression, which means that the same drug could be used

Qu et al. applied integrative clinical transcriptomic analyses for finding new drugs for treatment of psoriasis. First, gene expression analysis of samples collected from psoriasis patient and normal volunteers were used to identify molecular targets associated with the disease, and then, connectivity map analysis revealed potential drugs for the identified targets, which were resveratrol **(16)**, tiabendazole **(17)**, monobenzone **(18)**, parthenolide **(18)**, doxycycline **(19)**, and methotrexate **(20)** [32].

Also, Patrick et al. gathered drug-related information from more than 20 million articles using machine learning based on word embedding to build a model that highlights drug-disease relationship in order to repurpose drugs for treatment of immune-mediated dermatological conditions, where prednisone **(21)**, triamcinolone **(22)**, budesonide **(23)**, hydroxychloroquine **(24)**, and leflunomide **(25)** were among the top five predicted drugs for treatment of psoriasis [33]. The chemical

*2.2.1 Application of data mining and omics in drug repositioning*

structure of compounds **(15–25)** is demonstrated in **Figure 7**.

**2.2 Disease-centered drug repositioning**

for different types of immunity-related condition.

*Chemical structure of resveratrol* **(16)***, tiabendazole* **(17)***, monobenzone* **(18)***, parthenolide* **(18)***, doxycycline*  **(19)***, methotrexate* **(20)** *prednisone* **(21)***, triamcinolone* **(22)***, budesonide* **(23)***, hydroxychloroquine* **(24)***, and* 

**54**

**Figure 7.**

*leflunomide* **(25)***.*

Bimatoprost **(26)**, a prostaglandin analog, was used for treatment of glaucoma patient, but several clinical observations reported the occurrence of eyelash hypertrichosis; so, it was used for induction of eyelash regrowth in alopecia areata and for cosmeceutical purposes [34, 35].

Phenytoin **(27)** is one of the first discovered antiepileptic drugs; after its introduction to the market, gingival hyperplasia was reported as a side effect for the treatment, which triggered dermatologist to evaluate its ability to heal wounds; so, phenytoin has been evaluated by several clinical studies, where it proved to be useful in treatment of wounds in topical and oral forms; however, the exact mechanism of action is still ambiguous [36].

Bevacizumab, a monoclonal antibody that is used for treatment of several types of cancer, was observed to achieve complete remission of psoriasis in metastatic colon cancer without any other treatment for psoriasis [37]; a case which was reported again in another study that described the same effect in metastatic renal cell cancer, psoriasis, and psoriatic arthritis patient, which means the bevacizumab could be repurposed for treatment of these dermatoses; also, it sheds the light on the importance of (VEGF) as a target for treatment of inflammatory skin conditions [38].

The Janus kinase (JAK) inhibitor, tofacitinib **(28)**, was developed originally for management of rheumatoid arthritis, ulcerative colitis and other autoimmune diseases, but it was repurposed for psoriasis and atopic dermatitis since JAK was found to be contributing in the pathogenesis of these diseases, and currently, several clinical trials were performed to assess its clinical significance and concluded that response rates in tofacitinib-treated group were significantly higher compared to that in placebo [39–41].

Metformin **(29)**, a type-2 diabetes medication, reduces insulin resistance; however, its mechanism is not completely understood; so, it was suggested as a treatment of several dermatological conditions associated with insulin resistance such as acanthosis nigricans and acne; this was supported by several clinical trials where the patients showed complete resolution. It also was employed in treatment of hyperpigmentation due to its inhibitory effect on tyrosinases, the key enzymes in melanin biosynthesis. The anti-melanogenic effect of metformin was demonstrated experimentally on human skin biopsies and reconstituted human epidermis; also, clinical trials showed that metformin efficacy is comparable to TCC in treating melasma [42–44].

Finally, minoxidil **(30)**, which is a well-known case in drug repositioning, was initially used for treatment of hypertension since its strong vasodilator effect but during clinical trials, hair regrowth was noticed in patients with androgenic alopecia such effect is contributed by stimulating the vascular bed nearby the hair follicles which lead to better environment for hair growth. It was suggested that the ability of minoxidil to activate cytoprotective prostaglandin synthase-1 and stimulate adipose-derived stem cells (ASCs) [45, 46].

#### *2.2.3 Phenotypic screening for drug repositioning*

Niclosamide (NCL) **(31)** is an anti-helminthic drug that has been utilized for long time with considerable safety profile; several studies reported its antiinflammatory and anticancer activities, highlighting the potential of repurposing for different indications; Thatikonda et al. used imiquimod (IMQ )-induced BALB/c mouse model to evaluate the efficacy of NCL for treatment of psoriasis, where it alleviated epidermal hyperplasia and inflammation induced by IMQ via downregulating p65, STAT3, NFATc-1, and NF-κB transcription factors along with Ki-67, ICAM-1, and Akt protein expression [47].

**Figure 8.**

*Chemical structure of bimatoprost* **(26)***, phenytoin* **(27)***, tofacitinib* **(28)***, metformin* **(29)***, minoxidil* **(30)***, niclosamide* **(31)***, carvedilol* **(32)***, and cannabidiol (CBD)* **(33)***.*

Hall et al. used zebrafish neutrophil migration assay, for evaluation of the suppressive effect of 1280 approved drugs on recruitment of neutrophils; where drugs showing prominent anti-inflammatory activity were further tested in atopic dermatitis animal model, among them 11 drugs which was not reported previously as anti-inflammatory agent [48].

Chang et al. used in vivo model of chemically induced murine skin tumorigenesis to confirm the hypothesis of repositioning of beta blocker for treatment of skin cancer, since several studies showed that stress-related catecholamine hormone expression can affect tumor progression [49].

Carvedilol **(32)**, when administrated orally and topically, prevented DMBAinduced epidermal hyperplasia, suggesting that it may serve as a new agent for protecting against skin cancer [50], which was supported by another study that demonstrated the preventive effect of carvedilol applied topically after UV exposure; so, it can be repositioned as prophylactic agent against skin inflammation and cancer [51].

Cannabidiol (CBD) **(33)** is a nonpsychoactive phytocannabinoid found in *Cannabis sativa*. It is approved recently for the treatment of seizures associated with two uncommon and serious forms of epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome. Oláh et al. reported that CBD-treated human sebocytes and human skin organ in vitro showed strong antiproliferative, lipostatic, and antiinflammatory effects mediated by a plethora of receptors, ion channels, and other components of the endocannabinoid system [52]. These findings were confirmed later by clinical trial showing that CBD administrated as an ointment is an effective and noninvasive option for enhancing the quality of life in patients with some skin disorders, especially those with inflammatory background [53]. The chemical structure of compounds **(26–33)** is depicted in **Figure 8**.

#### **3. Concluding remarks and future perspective**

Drug repositioning is an important strategy to maximize the benefits from already approved drugs; it will not only contribute to reduction of time and cost

**57**

**Author details**

**Conflict of interest**

Farid A. Badria1

Mansoura, Egypt

Kafrelsheikh, Egypt

\* and Abdullah A. Elgazar2

\*Address all correspondence to: faridbadria@gmail.com

provided the original work is properly cited.

1 Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University,

2 Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Drug Repurposing in Dermatology: Molecular Biology and Omics Approach*

logical condition and enhance the quality of life of patients.

The authors declare no conflict of interest.

for drug discovery but also could help to develop new therapeutics for orphan and ignored diseases. While historic cases of drug repositioning were inspired by serendipity and observations, more systematic approaches became well established by time. In silico and data mining tools could help to analyze the large amount of data available from omics, phenotypic assay, and clinical investigations by revealing novel relationship between drugs, targets, and different pathways of diseases as described in this chapter; the integration of different tools of drug repurposing will allow the identification of safe and effective therapeutics for treatment of dermato-

*DOI: http://dx.doi.org/10.5772/intechopen.93344*

*Drug Repurposing in Dermatology: Molecular Biology and Omics Approach DOI: http://dx.doi.org/10.5772/intechopen.93344*

for drug discovery but also could help to develop new therapeutics for orphan and ignored diseases. While historic cases of drug repositioning were inspired by serendipity and observations, more systematic approaches became well established by time. In silico and data mining tools could help to analyze the large amount of data available from omics, phenotypic assay, and clinical investigations by revealing novel relationship between drugs, targets, and different pathways of diseases as described in this chapter; the integration of different tools of drug repurposing will allow the identification of safe and effective therapeutics for treatment of dermatological condition and enhance the quality of life of patients.
