Acanthosis nigricans (AN) is a common dermatologic manifestation of systemic disease that is associated with insulin resistance, diabetes mellitus, obesity, internal malignancy, endocrine disorders, and drug reactions. Treatment of AN primarily focuses on resolution of the underlying disease processes causing the velvety, hyperpigmented, hyperkeratotic plaques found on the skin. While the goal of therapy is to treat the primary cause, cosmetic resolution of AN lesions can be important for patients and their quality of life. Treatment options for AN have not been extensively studied; however, smaller powered clinical trials and case reports exist in the literature. Our review aims to explore and evaluate the current treatment options that exist for AN.

Feline calicivirus (FCV) is a major cause of upper respiratory tract disease in cats, with widespread distribution in the feline population. Recently, virulent systemic diseases caused by FCV infection has been associated with mortality rates up to 50%. Currently, there are no direct-acting antivirals approved for the treatment of FCV infection. Here, we tested 15 compounds from different antiviral classes against FCV using in vitro protein and cell culture assays. After the expression of FCV protease-polymerase protein, we established two in vitro assays to assess the inhibitory activity of compounds directly against the FCV protease or polymerase. Using this recombinant enzyme, we identified quercetagetin and PPNDS as inhibitors of FCV polymerase activity (IC50 values of 2.8 μM and 2.7 μM, respectively). We also demonstrate the inhibition of FCV protease activity by GC376 (IC50 of 18 µM). Using cell culture assays, PPNDS, quercetagetin and GC376 did not display antivirals effects, however, we identified nitazoxanide and 2'-C-methylcytidine (2CMC) as potent inhibitors of FCV replication, with EC50 values in the low micromolar range (0.6 μM and 2.5 μM, respectively). In conclusion, we established two in vitro assays that will accelerate the research for FCV antivirals and can be used for the high-throughput screening of direct-acting antivirals.

Norovirus is the main cause of viral gastroenteritis worldwide. Although norovirus gastroenteritis is self-limiting in immunocompetent individuals, chronic infections with debilitating and life-threatening complications occur in immunocompromised patients. Nitazoxanide (NTZ) has been empirically used in the clinic and demonstrated effectiveness against norovirus gastroenteritis. In this study we aimed at uncovering the antiviral potential and mechanisms of NTZ and its active metabolite, tizoxanide (TIZ) using a human norovirus (HuNV) replicon. NTZ and TIZ, collectively referred to as thiazolides (TZD) potently inhibited replication of HuNV and a norovirus surrogate feline calicivirus. Mechanistic studies revealed that TZD activated cellular antiviral response and stimulated the expression of a subset of interferon-stimulated genes (ISGs), particularly IRF-1 not only in Huh7-based HuNV replicon but also in naïve Huh7, Caco-2 and novel human intestinal organoids. Overexpression of exogenous IRF-1 inhibited HuNV replication; whereas knockdown of IRF-1 largely attenuated the antiviral activity of TZD, suggesting that IRF-1 mediated TZD inhibition of HuNV. By using a JAK inhibitor CP-690550 and STAT1 knockout approach, we found that TZD induced antiviral response independent of the classical Janus Kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Furthermore, TZD and ribavirin synergized to inhibit HuNV replication and completely depleted the replicons from host cells after long-term treatment. In summary, our results demonstrated that TZD combated HuNV replication through activation of cellular antiviral response, in particular inducing a prominent antiviral effector IRF-1. NTZ monotherapy or combination with ribavirin represented promising options for treating norovirus gastroenteritis, especially in immunocompromised patients.

Nitazoxanide has antiparasitic and antibiotic activities including activity against Mycobacterium tuberculosis. We prepared and evaluated a set of its analogues to determine the structure-activity relationship, and identified several amide- and urea-based analogues with low micromolar activity against M. tuberculosis in vitro. Pharmacokinetics in the rat suggested a path forward to obtain bioavailable compounds. The series had a good microbiological profile with bactericidal activity in vitro against replicating and nonreplicating M. tuberculosis. Analogues had limited activity against other Gram-positive bacteria but no activity against Gram-negative bacteria. Our studies identified the key liability in this series as cytotoxicity. Future work concentrating on identifying the target(s) could assist in removing activity against eukaryotic cells.

Cryptosporidium is a protozoan pathogen that can cause diarrheal disease in healthy and immunosuppressed individuals, worldwide. Recent studies have highlighted the impact of cryptosporidiosis on children in resource-limited countries. Nitazoxanide is the only Food and Drug Administration approved treatment, but it is not consistently effective therapy for cryptosporidiosis in the most vulnerable populations. Areas covered: This review focused on recent published studies evaluating novel drugs and new compounds for the treatment of cryptosporidiosis. Expert commentary: Combinations of approved drugs have demonstrated some activity. Broad screens have demonstrated activity against Cryptosporidium for a number of available drugs, including statins and clofazimine, and the latter has advanced into clinical trials. Cryptosporidium calcium-dependent protein kinase 1 (CDPK1) has been identified as an attractive target for treatment, and bumped kinase inhibitors have been developed which inhibit CDPK1 and are active against Cryptosporidium growth both in vitro and in vivo. Inhibition of Plasmodium lipid kinase PI(4)K8 of Cryptosporidium by KDU731 greatly reduced oocyst shedding and improved diarrhea in calves with limited effects on the human PI(4)K. Another novel potent inhibitor MMV665917 was efficacious in mouse models with cidal activity against Cryptosporidium. Additional compounds have proved active in vitro. So far, only clofazimine has entered human trials.

Limited information indicates that a maternal dose of 500 mg of nitazoxanide produces low levels of an active metabolite, tizoxanide, in breastmilk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. But until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity. Herein we identify the antiprotozoal/antimicrobial nitazoxanide as a potential anti-paramyxovirus drug targeting the F-protein. We show that nitazoxanide and its circulating-metabolite tizoxanide act at post-entry level by provoking Sendai virus and RSV F-protein aggregate formation, halting F-trafficking to the host plasma membrane. F-protein folding depends on ER-resident glycoprotein-specific thiol-oxidoreductase ERp57 for correct disulfide-bond architecture. We found that tizoxanide behaves as an ERp57 non-competitive inhibitor; the putative drug binding-site was located at the ERp57-b/b' non-catalytic domains interface. ERp57-silencing mimicked thiazolide-induced F-protein alterations, suggesting an important role of this foldase in thiazolides anti-paramyxovirus activity. Nitazoxanide is used in the clinic as a safe and effective antiprotozoal/antimicrobial drug; its antiviral activity was shown in patients infected with hepatitis-C virus, rotavirus and influenza viruses. Our results now suggest that nitazoxanide may be effective also against paramyxovirus infection.

In many developing areas in the world, a high burden of enteric pathogens in early childhood are associated with growth deficits. The tryptophan-kynurenine-niacin pathway has been linked to enteric inflammatory responses to intestinal infections. However, it is not known in these settings whether scheduled antimicrobial intervention to reduce subclinical enteric pathogen carriage or repletion of the tryptophan-kynurenine-niacin pathway improves linear growth and development.