**3.3. Cardiotonic steroids—digoxin and digitoxin**

Very surprising recently (2017), the cardiotonic steroids entered in the scope of the struggle with AdV infections. As a theoretic prerequisite of their effects were the data on dependents of AdV on the host pre-RNA splicing machinery for expression of its complete genome. On such base modulators of RNA splicing as digoxin and digitoxin could be considered as antivirals versus human AdVs. Grosso et al. [3] proved that both drugs reduced of a series of AdVs of four different species (A to D) by 2–3 logs. This is a result of affecting several steps needed for AdV genome replication (late proteins E4 or f6 and the major late capsid hexon protein is compromised). The authors proved that these two drugs altered EiA RNA splicing early in infection and partially blocked the translation from 12S and 13S to 9S RNA at later stages of viral replication. By blocking AdV replication at one or more steps beyond the onset of E1A expression and before genome replication, digoxin and digitoxin manifest very prospective potential as antivirals for the treatment of serious AdV infections.

**4. Clinical trials**

confer long-term protection [53].

studies [58].

conjunctivitis [60].

toxicity to the kidney and gastrointestinal tract.

0.3% Hypromellose gel (Genteal gel®), serving as placebo (Phase IV).

ment of AdV infections in immunocompromised patients.

Prophylaxis with effective antivirals versus AdV EKC would be particularly useful for pre-

Chemotherapy of Adenovirus Infections http://dx.doi.org/10.5772/intechopen.79160 21

Cidofovir eye drops 1% prevent severe corneal opacities in EKC patients, dose-dependent local toxicity at frequent administration been registered [50, 51]. This anomalous nucleoside at concentration of 1% applied topically in a combination with 1% cyclosporine demonstrated therapeutic effect on patients with EKC in a controlled clinical pilot study [51]. No placebocontrolled randomized trials have been carried out on immunocompromised patients.

Controversial results were obtained with cidofovir the treatment of AdV infections in children undergoing bone marrow or stem cell transplantation [52]. Evidence was accumulated that as earlier AdV infection is detected for starting cidofovir treatment the better curative results were registered. Although cidofovir exhibits antiviral activity versus all AdV species, it possesses low oral bioavailability and significant toxicity (tubular necrosis) and does not

However, the lipid conjugate of cidofovir, brincyclovir (BCV; hexadecyloxy propyl-cidofovir; CMX001) is currently in Phase II clinical trial [25, 54], unfortunately manifesting a significant

The topical ganciclovir application against EKC [55] merits special attention. In a published clinical study, treatment with 0.15% GCV ophthalmic gel improved outcome of AdV conjunctivitis [56]. Three other clinical trials evaluating 0.15% GCV ophthalmic gel were organized, two of them finished: (1) Efficacy and Safety of GV 550 in Acute Adenovirus Keratoconjunctivitis (Clinical Trials.gov. trial NCT01156025) and (2) Efficacy and Safety of GV 550 in Acute Adenovirus Keratoconjunctivitis (a Clinicaltrialsregister.eu trial). Both included placebo and treatment groups on 40 persons each (in fact Phase II of clinical trial). In the third trial, Clinical Trials.gov trial NCT1533480 (A Placebo Controlled Comparison of Topical ZIRGAN Versus Genteal for the treatment of Adenovirus Conjunctivitis) which is currently in course, GCV is administered topically as 0.15% gel (ZIRGAN®) compared with

On the base of the promising results with povidone-iodine (PVP-I), a microbicidal agent possessing also virucidal properties [57], topical ganciclovir and PVP-I combination drops have shown the most recent potential, but both therapeutics need to be investigated in larger scale

The experimental data in vivo are in favor of GCV to be considered as an option for the treat-

N-chlorotaurine (a week oxidant) manifested effectivity in phase II clinical trials with viral

During a severe outbreak of EKC caused by AdV 8 in 1972–1973 in Bulgaria abitylguanide was tested in two double-blind, randomized trials, carried out on total 349 patients (trial

Ribavirin efficacy for the treatment of AdV infections was very controversial [36, 59].

1–151 patients; trial 2–198 patients) with virologically confirmed diagnosis.

venting AdV transmission to the second eye as well as to the contact persons.

Convallatoxin, a synthetic cardiotonic steroid, manifested a stronger activity versus AdV5 when compared with digoxin and digitoxin. In general, these three substances alter the cascade of AdV gene expression—an effect starting after initiation of early gene expression attaining a blocking of AdV DNA replication and of viral structural proteins. These findings open a novel approach of treating AdV infections and guide the development of novel antiviral therapies.

### **3.4. NMSO3 (sulfated sialic acid derivative)**

This compound inhibits selectively cellular binding sites (sialic acid-containing receptors) of several AdV serotypes. It was established that ADVs possess this cellular tropism. NMSO<sup>3</sup> could be used for the topical treatment of ocular AdV infections [43, 44].
