Gerald E. Underwood

Activity of 1-β-D-Arabinofuranosylcytosine Hydrochloride Against Herpes Simplex Keratitis

Summary The antiviral activity of 5-iodo-2′-deoxyuridine in treating herpes simplex keratitis in rabbits was confirmed. Another pyrimidine nucleoside, 1-β-D-arabinofurano-sylcytosine hydrochloride, was found to be at least as effective as IUDR in treating this infection.

Antiviral and Interferon-Inducing Properties of 1,5-Diamino Anthraquinones

A series of anthraquinones with amino substituents at the 1,5 positions were found to induce interferon in mice. A prototype compound, 1,5-bis[(3-morpholinopropyl)amino]-anthraquinone (Ia), was an effective antiviral agent when administered either orally or parenterally. Peak interferon titers were found 12 to 24 h after drug treatment. The minimum oral dose of Ia required to induce serum interferon or to protect mice against a lethal virus infection was 62 mg/kg. Mice tolerated an oral dose of at least 30 times this minimum effective dose. A single dose of Ia given up to 6 days prior to infection had significant protective activity. Biological properties of Ia were compared with those of three other 1,5-diamino anthraquinones, which also induced interferon and demonstrated antiviral activity in mice. The most active compound was 1,5-bis[[2-(diethylamino)ethyl]amino]-anthraquinone (Ib), which protected mice against virus infection at a dose as low as 8 mg/kg (less than 1/60 its maximum tolerated dose). Mice developed hyporeactivity to interferon induction if the same inducer was injected daily, although by alternating between different inducers the loss of interferon responsiveness could be avoided.

Herpes keratitis in rabbits: pathogenesis and effect of antiviral nucleosides.

Certain pyrimidine nucleosides have proved to be effective antiviral agents. The two that have received most attention are 5-iodo-2’-deoxyuridine (idoxuridine or IDU) and 1-/3-D-arabinofuranosylcytosine (cytarabine or CA) . IDU was first reported by Herrmann (1961) to show activity against herpes simplex virus in cell culture; subsequently, Kaufman (1962; see also Kaufman et al., 1962) found the compound to be markedly effective in treating herpetic keratitis in rabbits and in man. Shortly thereafter, CA, a nucleoside that contains a metabolically normal base but an abnormal sugar, was found in our laboratory to be similarly active against herpes virus in both cell cultures and rabbit eyes (Underwood, 1962; Buthala, 1964). CA also has demonstrated clinical efficacy in treatment of herpes keratitis (Kaufman & Maloney, 1963). Considerable interest has resulted from these reports describing successful therapy of established viral disease in man. Several publications have reported virus levels in the corneal epithelium of infected eyes treated with IDU (Jawetz et al., 1963; Ey et al., 1964; Engle & Stewart, 1964); however, these virus studies did not include other parts of the eye, nor was the effect of CA evaluated. There also are several papers describing the pathogenesis of experimental herpes keratitis (Wolter et al., 1956; Kimura, 1962; Hogan et al., 1964), but detailed studies on the pathology associated with virus infection in treated eyes are lacking. We undertook a comprehensive study of treated versus nontreated herpes eye infections in albino rabbits and will summarize the salient results in this report.

Kethoxal for treatment of cutaneous herpes simplex.

Summary Cutaneous herpes simplex infection was produced experimentally in baby rabbits and hairless mice. Infection in rabbits progressed to give a flaccid hind limb paralysis, whereas massive skin lesions without the flaccid paralysis occurred in hairless mice. Progression of infection was readily scored in both baby rabbits and hairless mice so that these provided good systems for evaluation of antiviral agents. Kethoxal (α-keto-β-ethoxybutyraldehyde hydrate), a potent virucidal compound, showed marked antiherpes activity in both baby rabbits and hairless mice when applied topically. It is suggested that kethoxal may have potential utility in treatment of cutaneous herpes in man.

Glyoxal and related compounds as potential blood sterilizing agents.

Summary Both glyoxal and β-ethoxy-α-ketobutyraldehyde (Kethoxal) were more potent virucidal agents than β-propiolactone (BPL). Glyoxal was less lytic for human erythrocytes than was Kethoxal or BPL. None of the chemicals showed significant toxicity for plasma proteins as measured by electrophoresis. These experiments indicate that glyoxal may be of potential value in the sterilization of human blood and plasma.

Efficacy of 5,6-Dihydro-5-Azathymidine Against Cutaneous Herpes Simplex Virus in Hairless Mice

5,6-Dihydro-5-azathymidine, administered subcutaneously, was active both prophylactically and therapeutically against cutaneous herpesvirus infection of hairless mice. Activity was comparable to that obtained with adenine arabinoside.

Binding of an antiviral agent (kethoxal) by various metabolites.

Summary Kethoxal (β-ethoxy-α-ketobutyraldehyde hydrate) reacted chemically with a variety of normal metabolites. Some of these reactions (e.g., those with cysteine and arginine) resulted in rapid loss of antiviral activity; others (e.g., with glycine and intact gelatin) in a more gradual loss of activity, while still others, particularly with serine and threonine, gave products possessing apparently undiminished activity. It was concluded that lack of significant antiviral activity by Kethoxal in animals could be attributed principally to its rapid binding and inactivation by proteins, amino acids and other metabolites.

CLINICAL EVALUATION OF 4′-[2-NITRO-1- (P-TOLYLTHIO)ETHYL]ACETANILIDE (U-3243) AGAINST CUTANEOUS HERPES SIMPLEX

Some persons have recurrent herpes infections a t a single s i t e , often on the l i p or around the mouth or nose. Virus may be present i n the t i s sues between attacks, but no one has been able t o i so l a t e it during these quiescent periods. currences. sunlight, emotional upsets, menstruation, and physical injury. Such trauma appears t o stimulate v i rus synthesis, resu l t ing i n the format i on of a charac te r i s t ic herpetic lesion. A var ie ty of causes inc i t e reThese causes vary with individuals and include fever,

Efficacy of N6- (2-Hydroxyethyl) Adenine against Coe Virus Infection in Mice.

Summary The compound N6-(2-hydroxy-ethyl)adenine (HEA) was effective in favorably modifying experimental Coe virus infection in mice. HEA showed antiviral activity when a single injection, approximately one-tenth the lethal dose, was given from 24 hours before to 17 hours after virus inoculation. The toxicity, but not the antiviral activity of HEA, was partly reversed by simultaneous treatment with a xanthine oxidase inhibitor.