Adenine Arabinoside Research Articles

Antiviral Treatment of Chronic Type B Hepatitis

Excerpt Vidarabine (adenine arabinoside; Ara-A) is an adenine analogue with potent activity against several DNA viruses including most herpesviruses. In a large, multicenter trial done in the mid-1...

Adenine Arabinoside Monophosphate (Vidarabine Phosphate) in Combination with Human Leukocyte Interferon in the Treatment of Chronic Hepatitis B

To determine the efficacy of adenine arabinoside monophosphate (Ara-AMP vidarabine phosphate) with or without human leukocyte interferon in chronic hepatitis B. Randomized, double-blinded, placebo-controlled trial with 6-month treatment and an 18-month follow-up. Referral-based liver-disease clinics at three university medical centers. Twenty-five patients with chronic active hepatitis or cirrhosis and 39 with chronic persistent hepatitis. Thirteen patients received intramuscular Ara-AMP, 2.5 mg/kg body weight, twice daily, alternated monthly for 6 months with subcutaneous human leukocyte interferon, 5 million units, twice daily. Painful paresthesia of the legs necessitated dosage reduction and early discontinuation of enrollment. Twenty-four patients received intramuscular Ara-AMP, 2.5 mg/kg, twice daily, alternated monthly for 6 months with a matching placebo given subcutaneously twice daily. Twenty-seven patients received placebo by intramuscular and subcutaneous injections twice daily for 6 months. Of the 64 patients, 95% had symptomatic and virologic data available and 64% had biopsies at 12 months; at 24 months, 77% had data available and 56% had repeat biopsies. The highest dropout rate was seen in the group receiving Ara-AMP. The group receiving the placebo was less symptomatic (Karnofsky score of 96% compared with 91% in the group receiving Ara-AMP/placebo and 92% in the group receiving Ara-AMP/human leukocyte interferon, p = 0.02) at 12 but not at 24 months. Loss of DNA polymerase, the hepatitis B e antigen, and the serum hepatitis B virus DNA was similar in all three groups. Histologically, erosion of the limiting plate and lobular activity favored Ara-AMP at 12 but not at 24 months and these differences did not result in differences in the histologic diagnosis. These results do not support the use of Ara-AMP and human leukocyte interferon in chronic persistent or chronic active hepatitis B.

Southwestern Internal Medicine Conference: Pneumonias in Adults Due to Mycoplasma, Chlamydiae, and Viruses

Pneumonias in adults due to mycoplasma, chlamydiae, and viruses are a common clinical problem. These microorganisms contribute to the etiologies in 6–35% of all cases of pneumonia and are the sole pathogens in 1–17% of hospitalized cases. Important trends and developments in the field include (1) the emergence of a Chlamydia psittaci strain (TWAR) that is passaged from human to human, causes a mycoplasma-like illness, and that is relatively resistant to erythromycin, (2) the recognition of respiratory syncytial virus as a pathogen in nursing home outbreaks and in immunosuppressed adults, the continuing high lethality of fully developed influenza pneumonia, (4) the efficacy of acyclovir and adenine arabinoside in limiting the complications of varicella-zoster virus infections, and (5) the increasing frequency of pneumonia caused by cytomegalovirus and the severity of this disorder in highly immunosuppressed patients. Developments in the rapid diagnosis and therapy of respiratory syncytial virus infections with an aerosolized antiviral drug in children may pave the way for comparable advances in difficult pneumonias in adult patients.

Natural killer activity in patients with chronic hepatitis treated with OK432, interferon, adenine arabinoside and glycyrrhizin.

Natural killer (NK) activity in the peripheral blood of patients with chronic liver disease was measured using 51Cr labeled K562 cells as target cells. NK activity was elevated but not significantly in patients with chronic hepatitis compared with healthy controls and significantly lower in the patients with hepatocellular carcinoma. The activity decreased in the order of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the level of NK activity in patients with chronic hepatitis did not correlate with the level of alanine aminotransferase (ALT), it tended to be elevated in association with elevation of ALT in patients treated with OK432, interferon-beta, glycyrrhizin or adenine arabinoside. In chronic liver disease, phytohemagglutinin (PHA) skin test showed a positive correlation with NK activity. In all patients who were treated with the immunopotentiator, OK432, and whose HBeAg became negative, NK activity was elevated during the treatment. These results suggest that the NK activity in peripheral blood may be related to hepatocytic injury even if this is not the effector mechanism of the injury.

In vitro interferon producing activity of peripheral mononuclear cells in patients with chronic liver disease.

Interferon-gamma (IFN-gamma) was induced from a human peripheral mononuclear fraction by incubation with a streptococcal preparation stabilized with penicillin G (OK432). This IFN-gamma-producing activity was significantly reduced in patients with chronic hepatitis and hepatocellular carcinoma. In patients with liver cirrhosis it was also reduced but not significantly. Serum hepatitis B virus DNA and skin tests for the purified protein derivative of tuberculin, phytohemagglutinin-P and a polysaccharide fraction prepared from streptococcus pyogenes Su strain were determined to have no significant relation to this IFN-gamma-producing activity. Although the addition of interleukin 2 (IL-2) to the culture medium enhanced the IFN-gamma-producing activity, there was no difference in this enhancement between normal control and chronic hepatitis. Therefore reduction of the IFN-gamma-producing activity observed in chronic hepatitis seems to be caused by a decreased number of IFN-gamma-producing activity cells or hypofunction of these cells or both. Since HBeAg became negative in patients whose IFN-gamma-producing activity was increased by the administration of the immunopotentiator OK432 or IFN-beta, the IFN-producing system in the patients with B type hepatitis may contribute to the elimination of HBV. Adenine arabinoside suppressed IFN-gamma-producing activity both in vivo and in vitro.

Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro

One of the plant extracts, glycyrrhizin (GL) was investigated for its antiviral action on varicella-zoster virus (VZV) in vitro. When human embryonic fibroblast (HEF) cells were treated with GL after inoculation of virus (post-treatment), the average 50%-inhibitory dose (ID 50) for five VZV strains was 0.71 mM, and the selectivity index (ratio of ID 50 for host-cell DNA synthesis to ID 50 for VZV replication) was 30. GL was also effective against VZV replication when HEF cells were treated 24 h before the inoculation (pretreatment). Furthermore, at a concentration of 2.4 mM GL inactivated more than 99% of virus particles within 30 min at 37°C. In combination with other anti-herpes drugs (acyclovir, adenine arabinoside, bromovinyldeoxyuridine, and phosphonoformate) or human native beta-interferon, GL had an additive or slightly synergistic effect on VZV replication. The mechanism of anti-VZV action is still unclear. We postulate that GL inhibits the penetration, uncoating or release of virus particles.

Herpes zoster and its neurological complications.

Ninety-three Chinese patients with cutaneous herpes zoster were seen during a 4-year period. Thoracic zoster occurred most commonly, followed by ophthalmic, cervical and lumbosacral zoster. Neurological complications were present in eleven patients (11.8%), the commonest being Ramsay-Hunt syndrome and segmental limb paresis. The clinical picture, pathogenesis, treatment and outcome of segmental limb paresis, myelitis and delayed contralateral hemiparesis following zoster ophthalmicus are discussed. Nine immunocompromised patients received intravenous adenine arabinoside (vidarabine) or acycloguanosine (acyclovir), and no cutaneous or visceral spread occurred in these patients.

Effects of adenine arabinoside on serum and intrahepatic replicative forms of duck hepatitis B virus in chronic infection.

Adenine arabinoside is an antiviral agent which has been used in a number of clinical studies for the treatment of chronic infections with hepatitis B virus. In order to better understand its effects and mode of action, we treated ducks chronically infected with duck hepatitis B virus with a 2-week course and monitored the effects of the drug on viral replication by studying duck hepatitis B virus DNA in liver and serum using molecular biological techniques. We found the drug to be effective in ducks only at much higher doses than those used in humans. At high doses, adenine arabinoside had a dose-related inhibitory effect on viral replication during treatment, but there was a rapid return toward baseline values soon after the cessation of treatment. The supercoiled form of viral DNA was found to be most resistant to adenine arabinoside therapy, and the drug had a disproportionate inhibitory effect on viral plus (noncoding) strand synthesis. We conclude that adenine arabinoside likely exerts its effect in hepadna virus infections predominantly through inhibition of viral DNA polymerase. On the basis of our current study and previous trials in hepatitis B virus-infected patients, we predict that adenine arabinoside will not efficiently eliminate viral replication in chronic hepadna virus infection, when used as the sole therapeutic modality. Adenine arabinoside may have a role to play as an adjunct to immunomodulation or interferon therapy in chronic hepatitis B virus infection in man.

A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the royal free hospital studies of hepatitis B virus carrier treatment: Identification of factors influencing response rates

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However in this group, lymphoblastoid interferon will produce a response in over 50% of cases. This lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferons are effective in approximately 50% to 60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least two mechanisms by which the chronic carrier state may arise. In 5% to 10% of adults, a relative deficiency of alpha interferon production exists, and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and, along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Side effects in the treatment of herpetic keratitis.

Various side effects due to antiherpetic drugs observed in the last ten years in our department were studied. A total of 132 patients were treated with 5-iodo-2'-deoxyuridine (IDU), 69 with trifluorothymidine (F3T), 58 with acyclovir (ACV) and 33 with adenine arabinoside (ara-A). Patch tests were routinely done when patients exhibited contact dermatitis. Of the patients treated with IDU, 3 (2.3%) showed contact dermatitis, 2 (1.5%) follicular conjunctivitis and 1 (0.8%) punctate keratopathy. Of the patients treated with F3T, 7 (10.1%) exhibited contact dermatitis and 1 (1.4%) follicular conjunctivitis. In the group treated with ACV, 2 (3.4%) patients showed punctate keratopathy. The patients who received ara-A did not show any side effects. We found that F3T caused contact dermatitis more frequently in Japanese people than Europeans. These side effects were resolved by switching to another anti-herpetic drug without the occurrence of cross-allergy. Therefore, switching to another drug is strongly recommended when patients exhibit side effects in the treatment of herpetic keratitis. Other complications were allergy to atropine and to drug preservative.

Controlled trial of thymostimulin and adenine arabinoside monophosphate for type B hepatitis

Controlled trial of thymostimulin and adenine arabinoside monophosphate for type B hepatitis

A randomized controlled trial of adenine arabinoside 5′-phosphate in chronic active hepatitis B: Comparison of the efficacy of the treatment in heterosexual and homosexual patients

A randomized controlled trial of adenine arabinoside 5′-phosphate in chronic active hepatitis B: Comparison of the efficacy of the treatment in heterosexual and homosexual patients

Neurotoxicity due to adenine arabinoside therapy during varicella-zoster virus infections in immunocompromised children.

Neurotoxicity due to adenine arabinoside therapy during varicella-zoster virus infections in immunocompromised children.

In vitro activity of ketoconazole against herpes simplex virus.

The effects of ketoconazole alone and in combination with acyclovir and adenine arabinoside upon the replication of herpes simplex virus types 1 and 2 (HSV-1 and -2) were investigated by using a yield reduction assay. Ketoconazole demonstrated antiviral activity against HSV-1 and -2 and synergistic antiviral activity when it was combined with acyclovir. Combinations of ketoconazole with adenine arabinoside resulted in either interference or indifference. The effects of ketoconazole upon the protein synthesis of HSV-2-infected cells were also determined in an effort to define the mechanism of action for the antiviral activity of ketoconazole. There was no reduction of HSV proteins when compared with acyclovir. These findings suggest that further investigations of the use of ketoconazole for the treatment of HSV infections are warranted.

Acyclovir treatment of disseminated herpes simplex virus type 2 infection in weanling mice: Alteration of mortality and pathogenesis

Intranasal inoculation of weanling mice with herpes simplex virus type 2 (HSV-2) provides an experimental infection that closely resembles disseminated and central nervous system HSV infections of human neonates. Intraperitoneal treatment with acyclovir (ACV) successfully reduced mortality even when therapy was begun as late as 2 days and oral therapy as late as 4 days after viral challenge. Treatment with ACV beginning on day 1 completely inhibited HSV-2 replication in lung, spleen, kidney, olfactory lobe, and cerebrum and decreased viral titers in the pons by 2–3 logs. Comparison of these data with our previous experiments using adenine arabinoside and adenine arabinoside 5′ monophosphate indicates that ACV is more effective in the murine model of neonatal disease and suggests that ACV may also be more effective in treating the disease in humans.

Hepatitis B-associated membranous glomerulonephritis treated with adenine arabinoside monophosphate

Hepatitis B-associated membranous glomerulonephritis treated with adenine arabinoside monophosphate

Effects of adenine arabinoside on cellular immune responses in patients with chronic hepatitis B.

The lymphocyte subsets in the peripheral blood and in liver biopsies from 4 patients with chronic hepatitis B obtained about 2-7 weeks before and after treatment with adenine arabinoside (Ara-A) were studied by a peroxidase-labeled antibody method using monoclonal antibodies against Leu-1, Leu-2a, Leu-3a, Leu-7 and Leu-10 antigens. In the peripheral blood, the percentage of Leu-2a+ (cytotoxic/suppressor) cells was significantly reduced and the ratio of Leu-3a+ (helper/inducer) to Leu-2a+ cells was increased after the treatment with Ara-A. In the liver biopsies, the numbers of Leu-1+ (pan T) and Leu-2a+ cells were significantly decreased after the treatment with Ara-A. As a result, the Leu-3a+/Leu-2a+ ratio was significantly elevated in the liver after the therapy. The majority of lymphocytes distributed at sites of hepatocytic necrosis were positive for Leu-2a. The reduced numbers of Leu-1+ and Leu-2a+ cells after the treatment were mainly due to the decrease of these cells infiltrating to the sites of hepatocytic necrosis. The numbers of other subsets (Leu-3a+, Leu-7+ and Leu-10+) changed without any specific tendency both in the peripheral blood and in the liver biopsies after the treatment. With respect to viral replication, most of the patients showed a decrease of serum DNA polymerase activity or demonstrable intrahepatic HBsAg and HBcAg after the treatment. These data suggest that T cell-mediated cytotoxicity against HBV-infected hepatocytes is diminished after treatment with Ara-A.

Therapy of chronic type B hepatitis with adenine arabinoside and adenine arabinoside monophosphate

Adenine arabinoside (ARA-A) and its monophosphate (ARA-AMP) are potent inhibitors of hepatitis B virus, but they have not been shown to beneficially alter the natural history of chronic type B hepatitis. Analysis of responders to ARA-AMP therapy has shown that responses can be temporary and that truly long-term beneficial responses are rare. Most long-term responses occur in patients with marked elevations in serum aminotransferase activities and severe chronic active hepatitis. This group of patients, however, may also be the most likely to have a spontaneous improvement in chronic hepatitis. Analyses from England suggest that male homosexual patients have a lower response rate to ARA-AMP than heterosexual patients. This difference has not been shown in studies from the United States. The effect of HTLV-III infection on the course and outcome of hepatitis B virus infection and on clinical responses to antiviral therapy needs further evaluation. In view of the side-effects of ARA-AMP and its marginal efficacy, it is unlikely to play a role as a single agent in the therapy of this important chronic liver disease. However, the use of ARA-AMP after a short course of immunosuppressive therapy is an approach to therapy that deserves future investigation in prospective controlled trials.

Combination of prednisolone withdrawal and antiviral agents (adenine arabinoside, interferon) in chronic hepatitis B: A long-term follow-up study

In 1981, we initiated combination therapy of short-term prednisolone withdrawal and adenine arabinoside (ARA-A) or interferon (IF) for the treatment of chronic hepatitis B. Long-term follow up (range 12-48 months) of 79 HBeAg-positive patients showed that at 24 months serum HBeAg was still positive in 77% of controls, 73% of patients receiving ARA-A or IF alone, 38% of patients receiving prednisolone withdrawal alone, and 25% of those receiving the combination therapy. The long-term follow up study revealed that the combination of an immunomodulating therapy and antiviral agents appears more effective in reducing hepatitis B virus replication than single agent treatment.

Inhibitory effects of selected antiviral compounds on newly isolated clinical varicella-zoster virus strains.

Nine anti-herpes compounds, idoxuridine (IDU), bromovinyldeoxyuridine (BVDU), bromovinylarabinofuranosylurasil (BVaraU), carbocyclic bromovinyldeoxyuridine (C-BVDU), chloroethyldeoxyuridine (CEDU), acyclovir (ACV), dihydroxypropoxymethylguanine (DHPG), adenine arabinoside (Ara-A), and phosphonoformate (PFA) were examined for their inhibitory activities against the replication of twenty-six newly isolated clinical strains of varicella-zoster virus (VZV) in human embryonic fibroblast cell cultures. The order of (decreasing) efficacy was: BVaraU greater than BVDU greater than or equal to C-BVDU greater than CEDU greater than or equal to IDU greater than ACV greater than Ara-A greater than DHPG greater than PFA. There was little variation in the susceptibility of the 26 VZV strains to each particular compound, except for one strain which was resistant to IDU.