DNA isolated from the hepatitis B antigen form known as the Dane particle was examined by electron microscopy before and after the endogenous Dane particle DNA polymerase reaction. The most frequently occurring form was an untwisted circular double-stranded DNA molecule approximately 1 mum in length. Less frequently occurring forms included circular DNA of approximately unit length and having one or more small single-stranded regions, similar circular molecules with one or more tails either shorter or longer than 1 mum in length, and very small circular molecules with tails. There was no increase in frequency or length of tails after a DNA polymerase reaction, suggesting that tails were not formed during this reaction. The mean length of circular molecules increased by 23% when DNA was spread in formamide compared with aqueous spreading, suggesting that single-stranded regions are present in most of the molecules. The mean length of circular molecules obtained from aqueous spreading increased by 27% after a Dane particle DNA polymerase reaction. This indicates that single-stranded regions were converted to double-stranded DNA during the reaction.
In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/ kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.As antiviral chemotherapy is established as a clinically useful modality, the spectrum of treatable disease expands, and the manifestations of toxicity are more likely to appear. As experience with a drug grows, modification of therapy on the basis of known risk factors, pharmacokinetic predictions, and drug monitoring become feasible. Clinical trials with adenine arabinoside (9-1-D-arabinofuranosyladenine; vidarabine) have been underway since 1974, and drug toxicity has been observed infrequently (10). The toxic reactions have included nausea, vomiting or diarrhea (or both), leukopenia, and thrombocytopenia in patients with cancer receiving very high doses (1 g/m2 per day),
Treatment of chronic ground squirrel hepatitis virus infection with arabinosyladenine monophosphate at 20 mg/kg per day for 3 weeks caused marked decreases in serum virion-associated DNA polymerase concentrations in three of five squirrels. Statistically significant but less dramatic decreases in enzymatic activity were noted in two of six squirrels treated with 50 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine per kg per day. After therapy, DNA polymerase activities rose to pretreatment levels.
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