The bioavailability of oral ketoconazole is reduced in patients with AIDS, largely as a result of gastric hypochlorhydria. Ketoconazole tablets should therefore be given with acid in these patients.

The acyclic guanosine analog (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, (+-)2HM-HBG, is an effective inhibitor of herpes simplex virus and varicella-zoster virus infections in vitro. This report is concerned with the pharmacokinetic evaluation of the drug in rats and monkeys and its antiviral activity in African green monkeys infected with simian varicella virus (SVV), a virus closely related to varicella-zoster virus that is also susceptible to inhibition by (+)2HM-HBG. Elimination half-lives in plasma following intravenous administration to monkeys (100 ,mol/kg of body weight) ranged from 1.8 to 2.2 h, and total body clearance was 9.0 ± 0.4 ml/min per kg (mean ± standard error). After oral administration, levels in plasma were low, with a maximum concentration of the drug of only 3.1 ± 0.8 ,M, a time to reach maximum concentration of drug of 2.7 ± 0.4 h, and an oral bioavailability of 10.6 ± 1.4%. Because of the low oral bioavailability, SW-infected monkeys were treated intramuscularly with (±)2HM-HBG. (±)2HM-HBG at a dosage of 10 mg/kg of body weight per day allowed moderate viremia, whereas a dosage of 30 mg/kg of body weight per day strongly suppressed viremia with minimal numbers of virus plaques fromn blood specimens collected at days 3, 5, and 7 postinfection and complete clearance at day 9 postinfection. Titers of antibody to SVV were also low. Treatment three times daily was somewhat more efficacious than treatment twice daily. Thus, (±)2HM-HBG is an effective inhibitor of SW replication in vivo, despite the fact that levels of (-)2HM-HBG in plasma were low at extended periods of time and below the concentration of drug giving 50% inhibition of plaque formation obtained in vitro.

Replication of hepadnaviruses involves a viral DNA polymerase containing both a DNA-dependent and an RNA dependent activity. This polymerase is a potential target for chemotherapy against hepatitis B. We have used human hepatitis B virus DNA-dependent DNA polymerase from human serum and duck hepatitis B virus DNA-dependent DNA polymerase from duck serum as well as RNA-dependent DNA polymerase activity from duck hepatitis B-infected duck liver. Triphosphates of thymidine analogs have been synthesized and tested for their inhibitory activities against these enzymes with the intention both to explore differences between these enzymes and structural requirements for inhibitors. The results showed that with the inhibitors tested, hepatitis B virus DNA-dependent DNA polymerase was the most sensitive enzyme and the triphosphate of 5-propenyl-2'-deoxyuridine was the most active inhibitor. In addition, the 5'-triphosphate of 5-propenyl-arabinofuranosyluracil also inhibited the hepadnavirus DNA-dependent DNA polymerases, and was a competitive inhibitor with respect to 2'-deoxythymidine triphosphate as showed by kinetic studies with duck hepatitis B virus DNA-dependent DNA polymerase from serum. Pharmacokinetic analysis showed 5-propenyl-2'-deoxyuridine to be well absorbed orally, but rapidly cleared from plasma. The arabinofuranosyl analog was also well absorbed but cleared less rapidly. Hence, these results indicate the potential of 5-propenyl-2'-deoxyuridine and 5-propenyl-arabinofuransyluracil for chemotherapy of hepatitis B.

An iron carbohydrate complex, iron‐poly (sorbitol‐gluconic acid), Ferastral®, was labelled with 59Fe, and its distribution in rats was studied. The animals were intramuscularly treated with a dose of 10 mg of iron/kg. Three groups of animals were used: group A: non‐anaemic and group B: anaemic rats, both kept on iron‐deficient diet, and group C: non‐anaemic rats kept on iron‐supplemented diet. Urinary and faecal excretion, distribution in the body and incorporation in blood of the 59Fe was followed up to 28 days. The total excretion after that time was 15%. There was a rapid initial phase followed by a slower continuous one. After 28 days group A had 25, group B 13 and group C 40% of the given dose remaining at the site of injection. The corresponding values in liver after 28 days were 7, 4 and 17% of the given dose, respectively. In blood a continuous increase was observed. At 28 days after administration 26, 43 and 17% of the given dose had been incorporated in the red blood corpuscles of the respective groups. These results show that the iron complex is absorbed from the site of injection and is utilized for haemoglobin synthesis. They also show that the disposition of the complex is influenced by the iron content of the diet.

The effects of the dopamine D2 selective receptor antagonist, remoxipride, on dopamine turnover in the rat brain were studied after acute and repeated administration and compared with the effects of haloperidol. Acute administration of remoxipride produced a dose-dependent increase of the concentrations of DOPAC and HVA in both striatum and olfactory tubercle + nucleus accumbens. The maximal effect of both acute remoxipride and haloperidol on dopamine turnover was attained approximately 2 hours after a single intraperitoneal administration, whereas a biphasic response was seen after oral remoxipride. Tolerance to the effects of repeated haloperidol (20 mumol/kg orally) treatment on dopamine turnover was observed as soon as after 3 days, whereas no such tolerance could be found during the first 15 days of repeated treatment with remoxipride (20 mumol/kg orally). A dose-related tolerance to the effects of remoxipride was, however, seen at higher dosages (40, 150 and 600 mumol/kg orally) and after a longer period (6 months) of treatment.