No abstract

Studies were carried out to determine whether treatment of mice with the synthetic adjuvant muramyl dipeptide afforded any resistance to infection with the obligate intracellular protozoan Toxoplasma gondii. Marked resistance to lethal challenge infection was observed in CBA but not C57BL/6 mice pretreated with muramyl dipeptide. In CBA mice, a single muramyl dipeptide treatment administered 14, 7, or 4 days before Toxoplasma challenge did not afford protection, whereas mice treated at-1 day were highly resistant. Additional studies carried out to investigate the mechanisms underlying the enhanced resistance to Toxoplasma in muramyl dipeptide-treated mice failed to reveal either enhanced cytolytic antibodies to the parasite or evidence that peritoneal macrophages from treated mice were activated as determined in vitro by their microbicidal capacity for Toxoplasma or cytotoxic capacity for tumor target cells.

In two phase I-II trials, 33 patients were given recombinant interferon alpha-2 daily at dosages of 3, 10, 30, 50, or 100 MU/d for up to 4 weeks by intramuscular or intravenous routes. Dose-limiting toxicities, including neutropenia, elevated hepatocellular enzyme levels, fatigue, and disturbed mentation, correlated with differing serum pharmacokinetics of interferon in the two trials. In the intramuscular study, dose-limiting toxicity occurred at all dosages greater than 10 MU/d, at a median of 6 to 9 days of treatment. In the intravenous dose-study, limiting toxicity was seen only at dosages of 100 MU/d, at a median of day 8. Twenty-three patients had metastatic melanoma and 4 had objective partial or complete responses at dosages of 10 to 50 MU/d in the first month. Two patients with complete responses are free of tumor after 2.5 years of follow-up. A fifth patient had delayed complete regression, requiring 1 year to achieve maximum response, but remains free of disease at 26 months since entry to the trial. Interferon had antitumor activity against melanoma by both routes tested, at dosages of 10 to 50 MU/d.

A multicenter phase II study of INTRON, recombinant alpha-2 interferon (Schering Corp, Kenilworth, NJ), in patients with relapsing or refractory myeloma was initiated. Patients received either intravenous therapy for two weeks followed by subcutaneous therapy or subcutaneous dosing from initiation of treatment. Of 38 evaluable patients, 19 were refractory and 19 had relapsed at entry. Twenty-five of 38 had received prior treatment with multiple drugs. Responses were seen among 2/19 refractory patients and 5/19 relapsing patients. Three of seven responders continue to respond for more than one year while receiving maintenance therapy. Most patients experienced improvement in bone pain, and one patient, with a complete response, had healing of bone lesions. Survival curves show a statistically significant improvement in survival for responders v nonresponders. INTRON was well-tolerated with only four patients discontinuing treatment due to adverse effects. Thirty-two percent of patients had hematologic toxicity requiring dose adjustment; however, there was no evidence of cumulative hematologic toxicity. No patients developed serum neutralizing factors to interferon. Additional trials are warranted to study the activity of INTRON in previously untreated patients.

N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide [MDP]) enhanced resistance against Trypanosoma cruzi infection in mice. This effect was evidenced by significant reductions in both parasitemias and mortality rates and increased survival time in MDP-treated animals compared with untreated infected mice. MDP effectively augmented host resistance when administered in any one of the following ways: (i) continuous subcutaneous release from an osmotic minipump for a 7-day period starting 2 days before infection; (ii) as a single dose of 0.5 mg injected intraperitoneally 48 h before infection; or (iii) injected intraperitoneally at 48-h intervals during the first 16 days after infection. CBA/J mice, which exhibit very low, insignificant augmentation of reticuloendothelial activity by MDP but are susceptible to its adjuvant effect, failed to manifest enhancement of resistance to T. cruzi infection when treated with MDP under regimens that cause increased resistance in other mouse strains. These results suggest that MDP enhances resistance against T. cruzi infection by stimulating the activity of the phagocytic cells of the host. Adjuvant effect appears to play either a less significant role or no relevant role, except when MDP is administered repeatedly after infection. Although it has been about 70 years since the discovery of Trypanosoma cruzi, the unicellular parasite which causes Chagas' disease in humans, effective prophylactic and therapeutic treatments for this disease are yet to be developed. To facilitate the development of effective means of control for Chagas' disease, a better understanding of both host-T. cruzi relation