A phase I trial of recombinant human interferon-γ in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS)

Abstract

A Phase I study of recombinant interferon-gamma (rIFN-gamma) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-gamma. rIFN-gamma was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2-4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7-12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1-1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-gamma is given at doses at or near this MTD.

Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma

“…Additional concerns were that there is some laboratory evidence that IFN-␥ may enhance replication of KSHV in peripheral blood mononuclear cells 60,61 and that no anti-KS activity had been seen in 2 small trials of partial purified IFN-␥ conducted before the development of effective anti-HIV therapy. 62,63 In spite of these concerns, IL-12 appeared to be active in a high percentage of the patients with KS. As noted previously, several factors make it unlikely that these responses were simply from the administration of HAART.…”

Migraine and Function of the Immune System: A Meta-Analysis of Clinical Literature Published Between 1966 and 1999

“…Cytokines not only mediate the communication between the different cells of the immune system but also between the immune system and the brain. Cytokines have been shown to induce headache (86–92), but few studies examined cytokine levels in migraine patients. Migraine patients without aura showed higher serum levels of TNF‐α (93) and IL‐1β (94) interictally (the latter only in three patients) but during the attack the plasma levels of IL‐1α, IL‐1β and TNF‐α were not increased.…”

A Mathematical Model for the Treatment of Aids-Related Kaposi's Sarcoma

“…Several clinical trials have been conducted in HIV-KS patients to determine the feasibility and pharmacokinetics of IL-12, 11 IL-2 12 and IFN-γ. 13 A number of studies support the prolonged efficacy of HAART on AIDS-KS, even in the absence of specific KS therapy. 14-16 Nevertheless, a study by Bihl et al 17 has suggested that combination therapy (HAART plus chemotherapy) reduces the HHV-8 load much more efficiently than HAART alone.…”