A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

The effects of a novel histamine-3 receptor inverse agonist on essential tremor in comparison to stable levels of alcohol.

Essential tremor (ET) is a common movement disorder. Animal studies show that histaminergic modulation may affect the pathological processes involved in the generation of ET. Histamine-3 receptor inverse agonists (H3RIA) have demonstrated attenuating effects on ET in the harmaline rat model. In this double-blind, three-way cross-over, single-dose, double-dummy study the effects of 25 mg of a novel H3RIA (MK-0249) and a stable alcohol level (0.6 g L(-1)) were compared with placebo, in 18 patients with ET. Tremor was evaluated using laboratory tremorography, portable tremorography and a clinical rating scale. The Leeds Sleep Evaluation Questionnaire (LSEQ) and a choice reaction time (CRT) test were performed to evaluate potential effects on sleep and attention, respectively. A steady state of alcohol significantly diminished tremor as assessed by laboratory tremorography, portable tremorography and clinical ratings compared with placebo. A high single MK-0249 dose was not effective in reducing tremor, but caused significant effects on the LSEQ and the CRT test. These results suggest that treatment with a single dose of MK-0249 does not improve tremor in alcohol-responsive patients with ET, whereas stable levels of alcohol as a positive control reproduced the commonly reported tremor-diminishing effects of alcohol.

Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort.

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

Effect of different durations of ketoconazole dosing on the single-dose pharmacokinetics of midazolam: shortening the paradigm.

Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compound's sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole+midazolamday 5/ketoconazole+midazolamday 1 and ketoconazole+midazolamday 5/ketoconazole+midazolamday 2) for midazolam AUC0-infinity were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short-term drug-drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments.

Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A.

BACKGROUND: Mild, transient alanine aminotransferase (ALT) elevations were seen in Phase I studies of caspofungin and cyclosporin A (CsA). METHODS: We conducted a retrospective chart review at four sites to characterize the hepatic safety in patients receiving > or =1 day of both drugs over a 20-month period. Investigators assessed reasons for discontinuing concomitant therapy and the presence/etiology of any hepatotoxicity. RESULTS: Forty patients receiving concomitant therapy for 1-290 days (median 17.5 days) were identified. Although common, liver enzyme abnormalities were frequently attributed to other comorbidities or medications. ALT and/or aspartate aminotransferase (AST) elevations occurred in 14 patients (35%). Five had AST elevations at least possibly related to caspofungin/CsA, but none were >3.6 times the normal upper limit. No ALT elevations were related to caspofungin/CsA. Two of 4 patients had discontinuation of therapy because of hepatotoxicity possibly related to caspofungin/CsA. No serious adverse events occurred because of caspofungin. CONCLUSIONS: These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin/CsA.

Safety and tolerability of caspofungin acetate in the treatment of fungal infections.

Caspofungin acetate is the first member of the novel echinocandin class of antifungal drugs to be marketed in the United States. It has recently been approved for use in patients with invasive aspergillosis who are refractory to or intolerant of conventional therapy. Accordingly, its safety profile is particularly important to review. The safety and tolerability of caspofungin have been examined in 623 persons, including 295 patients who received >/= 50 mg/day for at least one week in clinical studies. In the 263 patients, given caspofungin in randomized double-blind active-control trials to date, there have been no serious clinical or laboratory drug-related adverse events; caspofungin was discontinued in only 2% of these patients because of drug-related adverse experiences. Caspofungin may have potentially important drug interactions with cyclosporine and tacrolimus.

Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine.

OBJECTIVES: To compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. DESIGN: Two multicenter, open-label, randomized 24-week studies. METHODS: Adults HIV-1 infection, HIV-1 RNA greater than 10000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. RESULTS: In Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). CONCLUSION: Three-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug-drug interactions.

3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine.

BACKGROUND: Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known. OBJECTIVE: To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial. DESIGN: Open-label extension of a randomized, double-blind study. SETTING: Four clinical research units. PATIENTS: 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20,000 copies/mL and CD4 counts ranging from 50 to 400 cells/mm3. INTERVENTION: Indinavir, zidovudine, and lamivudine. MEASUREMENTS: Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses. RESULTS: After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3). Nephrolithiasis occurred in 12 of 33 patients (36%). CONCLUSION: A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.

Modeling the long-term outcomes and costs of HIV antiretroviral therapy using HIV RNA levels: application to a clinical trial.

A model was developed to gain insight into the potential clinical and economic impact of antiretroviral therapy for HIV-infected patients. Observed HIV RNA levels and CD4 cell counts are used in the model to estimate the probability that an individual progresses from asymptomatic infection to the first AIDS-defining illness and death and to estimate the total net cost of care and long-term cost-effectiveness of antiretroviral therapy. The model was applied to patients in a clinical trial (Merck protocol 035) that compared the surrogate marker response to triple therapy with indinavir (IDV; 800 mg every 8 hr) plus zidovudine (ZDV; 200 mg every 8 hr) plus lamivudine (3TC; 150 mg twice a day) to double therapy with ZDV+3TC. The model projected that for an individual without AIDS who received triple therapy the progression to AIDS and death would be delayed more than for a patient who received double therapy with ZDV+3TC if no other treatment options were offered. Because of this delay in disease progression, the total discounted cost over the initial 5-year period was projected to be $5100 lower for patients who received triple therapy compared with double therapy if suppression with triple therapy lasts up to 3 years. If suppression with triple therapy lasts up to 5 years, costs were projected to be higher with the triple combination, but 81% of the cost is offset by lower disease costs as a result of fewer patients progressing to AIDS. Over 20 years, total discounted cost was projected to be higher for the triple-therapy regimen primarily because of a longer estimated survival time. At 20 years, the incremental cost per life-year gained by adding IDV to a ZDV+3TC regimen was estimated at $13,229, which is well within the range of other widely accepted medical interventions.

Factors influencing the emergence of resistance to indinavir: role of virologic, immunologic, and pharmacologic variables.

A major problem with the use of human immunodeficiency virus type 1 (HIV-1) protease inhibitors as monotherapy has been an unacceptably high rate of emergence of resistance. To examine possible influences on the time to emergence of resistance, 24-week data were examined from five studies in which indinavir had been administered as monotherapy or as a component of combination therapy. Monotherapy data indicated a correlation between the level of HIV-1 RNA achieved and the risk of emergence of resistance: the lower the level, the lower the risk. When combination and monotherapy regimens were compared, the group receiving indinavir + lamivudine + zidovudine had a significantly lower risk of resistance, even after adjusting for the minimum HIV-1 RNA level achieved. The findings indicate that if at all possible, HIV-1-infected patients should receive combination chemotherapy to minimize the emergence of resistance to the protease inhibitor portion of the regimen. The goal of therapy should be to decrease the HIV-1 RNA load to a less-than-detectable level.

Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up.

CONTEXT: Combination antiretroviral therapy can markedly suppress human immunodeficiency virus (HIV) replication but the duration of HIV suppression varies among patients. OBJECTIVE: To compare the antiretroviral effect of a 3-drug regimen started simultaneously or sequentially in patients with HIV infection. DESIGN: A multicenter, randomized, double-blind study, modified after at least 24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up through 100 weeks. SETTING: Four clinical research units PATIENTS: Ninety-seven patients with HIV infection who had taken zidovudine for at least 6 months with serum HIV RNA level of at least 20000 copies/mL and CD4 cell count of 0.05 to 0.40 x 10(9)/L. INTERVENTIONS: Patients were initially randomized to receive 1 of 3 antiretroviral regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks of blinded therapy, all patients received open-label 3-drug therapy. MAIN OUTCOME MEASURES: Antiretroviral activity was assessed by changes in HIV RNA level and CD4 cell count from baseline. Data through 100 weeks were summarized. RESULTS: Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL and increased CD4 cell count to a median of 0.209 x 10(9)/L above baseline at 100 weeks. When these 3 drugs were initiated sequentially, only 30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine group and 13 of 29 in the indinavir group, respectively) had a sustained reduction in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased to 0.101 to 0.163 x 10(9)/L above baseline at 100 weeks. CONCLUSIONS: A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years. Sequential initiation of the same 3 drugs is much less effective.

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team.

BACKGROUND: The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.

Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy.

BACKGROUND: The new protease inhibitors are potent inhibitors of the human immunodeficiency virus (HIV), and in combination with other antiretroviral drugs they may be able to cause profound and sustained suppression of HIV replication. METHODS: In this double-blind study, 97 HIV-infected patients who had received zidovudine treatment for at least 6 months and had 50 to 400 CD4 cells per cubic millimeter and at least 20,000 copies of HIV RNA per milliliter were randomly assigned to one of three treatments for up to 52 weeks: 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours combined with 150 mg of lamivudine twice daily; or all three drugs. The patients were followed to monitor the occurrence of adverse events and changes in viral load and CD4 cell counts. RESULTS: The decrease in HIV RNA over the first 24 weeks was greater in the three-drug group than in the other groups (P<0.001 for each comparison). RNA levels decreased to less than 500 copies per milliliter at week 24 in 28 of 31 patients in the three-drug group (90 percent), 12 of 28 patients in the indinavir group (43 percent), and none of 30 patients in the zidovudine-lamivudine group. The increase in CD4 cell counts over the first 24 weeks was greater in the two groups receiving indinavir than in the zidovudine-lamivudine group (P< or =0.01 for each comparison). The changes in the viral load and the CD4 cell count persisted for up to 52 weeks. All the regimens were generally well tolerated. CONCLUSIONS: In most HIV-infected patients with prior antiretroviral therapy, the combination of indinavir, zidovudine, and lamivudine reduces levels of HIV RNA to less than 500 copies per milliliter for as long as one year.

Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor.

Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.

Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases.

Ivermectin is highly effective against animal intestinal nematodes and is used in the treatment of onchocerciasis in humans. A study was undertaken to compare the efficacy of the drug with that of albendazole in the treatment of uncomplicated strongyloidiasis. Sixty patients with confirmed Strongyloides stercoralis infection were enrolled in an open randomized study and given either albendazole, 400 mg/d for 3 d or ivermectin, 150-200 micrograms/kg in a single dose. Efficacy and tolerance were evaluated on days 7, 30 and 90. Each visit included a parasitological examination of 3 stool specimens, using saline and Kato smears and formalin-ether and Baermann concentrations. Fifty-three patients were eligible for evaluation. Parasitological cure was obtained in 24 of the 29 patients treated with ivermectin (83%) and in 9 of the 24 patients who were given albendazole (38%); ivermectin was significantly more effective than albendazole (P < 0.01). Clinical and biological adverse reactions were negligible in both treatment groups. The 20 patients who failed therapy were given a second treatment course with 150-200 micrograms/kg of ivermectin in a single dose or on 2 consecutive days. Sixteen patients were cured and the other 4 had only incomplete follow-up. Ivermectin therefore constitutes an acceptable therapeutic alternative for uncomplicated strongyloidiasis.

Tolerance and efficacy of single high-dose ivermectin for the treatment of loiasis.

A study was carried out in southeastern Gabon to evaluate the tolerance and efficacy of single high doses of ivermectin in 31 Loa loa-infected subjects with low-to-moderate parasitemia (7-7,700 microfilaria/ml). The first group of 16 subjects received 300 micrograms/kg of ivermectin and, seven days later, a second group of 15 received 400 micrograms/kg. Complete clinical and biological monitoring was carried out during the first 10 days post-treatment and again after one and three months. All subjects continued with their usual activities during the study. The clinical tolerance of treatment was very good, and except in one case, only mild adverse reactions were observed, with pruritus being the most common symptom. There were no significant changes in blood or urine function test results or in hematologic results, except for a pronounced eosinophil reaction. The 400 micrograms/kg dose of ivermectin equaled or surpassed in tolerance that of 300 micrograms/kg dose. After treatment, L. loa microfilaremia decreased rapidly to less than 9% of the pretreatment value by day 10. This decrease was enhanced with the 400 micrograms/kg dose, although differences between the two groups diminished slightly with time. At 100 days post-treatment, the microfilaremia was still at less than 10% of the initial values in the two groups, which may indicate an effect of ivermectin on the adult worms.

Macrophage colony-stimulating factor production by murine and human keratinocytes. Enhancement by bacterial lipopolysaccharide.

CSF have a broad range of effects on differentiated cells outside the bone marrow. Site-specific elaboration of these factors may influence local immune reactions. Keratinocytes have been demonstrated to produce a number of immunoactive cytokines, including factors capable of modifying macrophage function. We have previously identified at least two products of keratinocytes that induce DNA synthesis by elicited peritoneal macrophages; one factor has been identified as granulocyte-macrophage CSF. In the present study, the second keratinocyte product has been characterized and identified as macrophage-CSF (M-CSF). Conditioned media from cultures of normal human keratinocytes and the transformed murine keratinocyte cell line PAM 212 induce formation of macrophage colonies in soft agar as well as dose-dependent proliferation of the M-CSF-dependent cell line BAC1.2F5. The bioactivity in both assays is blocked by neutralizing anti-M-CSF antibody. Western blot analysis of cell lysates from both PAM 212 and normal human keratinocytes demonstrates multiple molecular mass forms of M-CSF (45 to 98 kDa). Northern blot analysis (PAM 212 cells) and in situ hybridization (normal keratinocytes) demonstrate expression of M-CSF mRNA. Stimulation of keratinocytes with LPS increases M-CSF synthesis as measured both by bioactivity and level of mRNA expression. Thus, both murine and human keratinocytes produce M-CSF in vitro. Furthermore, production of keratinocyte-derived M-CSF is increased by bacterial LPS. CSF production by keratinocytes may play an important role in regulating the cutaneous immune response.

Septic arthritis and osteomyelitis from a cat bite.

A 39-year-old man with no prior history of underlying arthritis developed osteomyelitis and septic arthritis in his hand following a cat bite. This case illustrates the virulence of Pasteurella multocida infections associated with animal bites, particularly those of cats, whose teeth can inoculate bone directly. The onset of cellulitis caused by P. multocida infections is often rapid, and the drug of choice for such infections remains penicillin. Appropriate antibiotic therapy, however, does not always prevent complications such as those seen in this patient.

Keratinocyte derived T-cell growth factor (KTGF) is identical to granulocyte macrophage colony stimulating factor (GM-CSF).

Keratinocyte derived T-cell growth factor was initially described as a product of cultured neonatal keratinocytes and keratinocyte cell lines that induced the proliferation of HT-2 cells, a murine T-cell line that responds to IL-2 and IL-4 by incorporating 3H-Thymidine. Subsequently, KTGF has been purified to high specific activity and found to be distinct from IL-2 and IL-4 by a variety of biochemical, immunologic, and immunochemical criteria. Because it was found that certain HT-2 cell lines also proliferated in response to GM-CSF, the present study asked whether KTGF was related to GM-CSF. In this study, we demonstrate that antibodies to recombinant murine GM-CSF completely neutralize the capacity of KTGF to induce HT-2 proliferation without interfering with IL-2 or IL-4 induced HT-2 proliferation. Furthermore, poly-A+ RNA homologous to murine GM-CSF cDNA as judged by S1 nuclease analysis was detected in Pam 212 cells, and protein serologically homologous to GM-CSF was found in Pam 212 conditioned medium. We conclude that KTGF is identical to GM-CSF. The T-cell activating properties of GM-CSF require further exploration.

Granulocyte-macrophage colony-stimulating factor enhances selective effector functions of tissue-derived macrophages.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by a variety of cells at sites of exposure to antigens. GM-CSF has a stimulatory effect on a number of neutrophil functions, but the effect on macrophage function is less clear. We investigated the effect of purified murine recombinant GM-CSF on murine peritoneal macrophage oxidative metabolism, Fc-dependent phagocytosis, anti-Toxoplasma activity, and expression of class II major histocompatibility antigen (Iad). GM-CSF significantly increased phorbol myristate acetate- and zymosan-elicited H2O2 release by resident and thioglycollate-elicited macrophages after 48 hours in vitro. The effect of recombinant GM-CSF was blocked by polyclonal anti-GM-CSF antibody and was not altered by lipopolysaccharide (0.01 to 1.0 microgram/mL). GM-CSF also stimulated Fc-dependent phagocytosis by peritoneal macrophages, although the stimulation of resident macrophages (1.4-fold) was less dramatic than that of thioglycollate-elicited cells (2.1-fold). GM-CSF (at doses up to 100 U/mL) had no effect on macrophage anti-Toxoplasma activity or on expression of Iad. In addition to stimulating macrophage growth, GM-CSF selectively promotes the functional capacity of tissue-derived macrophages.