Nitric oxide synthase inhibitors--a mechanism-based treatment of septic shock.
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Clinical Trials, Phase III as Topic↗
Biomedical subjects
R Kilbourn
Publications and source records attributed to R Kilbourn.
A phase I trial of intermittent high-dose alpha-interferon and dexamethasone in metastatic renal cell carcinoma.
BACKGROUND: Evidence exists that the toxic of alpha-interferon can be ameliorated by co-administration of dexamethasone without compromise of therapeutic efficacy. We therefore conducted a phase I trial to determine the maximum tolerated dose of intermittent interferon when combined with oral dexamethasone. PATIENTS AND METHODS: Thirty patients with metastatic renal cell carcinoma were enrolled. The starting dose of interferon was 20 million IU/m2/day given as a subcutaneous injection days 1 to 4 of each 14 day cycle. Dose levels were escalated at increments of 5 million IU/m2. Dexamethasone 4 mg was administered orally every 6 hours during administration of high-dose interferon. Low-dose maintenance interferon, 3 million IU/m2/day, was administered without dose escalation on days 5 to 14 of each cycle. RESULTS: The maximum tolerated dose of intermittent high-dose interferon was 40 million IU/m2/day. The dose limiting toxicity was fatigue. EEG abnormalities developed in five patients and neuropsychiatric parameters deteriorated significantly in seventeen. CONCLUSIONS: We conclude that co-administration of dexamethasone improves the tolerance of intermittent high-dose interferon. The results of this trial may be useful in designing high-dose interferon regimens for renal cell carcinoma and other interferon-sensitive diseases.
Administration, Oral↗
Paclitaxel, cisplatin and methotrexate combination chemotherapy is active in the treatment of refractory urothelial malignancies.
PURPOSE: We investigated the activity of combination chemotherapy consisting of paclitaxel, cisplatin and methotrexate in patients with advanced urothelial cancers. MATERIALS AND METHODS: A total of 25 consecutive patients with metastatic refractory urothelial malignancies was treated with a combination of 200 mg./m.2 paclitaxel, 30 mg./m.2 methotrexate and 70 mg./m.2 cisplatin in a pilot study. RESULTS: There were no complete responses. Of 25 patients 10 (40%), including 3 of 7 with liver metastases, had a partial response. Hematological and nonhematological toxicity was tolerable. CONCLUSIONS: The combination chemotherapeutic regimen of paclitaxel, cisplatin and methotrexate is active in patients with advanced urothelial cancer and warrants further study.
Adult↗
Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer.
PURPOSE: A phase II clinical trial was performed to assess the antitumor activity and toxicity of ketoconazole in combination with doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) in patients with androgen-independent prostate cancer (AI PCa). PATIENTS AND METHODS: Thirty-nine consecutive patients whose disease progressed following castration were treated with oral ketoconazole (1,200 mg) daily and Adriamycin (20 mg/m2 in a 24-hour infusion) once weekly. Antitumor activity was assessed by the level of prostatic-specific antigen (PSA) decline. RESULTS: PSA levels decreased > or = 50% from baseline in 21 (55%; 95% confidence interval, 38% to 71%) of 38 assessable patients. We observed partial responses (PRs) in seven (58%) of 12 patients with measurable soft tissue disease (in the lung, lymph nodes, and liver). Two patients with history of atherosclerotic heart disease had a sudden cardiac death. Serious toxic reactions included grade III to V stomatitis and grade III to IV acral erythema in 11 patients (29%), and grade III to IV anal and urethral mucositis in five patients (13%). Grade III to IV neutropenia occurred in 11 patients (29%). Seventeen patients (45%) required hospitalization for complications. Fifteen patients (39%) developed hypokalemia, and 24 patients (63%) developed clinical adrenal insufficiency. CONCLUSION: The combination of ketoconazole and Adriamycin has a 55% PSA response rate in patients with AI PCa and is worthy of additional study. This treatment results in frequent adrenal insufficiency. Therefore, future studies should incorporate routine corticosteroid replacement. The cardiac complications caused by this combination should be studied further before it is widely used.
Administration, Oral↗
Phase II study of interferon-alpha and chemotherapy (5-fluorouracil and mitomycin C) in metastatic renal cell cancer.
A total of 49 patients with metastatic renal cell cancer underwent recombinant interferon-alpha 2a therapy combined with chemotherapy. Before therapy the patients without nephrectomy underwent angioinfarction of the primary renal tumor. Combined treatment included interferon at 5 x 10(6) units per m.2 intramuscularly daily, 5-fluorouracil at 750 mg./m.2 daily by continuous infusion intravenously (days 1 to 5) and mitomycin C at 5 mg./m.2 per day intravenously (days 1 and 2) repeated every 28 days. Of the patients 17 (35%, 95% confidence interval 22 to 49%) responded, and all 17 had partial remission that lasted a median of 7.1 months (range 4.2 to 20.9+ months). Response rate differed by metastatic sites: lung 46% (18 of 39 patients), lymph nodes 46% (6 of 13), mediastinum 20% (2 of 10) and liver 18% (2 of 11). Grade 3 to 4 toxicity (World Health Organization) included neutropenia (79% of the patients), thrombocytopenia (45%), stomatitis (34%), diarrhea (8%), nausea (18%) and central nervous system disorders (18%). The overall 35% response rate suggests that the combination of interferon-alpha 2a, 5-fluorouracil and mitomycin C is synergistic. Future studies are needed to confirm this finding and to assess the role of mitomycin C.
Antineoplastic Combined Chemotherapy Protocols↗
Association of germ cell tumors and Hodgkin's disease.
Two patients presented with synchronous Hodgkin's disease and testicular germ cell neoplasms. Both patients are in complete remission following treatment with multidrug chemotherapy and radiation therapy. Despite epidemiologic similarities between Hodgkin's disease and testicular cancer, only 13 cases of their association in the same patient have been reported in the literature, and in all those instances the tumors occurred metachronously. However, the very rare occurrence of synchronous presentation suggests a possible common pathogenetic factor in our 2 patients.
Adult↗
Circadian infusion of floxuridine in patients with metastatic renal cell carcinoma.
A total of 42 patients with metastatic renal cell carcinoma received floxuridine infusion for 14 days at monthly intervals. The drug was delivered via an external programmable pump on a time-modified or circadian schedule; the highest dose of 68% was given between 3 and 9 p.m. Of the 42 patients 25 (60%) had undergone prior nephrectomy. Of the 40 evaluable patients 4 (10%, 95% confidential interval 3 to 24%) achieved a partial response: 3 of the 4 had undergone prior nephrectomy, while 1 had undergone renal angioinfarction. Another 4 patients (10%) had responses at metastatic sites but no response in the primary kidney tumor. The median duration of response for these 2 groups of patients was 65 and 27 weeks, respectively, and the most responsive site was the lungs. The treatment was generally well tolerated and could be administered on an outpatient basis. Our study confirms the limited but definite activity of floxuridine infused on a circadian schedule in patients with metastatic renal cell carcinoma. We observed responses in metastasis equally in patients with or without prior nephrectomy.
Adult↗
Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract.
A total of 14 men with inoperable or metastatic squamous cell carcinoma of the genital tract received methotrexate, bleomycin and cisplatin. In 12 patients the penis was the primary site. Metastases were usually advanced, and 4 patients had ulceration and infection in the inguinal region or perineum secondary to tumor. Two patients had tumor-related hypercalcemia. Of the patients 11 received the 3 drugs intravenously, whereas 3 received methotrexate intravenously, and bleomycin and cisplatin intra-arterially for large unilateral nodal metastasis. Of the 14 patients 10 responded, for a response rate of 72% (95% confidence interval 57 to 92%) and the median response duration was 6 months (range 4 to 24 months). Two patients (14%) who were treated intravenously achieved complete responses lasting 6 and 24+ months. Responses occurred in 3 patients with infection and in both patients with hypercalcemia. The combination of methotrexate, bleomycin and cisplatin has significant activity in patients with advanced squamous cell carcinoma of the male genital tract. This chemotherapy regimen should be evaluated in earlier disease in the adjuvant or neoadjuvant setting.
Antineoplastic Combined Chemotherapy Protocols↗
Perianal ulcer in disseminated histoplasmosis.
A 65-year-old man with stage I testicular seminoma, treated with surgery and radiation, had fever of unknown origin, adrenal insufficiency, and an isolated perianal ulcer. Tissue diagnosis of disseminated histoplasmosis was established by biopsy of the perianal ulcer, an unusual cutaneous manifestation of the disease. Treatment with amphotericin B resulted in rapid clinical improvement and complete healing of the perianal ulcer.
Aged↗
Protease inhibitors block the macrophage-mediated inhibition of tumor cell mitochondrial respiration.
The antitumor activity of activated macrophages toward tumor cells, in vitro, appears to involve the production of toxic nitrogen intermediates. These intermediates, particularly nitric oxide, have been shown to cause the inhibition of cell division and to decrease cellular respiration by inhibiting electron transport. We studied the effects of proteolytic inhibitors on macrophage-mediated inhibition of L1210 tumor cell respiration and DNA synthesis, and found that chloromethyl ketone derivatives, which covalently modify serine proteases, can block macrophage cytotoxicity. Furthermore, these inhibitors decrease nitrite production by activated macrophages suggesting that the mechanism of action involves the inhibition of nitric oxide production.
Animals↗
Mononuclear phagocyte system cytotoxins: a review.
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Animals↗
Comparative functional analysis of lymphocytes and monocytes from plateletapheresis.
Large numbers (2.9 +/- 1.2 X 10(9)) of mononuclear cells can be obtained from incidental samples collected during routine plateletapheresis. We conducted studies comparing characteristics and functions of mononuclear cells derived from venous blood samples and from routine plateletapheresis in the same normal donors. Cell viability was similar in both samples (96 +/- 1% plateletapheresis vs 97 +/- 2% venous blood). Higher concentration of monocytes were observed in the plateletapheresis samples (32.3 +/- 6%) than in the venous blood (14.3 +/- 4%). The procedure of plateletapheresis does not seem to alter lymphocyte or monocyte function. Thus, the functional integrity of these cell populations was demonstrated in terms of natural killer cell activity, blastogenic response to mitogens, local graft-versus-host reactions, monocyte-mediated antibody-dependent cellular cytotoxicity against human red cells, monocyte-mediated tumor cell cytotoxicity, latex phagocytosis, and monocyte-dependent lymphocyte blastogenesis. We conclude that monocytes and lymphocytes obtained during routine plateletapheresis are functionally intact.
Antibody-Dependent Cell Cytotoxicity↗
5-Fluorouracil and interferon-alpha in chemotherapy refractory bladder carcinoma: an effective regimen.
Seventy-seven patients with metastatic transitional cell carcinoma of the bladder who were unable to receive primary Cisplatin-based therapy or failed primary chemotherapy received one of three sequential 5-Fluorouracil-based salvage regimens: a) 5-Fluorouracil (1000 mg/m2 B.S.A. x 5 days) and Mitomycin-C (14 mg/m2 B.S.A. 6 week intervals), b) 5-Fluorouracil (750 mg/m2 B.S.A. x 5 days) and a-Interferon (5 miu/m2 B.S.A. daily x 5 then 3 times a week (TIW), c) 5-Fluorouracil (500 mg/m2 B.S.A. x 5 days), a-Interferon (5 miu/m2 B.S.A. x 5 days then TIW) and 13-Cis Retinoic Acid in escalating doses daily. Only 1 (6%) of the patients with regimen A responded, whereas 9 (30%) of the patients with regimen B and 8 (27%) in regimen C responded. Although all responses were partial remissions, responses were seen in patients with advanced and initially refractory transitional cell carcinomas. This data reveals that a-Interferon and 5-Fluorouracil is an effective combination in the treatment of metastatic transitional cell carcinoma and worthy of further study.
Adult↗