R. Wayne Rundles

Potentiation by inhibition of drug degradation : 6-substituted purines and xanthine oxidase

Abstract The administration of the xanthine oxidase inhibitor. 4-hydroxypyrazolo (3, 4-d)pyrimidine, concurrently with 6-mercaptopurine, results in a marked decrease in the metabolic oxidation of the latter to 6-thiouric acid in both the mouse and man. The inhibition of metabolic degradation by this means results in several-fold potentiations of 6-mercaptopurine, 6-methylthiopurine, 6-propylthiopurine, and 6-chloropurine in trials against adenocarcinoma 755 and of 6-mercaptopurine and 6-chloropurine as inhibitors of the immune response of mice to sheep erythrocytes.

Metabolic studies of allopurinol, an inhibitor of xanthine oxidase

Abstract The metabolic disposition of allopurinol [4-hydroxypyrazolo(3,4-d)-pyrimidine) was determined in mice, dogs, and human subjects. The drug is a substrate for, as well as an inhibitor of, xanthine oxidase and is converted in all species to the corresponding xanthine analog, alloxanthine, which is its major metabolite. Neither is bound to human plasma proteins, and both are distributed more or less equally in total body water in the mouse. Both analogs are cleared rapidly by the mouse and dog kidney. In the human subject allopurinol is cleared rapidly, but alloxanthine resembles uric acid in having a slow clearance responsive to probenecid. The accumulation of alloxanthine during prolonged therapy with allopurinol may contribute significantly to the therapeutic effects of the drug in the control of hyperuricemias.

Allopurinol in the Treatment of Gout

Excerpt Allopurinol, 4-hydroxypyrazolo (3,4-d) pyrimidine (4-HPP),*recently introduced as a new type of agent useful in the treatment of gout, developed from studies undertaken to increase the ther...

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the commonest type of leukemia seen in Western countries. It affects an older group of individuals than most other varieties of leukemia, and men more often than women, in a ratio of 2:1. The incidence of CLL is significantly increased in some families. In most instances, CLL is due to the overgrowth or accumulation of immunoglobulin producing B lymphocytes. Hypogammaglobulinemia is a common feature, and anomalous immunoglobulin components occur in 3 to 5% of patients. The early symptoms and signs of CLL include fatigue, reduced exercise tolerance, enlarged lymph nodes, and splenomegaly. Fever, weight loss, and impairment of bone marrow function, with anemia, bleeding and susceptibility to infection are characteristic of severe or advanced disease. In the great majority of patients, the disease can be controlled for 6 to 10 or more years with simple regimens using chlorambucil or cyclophosphamide, often in combination with prednisone. Radiotherapy and splenectomy are useful in some instances. The terminal phase of the disease is characterized by exacerbation or increasing severity of the leukemia and the development of opportunistic infections associated with immunodeficiency.

Serum proteins in leukemia

T HE electrophoretic composition of the serum proteins in patients with Hodgkin’s disease and maiignant lymphoma at different stages of disease was reported in a previous paper.’ Abnormalities such as hypoalbuminemia or increased concentrations of alpha and/or gamma globulin were found in the sera of the great majority of those with active disease. With the possibIe exception of hypergammaglobulinemia, however, the changes were apparently related to systemic reactions rather than to the primary disorder. The present report is a summary of similar studies in patients with acute and chronic leukemia. The leukemias differ, of course, from the lymphoma group in that the cellular proliferation is anatomically more widespread, tissues concerned in protein synthesis are involved, and systemic reactions tend to be less severe or even absent. Significant differences were found in the serum protein composition in the two groups of hemopoietic malignancies.

Effects of Xanthine Oxidase Inhibitor on Clinical Manifestations and Purine Metabolism in Gout.

Excerpt A series of pyrazolopyrimidines synthesized some years ago as potential purine antagonists were found to be active in suppressing the growth of bacteria, fungi, tumor cells in culture, and ...

Comparison of methotrexate with 6‐mercaptopurine–prednisone in treatment of acute leukemia in adults

A randomized study of methotrexate vs. 6‐mercaptopurine and prednisone was carried out in 45 previously untreated patients with acute leukemia. Methotrexate was given orally in divided daily doses for 5‐day courses at intervals of ten to 14 days. Six‐mercaptopurine and prednisone were given daily until toxicity or hematologic response occurred. Patients surviving 6 weeks and failing to respond to the first treatment regimen were switched to the second program. Five of 29 patients who received methotrexate either as first or second treatment responded—four with partial remissions and one with a complete remission. Eight of 34 patients who received 6‐mercaptopurine and prednisone responded—two with complete remissions and six with partial remissions. The response rate in both groups of patients was low and there was no significant difference between the two groups. In a second unrandomized group of 20 patients treated with methotrexate there were two partial, responses.

Malignant lymphomas of the gastrointestinal tract

Malignant lymphomas involving the gastrointestinal tract are predominantly non‐Hodgkins varieties. Abnormal lymphoid tissue may grow to displace, invade, or encase the gastrointestinal tract at almost any level. Some varieties of malignant lymphomas arise in the abdominal area and produce malabsorption difficulties and abnormal serum proteins.

Malignant effusions in recurrent breast cancer. Steroid hormone receptor analysis of effusion fluid derived cells

Estrogen and progesterone receptor determination in breast cancer is of significance in determining a patients potential response to hormonal manipulation. One practical limitation to this procedure has been availability of material for receptor assay. We describe 12 patients in whom quantitative estrogen and/or progesterone receptor analysis was accomplished utilizing tumor cells obtained from malignant effusions. The ability to obtain quantitative steroid receptor data on material derived from malignant effusions provides an effective source for this important biochemical parameter in patients in whom no other tumor tissue is available for study.