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Biomedical subjects

D E Brenner

Publications and source records attributed to D E Brenner.

At least 73 records · Page 4Linked to original sources
PubMed1986

The effects of cimetidine upon the plasma pharmacokinetics of doxorubicin in rabbits.

Cimetidine is an H2 antagonist which inhibits cytochrome P-450 and reduces hepatic blood flow. To determine whether cimetidine interferes with the plasma pharmacokinetics of doxorubicin, we gave six female New Zealand rabbits doxorubicin 3 mg/kg, followed a month later by cimetidine 120 mg/kg every 12 h over 72 h and doxorubicin 3 mg/kg. Serial plasma specimens were obtained over 72 h and assayed for doxorubicin and its metabolites by high-performance liquid chromatography and fluorescence detection. Doxorubicin plasma pharmacokinetics were prolonged after cimetidine pretreatment [AUC 0.76 +/- 0.22 vs. 2.85 +/- 1.22 microM X h, no pretreatment vs pretreatment (p = 0.005), half-life = 11.7 +/- 6.55 vs 28.0 +/- 8.16 h (P = 0.0002), and clearance = 0.129 +/- 0.036 vs 0.036 +/- 0.011 l/min-1 kg-1 (P = 0.0007)]. No significant differences were found between the AUCs for doxorubicinol, 7-deoxy doxorubicinol aglycone, or two unidentified nonpolar metabolites in nonpretreatment and pretreatment studies. Cimetidine increases and prolongs the plasma exposure to doxorubicin in rabbits. Doxorubicin metabolism does not appear to be affected by cimetidine.

Animals↗
PubMed1986

Antiemetic effect of oral versus intravenous metoclopramide in patients receiving cisplatin: a randomized, double-blind trial.

In a study of the antiemetic effectiveness of high-dose oral metoclopramide, 66 previously untreated patients receiving 60 mg/m2 cisplatin were entered into a double-blind randomized trial. Patients were stratified according to age and tumor type, then randomized to receive either oral or intravenous (IV) high-dose metoclopramide. Patients were evaluated for antiemetic protection, toxicity, affect (anxiety, hostility, and depression), and autonomic arousal (pulse rate and blood pressure) at three-hour intervals on the day of their chemotherapy. Metoclopramide serum levels were measured by high-performance liquid chromatography. Results indicated no significant differences between the oral and IV groups on any measurement of antiemetic protection, affect, or autonomic arousal. There were also no significant differences in side effects except for frequency of stools; patients who received oral metoclopramide had significantly more stools than patients who received IV metoclopramide. The mean (+/- SD) serum metoclopramide level at four hours achieved orally was 1,171 +/- 660 ng/mL; the mean (+/- SD) level achieved IV was 1,030 +/- 392 ng/mL (P = .498). We conclude that high-dose oral and IV regimens of metoclopramide as administered in this study have equivalent antiemetic efficacy in previously untreated patients receiving 60 mg/m2 cisplatin.

Administration, Oral↗
PubMed1986

Toxicity of doxorubicin metabolites to human marrow erythroid and myeloid progenitors in vitro.

Doxorubicin and five synthesized metabolites (doxorubicinol, doxorubicin aglycone, doxorubicinol aglycone, 7-deoxydoxorubicin aglycone, and 7-deoxydoxorubicinol aglycone) were evaluated in vitro for their cytotoxic effect on human marrow erythroid burst- and granulocytic-monocytic colony-forming units (BFU-E, CFU-GM). The IC50 for doxorubicin was 0.39 +/- 0.099 micron and for doxorubicinol was 4.6 +/- 0.63 micron. There was no difference in cytotoxicity for BFU-E or CFU-GM. Incubation with aglycones in concentrations as high as 5.8 micron and prolongation of incubation time for as long as 3 hours had no effect on the growth of BFU-E and CFU-GM in vitro. We conclude that aglycones are not toxic to human marrow erythroid and myeloid progenitors in vitro and do not have a role in the development of doxorubicin-induced myelotoxicity. The mechanism of the lack of cytotoxicity remains unclear.

Cell Division↗
PubMed1985

Improved high-performance liquid chromatography assay of doxorubicin: detection of circulating aglycones in human plasma and comparison with thin-layer chromatography.

We compared doxorubicin and metabolite pharmacokinetic data obtained from thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) assay of plasma samples from six patients who had been treated with doxorubicin. Duplicate 1-ml samples were extracted with chloroform: isopropanol (1:1) and assayed using a sensitive HPLC system incorporating a dual pump gradient with tetrahydrofuran as the mobile phase and fluorescence detection. Duplicate 1-ml samples from the same specimens were assayed using a modification of a previously described TLC assay. Areas under the curve for doxorubicin by HPLC (3.36 +/- 2.30 microM X h) and TLC (4.16 +/- 2.50 microM X h) were not significantly different (P = 0.5). Terminal half-life of doxorubicin by HPLC (28.0 +/- 6.98 h) and TLC (23.2 +/- 7.8) (P = 0.29) and the calculated total-body clearances by HPLC (0.55 +/- 0.29 l/min) and TLC (0.45 +/- 0.23) (P = 0.55) were not significantly different. Areas under the curve for doxorubicinol by HPLC (2.75 +/- 1.4 microM X h) and TLC (2.53 +/- 7.1 microM X h) (P = 0.73) showed no significant differences. HPLC detected a mixed 7-deoxydoxorubicinol aglycone-doxorubicin aglycone peak, 7-deoxydoxorubicin aglycone, and two nonpolar, unidentified metabolites. TLC detected the following aglycone metabolites: doxorubicin aglycone, doxorubicinol aglycone, 7-deoxydoxorubicinol aglycone, an unidentified polar metabolite, and several unidentified nonpolar metabolites. From these data we conclude that HPLC and TLC detect concentrations of doxorubicin and doxorubicinol from human plasma equally well to concentrations of 7.0 nM (4 pmol injected doxorubicin). Aglycones do circulate in human plasma at concentrations above the detection limits of both assays. Doxorubicinol aglycone, which is detected by TLC but not by HPLC, may be formed from artifactual breakdown of doxorubicinol during TLC development. Unidentified nonpolar compounds seen on HPLC and TLC may represent further doxorubicin metabolism than previously described.

Chromatography, High Pressure Liquid↗
PubMed1985

Abdominopelvic computed tomography: evaluation in patients undergoing second-look laparotomy for ovarian carcinoma.

Preoperative abdominopelvic computed tomography results and operative findings were compared in 52 patients undergoing second-look laparotomy to confirm tumor status. Seventeen true-negative, 22 false-negative, and 13 true-positive scans were found. The sensitivity was 0.38, specificity was 1.0, and diagnostic accuracy was 0.58. Negative studies were associated with positive findings at laparotomy in 42% of all cases. Fourteen patients were identified who had computed tomography that would have enabled an attempt at the diagnosis of persistent cancer by computed tomography-directed needle aspiration or biopsy, thus avoiding laparotomy. Assuming 80% accuracy of needle aspiration, the cost of computed tomography in all 52 patients is considerably outweighed by the savings that could have been realized by eliminating the need for second-look surgery in these 11 women.

Antineoplastic Agents↗
PubMed1984

Acute doxorubicin toxicity. Relationship to pretreatment liver function, response, and pharmacokinetics in patients with acute nonlymphocytic leukemia.

To determine if there is a relationship between development of acute doxorubicin toxicity, pretreatment liver function studies, and response, 64 acute nonlymphocytic leukemia patients undergoing induction chemotherapy with doxorubicin and cytosine arabinoside were evaluated. No statistically significant correlation could be found between the development of acute toxicity (mucositis) and the number or type of abnormal pretreatment liver functions. Patients receiving full doses of doxorubicin with mild hepatic dysfunction as determined by bromsulphalein (BSP) retention and serum liver function studies had the same incidence of toxicity and complete response rate as those with normal hepatic function. There was no significant difference between duration of response (P = 0.41) or survival (P = 0.17) between the two groups. Ten patients receiving a decreased dose of doxorubicin due to hepatic dysfunction had the same complete response rate but a lower incidence of toxicity as patients receiving full doxorubicin dose. Pharmacokinetic data from fluorescence plasma assays suggest no difference among patients with normal or mildly abnormal liver function studies receiving full doxorubicin doses. The results suggest that leukemia patients with mild hepatic dysfunction receiving a combination of full-dose doxorubicin and cytosine arabinoside for acute leukemia will have the same plasma pharmacokinetics, incidence of toxicity, and complete response rate as those with normal hepatic function. Reduction of doxorubicin dose in patients with abnormal liver function tests results in lower plasma concentrations, less toxicity, and the same response rate, but may also yield a shorter duration of response and survival.

Adolescent↗
PubMed1983

Delta-9-tetrahydrocannabinol in cancer chemotherapy: research problems and issues.

A critical review of the literature assessing the antiemetic efficacy of delta-9-tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy showed considerable inconsistency in results. The equivocal nature of these results partly reflects the difficulty of doing research on antiemetic therapies, but also can be attributed to differences in the adequacy and nature of the research designs, procedures, and assessment instruments that have been used. Several factors were also identified that are seldom studied but may be important in determining whether THC will be effective: patient variables, such as chemotherapy regimen and age; pharmacologic variables, such as drug tolerance, dose, schedule, toxicity, route of administration, and drug interactions; and environmental variables associated with administration setting. The need to differentiate pharmacologically induced from conditioned nausea and vomiting was also pointed out. We believe that THC does have antiemetic efficacy, but the lack of controlled research does not allow precise knowledge of its true effectiveness and toxicity. Well-controlled trials are needed to help answer some of these questions.

Antiemetics↗
PubMed1983

Phase II study of vinblastine in advanced refractory ovarian carcinoma.

Fourteen patients with advanced ovarian carcinoma previously treated with chemotherapeutic agents including cisplatin were treated with vinblastine 0.1 mg/kg intravenously every week. There were no responses in 13 evaluable patients. The median survival was 19+ weeks following the initiation of vinblastine (VBL) therapy. Toxicity consisted of minimal myelo-suppression (WBC count less than 2500/microliter in 8/78 courses, WBC count less than 1500/microliter in 0/78 courses, platelets less than 150,000/microliter in 0/78 courses), nausea (4/13 patients), vomiting (2/13 patients), neuropathy (4/13 patients), and weakness and fatigue (6/13 and 5/13 patients, respectively). Although data derived from the human tumor stem cell assay (HTSCA) suggest that VBL may be an active agent against previously treated ovarian carcinoma, this study in patients with refractory advanced disease suggests that VBL is inactive (less than 20% response rate with 90% confidence levels) in that setting. Whether significant durable benefit can be achieved with VBL therapy in patients whose tumor is sensitive in the HTSCA remains to be seen.

Adult↗
PubMed1982

An evaluation of the computed tomographic scanner for the staging of carcinoma of the cervix.

Twenty patients with invasive carcinoma of the cervix (FIGO stages IB-IV) were staged by routine pelvic examination, intravenous urography, chemistry studies, and barium enema. All patients received a CT scan of the abdomen and pelvis followed by pelvic examination under anesthesia (EUA). CT agreed with EUA staging in 13 of 20 patients (65%). All patients had surgical para-aortic lymph node sampling. The sensitivity of CT for para-aortic lymph node involvement was 67% and the specificity was 92%. CT scanning is equal to other clinical staging procedures for carcinoma of the cervix. It offers the advantages of being noninvasive and visualizing tumor for the construction of radiation portals. CT is useful in the detection of para-aortic lymphadenopathy; however, the presence of normal sized or enlarged nodes makes pathologic examination, either by needle aspiration or surgery, necessary.

Female↗
PubMed1982

Volume determinations in computed tomography.

Modern computed tomographic (CT) scanners allow reasonably high-resolution cross-sectional visualization of most viscera and masses. To determine the accuracy of CT volume estimation, CT volumes of inanimate objects, cadaver kidneys and spleens, and in vivo balloons were performed. Regions of interest were outlined by a hand-operated cursor, and the computer program calculated the cross-sectional area in square millimeters and in pixels. A second computer program used Simpson's rule to calculate the volume from these multiple cross-sectional area. Calculated CT volumes were within +/-10% of directly measured volumes. Tumor masses being treated by chemotherapy were followed up clinically and by CT. Volume changes determined by CT are believed to be equal to and frequently more sensitive than clinical examination. From our experimental CT and clinical experiences, accuracy can be affected by (1) respiratory movement; (2) rapid changes in in vivo blood volume; (3) low CT number-gradient at the objects' periphery; (4) observer error in cursor tracing of the desired structure; and (5) mathematical errors inherent in Simpson's rule. We conclude that CT can estimate volumes of CT definable masses and can be useful in following tumor response to therapy.

Female↗
PubMed1982

A study of prostaglandin E2, parathormone, and response to indomethacin in patients with hypercalcemia of malignancy.

In order to evaluate the relationship of PGE2 to hypercalcemia in cancer patients, 101 patients were screened with a radioimmunoassay for plasma prostaglandin E2 (PGE2) (NL less than 100 pg/ml). Of the 101 patients, 31 were hypercalcemia. Mean PGE2 (+/- SEM) of the 31 patients was 199 +/- 36 pg/ml. Among the 70 normocalcemic patients, mean +/- SEM PGE2 was 85 +/- 12 pg/ml (range = less than 25--225 pg/ml) (P less than 0.001). Seventeen hypercalcemic patients were initially treated with saline and furosemide, then were prospectively screened for serum parathormone (iPTH) and PGE2. Fourteen of 17 patients were then treated empirically with indomethacin (25 mg b.i.d.) for 72 hours and the PGE2 assay was repeated. Prior to therapy with indomethacin (mean +/- SEM), Ca++ = 12.2 +/- 1.5 mg/dl (NL 8.4--10.6 mg/dl), PGE2 = 87.1 +/- 36.8 pg/ml, (range = less than 25--209 pg/ml), and iPTH = 406 +/- 266 pg/ml (NL less than 400 pg/ml) (range = less than 100--825 pg/ml). PGE2 was elevated before treatment in 6/14 patients (breast, colon, renal, lung, neck tumors, and myeloma). Following treatment with indomethacin, PGE2 and calcium fell to normal levels in three patients (breast, colon, renal carcinomas). These results suggest: (1) A bimodal distribution of PGEs exists in hypercalcemic cancer patients. (2). There was some evidence of lack of whole molecule iPTH suppression in these patients. (3) Multiple stimuli of calcium mobilization may play an important etiologic role in a few hyercalcemic cancer patients and may explain the failure of indomethacin to control serum Ca++ in some patients with elevated PGE2.

Humans↗
PubMed1982

Acute renal failure and renal tubular squamous metaplasia following treatment with streptozotocin.

Nephrotoxicity, in the form of transient proteinuria, azotemia, abnormalities of tubular function, and acute renal failure, is the major toxic condition following administration of streptozotocin. The renal morphologic and ultrastructural abnormalities associated with streptozotocin remain poorly defined. We describe a patient with metastatic islet cell tumor of the pancreas who was treated with 16 weekly courses of 1 g/m2 of streptozotocin without marked change in renal function. Following a six-week hiatus without change in renal function, a single course of 1 g/m2 of streptozotocin was administered and resulted in acute renal failure. Light microscopic examination of the kidneys showed irregularly dilated renal tubules lined by low cuboid epithelium. The cells were pleomorphic and showed some mitoses. Nuclei were irregular and variably hyperchromatic. Electron microscopic examination disclosed large aggregates of fine microfilaments in the proximal convoluted tubules and collecting ducts. Microfilament aggregates were both free in the cytoplasm and membrane bound. Microfilaments were proved to be tonofilaments by the demonstration of keratin within the epithelium, using the immunoperoxidase method. These data suggest that squamous metaplasia may be an important part of streptozotocin renal toxicity, and the suggestion is made that they may be an antecedent of neoplastic change.

Acute Kidney Injury↗
PubMed1982

A phase II trial of m-AMSA in the treatment of advanced gynecologic malignancies.

Thirty-two patients with advanced gynecologic malignancies were treated with m-AMSA, 120 mg/m2 intravenously every 3 weeks. Seventeen patients with advanced carcinoma of the cervix who were treated with m-AMSA had a median performance status (CALGB scale) of 2. There were two partial responses (PR) (14%) in 16 evaluable patients. The median duration of survival was 76 days following the initiation of m-AMSA treatment. In ovarian carcinoma, none of the nine evaluable patients who were treated responded. One PR occurred among four treated patients with endometrial adenocarcinoma. Toxicity was limited to myelosuppression (WBC greater than 2500/micrograms in 29/77 courses, WBC greater than 1500/micrograms in 16/77 courses, platelets greater than 100,000/micrograms in 10/77 courses, and drug-induced anemia in 7/77 courses) and mild to moderate nausea and vomiting (10/31 patients). Three patients required hospitalization for fever and granulocytopenia, and one patient died from drug-induced sepsis. Although toxicity was acceptable in this group of heavily pretreated patients, m-AMSA has limited activity in patients with advanced carcinoma of the cervix and no apparent activity in patients with advanced epithelial ovarian carcinomas. Continued trials are indicated in patients with adenocarcinoma of the endometrium.

Adenocarcinoma↗
PubMed1982

Computed tomographic evaluation of carcinoma of the cervix.

To assess the accuracy of computed tomography (CT) in staging advanced carcinoma of the cervix, 18 staging evaluations were performed in 16 patients with locally advanced (FIGO Stage IB-IVA) cervical carcinoma. CT staging results were compared with the results of clinical staging and postoperative staging. CT was accurate in 12/18 (66%) cases, clinical staging was accurate in 10/18 (55%) cases, and clinical staging with cystoscopy was accurate in 14/18 (78%) cases. CT staging failed to detect microscopic pelvic sidewall involvement and bladder involvement when there was no contrast material in the bladder. In the detection of para-aortic lymph node involvement by tumor, there were 12 true-negative, 4 true-positive, 1 false-positive, and 1 false-negative study (sensitivity = 80%, specificity = 92%). It is concluded that CT is equal in accuracy to other clinical staging techniques and offers the advantage of visualizing the tumor, which allows for more accurate determination of radiation portals.

Carcinoma↗