Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer

OBJECTIVE: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer. METHODS: Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted. RESULTS: A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity. CONCLUSION: The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity.     

盐酸拓扑替康腹腔注射对大鼠腹腔器官及外周血白细胞的影响

目的 :探索拓扑替康腹腔化疗的安全性和可行性。方法 :以健康SD雌性大鼠为研究对象 ,观察拓扑替康腹腔化疗对大鼠腹腔内器官和外周血白细胞的影响。结果 :在剂量与静脉化疗总量相同和加大一倍时 ,拓扑替康腹腔化疗除引起与对照组相同的子宫炎症反应外 ,大网膜产生炎症反应 ;对卵巢和胰腺等则均无明显影响 ;当应用 4倍剂量时 ,造成胰腺实质间质部炎症反应。对外周血白细胞计数的影响与剂量有关 ,虽然各剂量腹腔化疗后第 3天 ,外周血白细胞计数都有下降 ,但仅在相当于静脉化疗剂量 2倍时 ,下降有统计学意义 ,剂量加大至 4倍时 ,虽然无统计学意义 ,但此实验组的白细胞计数在化疗后 5天无明显回升 ,直至化疗后 8天才恢复。其他实验组白细胞计数在化疗后 5天已回升至化疗前水平。结论 :拓扑替康腹腔化疗对大鼠外周血白细胞计数无严重影响 ,在适当剂量下对腹腔各正常器官也无明显刺激 ,对其一般情况等无明显作用。所以 ,在适当剂量下拓扑替康腹腔化疗是安全的 ,它为治疗卵巢肿瘤 ,特别是晚期、复发及耐药的卵巢肿瘤提供了新的途径。     

Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer

PURPOSE; The aim of this study was to investigate the toxicity and efficacy of a more convenient topotecan administration schedule (in contrast to the "standard" 1.5 mg/m(2)/day x 5 days q 21 days) in the management of platinum- and paclitaxel-refractory ovarian cancer. METHODS: Patients with clinically defined platinum- and paclitaxel-refractory ovarian cancer participating in this phase 2 trial conducted by the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center received topotecan at a dose of 1.5 mg/m(2)/day x 3 days on a 21-day schedule. Both dose escalations and reductions were permitted in the protocol design. RESULTS: A total of 29 patients (median age: 61; range: 43-80) were treated with this modified topotecan schedule. These individuals had received a median of two prior regimens (range: 1-4) (retreatment with a platinum agent or paclitaxel considered a single regimen). The median number of topotecan courses delivered was 3 (range: 1-7). Major toxicity included grade 4 neutropenia (24% of patients); neutropenic fever (10%); grade 3 thrombocytopenia (10%); and requirement for blood transfusion (14%). Dose escalation was possible, and dose reductions required, in 14 and 28% of patients, respectively. Two patients exhibited evidence of a clinically relevant response to treatment. CONCLUSION: This 3-day topotecan program is more convenient and less toxic than the standard 5-day regimen. The limited level of activity observed is not inconsistent with that previously reported for the 5-day topotecan infusion schedule in platinum/paclitaxel-refractory ovarian cancer. Further investigation will be required to document the clinical utility of a 3-day topotecan schedule in a less heavily pretreated and more chemosensitive patient population.     

A randomised trial of oral versus vaginal administration of misoprostol for the purpose of mid-trimester termination of pregnancy

A prospective randomised controlled trial was undertaken to compare the efficacy of two routes of administration, oral versus vaginal, of the prostaglandin E1 analogue misoprostol (Cytotec) to effect termination of pregnancy in the mid-trimester. Fifty-five women were recruited into the trial; 26 to receive all doses orally and 29 via the vaginal route. The dosing regimen was 400 microg as the initial dose followed by a second dose of 200 microg two hours later and then four-hourly 200 microg doses until delivery or 32 hours from commencement of treatment. If delivery had not been effected by the last dose of misoprostol, a Syntocinon infusion was started synchronously Misoprostol administered vaginally was significantly more effective than when administered orally as judged by induction-to-delivery interval and also the need or otherwise to augment therapy with a Syntocinon infusion. The average induction-to-delivery interval was 17.5 hours in the vaginal group compared to 33 hours in the oral group (p = 0.0003). The percentages of women who delivered at 24 and 48 hours were 93% and 100% in the vaginal administration group and 19% and 70% in the oral administration group (p < 0.05). No significant differences in complication rates or side effects were noted between the two groups     

The effect of recombinant GM-CSF on IL-6 and TNF-alpha levels in epithelial ovarian cancer patients who received paclitaxel and cisplatinum: preliminary results

OBJECTIVE: We investigated the effects of GM-CSF factor on IL-6 and TNF-alpha levels prior to paclitaxel-cisplatinum combination chemotherapy for advanced epithelial ovarian cancer. MATERIALS AND METHODS: Twenty-three consecutive patients with FIGO (International Federation of Gynecology and Obstetrics) Stage III-IV epithelial ovarian cancer were enrolled in the study. Following cytoreductive surgery patients received 175 mg/m2 paclitaxel and 75 mg/m2 cisplatinum on the same day. These 23 patients also received RhuGM-CSF five days before at a dose of 5 microg/kg/day by subcutaneous injection for three days. IL-6 and TNF-alpha levels were measured before and 24 hours later following the last dose of RhuGM-CSF. RESULTS: White blood cell counts on the 10th day of the cycle were lower than preGM-CSF white blood cell counts and the difference was statistically significant (p = 0.003). Platelet levels on the 10th day of the chemotherapy cycle were lower than pre GM-CSF levels, however were not statistically significant (p = 0.097). Post GM-CSF TNF-alpha and IL-6 levels were higher than pre GM-CSF levels. This difference was statistically significant for TNF-alpha (p = 0.002) however for IL-6 a statistically significant difference was not detected (p = 0.55). GM-CSF does not significantly effect IL-6 levels in contrast to TNF-alpha. CONCLUSION: Clinical implications of increased levels of TNF-alpha are unclear and for a precise determination further studies are needed.     

The effect of surgical procedures on monocyte function in patients with carcinoma of the colon and rectum

The whole blood monocyte count (WBMC), migratory response (MMR), phagocytic index (MPI), chemiluminescence (MCL) and serum opsonic activity (SOA) were measured in a group of 31 patients before and after undergoing elective operation for carcinoma of the colon and rectum (group 1). In the early postoperative period, there was a reduction of the WBMC (preoperatively: 54.1 +/- 41.8, 24 hours; 38.4 +/- 24.8, 48 hours, and 39.1 +/- 24.2 X 10(4) per milliliter, both p less than 0.05), impairment of MMR (preoperatively, 72.2 +/- 34.4; 24 hours, 56.7 +/- 28.6, and 48 hours, 54.7 +/- 30.8 cells per high power field [HPF], both p less than 0.01), enhancement of the MPI (preoperatively, 208.1 +/- 44.1, 24 hours, 225.9 +/- 45.6, p less than 0.05, and 48 hours, 242.0 +/- 48.0, p less than 0.01) and an increase of the MCL (preoperatively, 26,091 +/- 14,419; 24 hours, 30,896 +/- 13,741, and counts per minute [CPM], not significant and 48 hours: 33,576 +/- 18,167 CPM, p less than 0.02). There was also a small reduction in monocyte SOA during this period (preoperatively, 89.4 +/- 13.9; 24 hours, 83.0 +/- 20.1, and 48 hours, 78.3 +/- 29.3 per cent control, both p less than 0.05). At one week after operation, monocyte function tended to return to the normal range in patients who had undergone uncomplicated curative resection. These functions tended to be increased in those patients with complications. The administration of the immunostimulant levamisole (5 milligrams per kilogram) preoperatively to a group of 20 patients with carcinoma of the colon and rectum (group 2) did not result in any significant differences of the postoperative monocyte functions when compared with the patients in group 1.     

A phase I/II trial of weekly topotecan and carboplatin in potentially platinum-sensitive relapsed ovarian and peritoneal carcinoma

OBJECTIVE: Topotecan and carboplatin are active in relapsed ovarian cancer, but attempts to combine these agents are limited by myelotoxicity. This phase I/II trial combined weekly topotecan, which is less myelosuppressive than the standard 5-day regimen, with carboplatin in patients with potentially platinum-sensitive relapsed ovarian or peritoneal carcinoma (PS-OVCa/PCa). METHODS: Eligible patients had PS-OVCa/PCa, performance status 0-2, and normal bone marrow, renal, and hepatic functions. On day 1 of a 21-day cycle, patients received carboplatin (area under the curve [AUC] 5) followed by topotecan 2.0 mg/m2, both via 30-min intravenous infusion. Topotecan 2.0 mg/m2 also was administered on days 8 and 15. Treatment was withheld for neutropenia or thrombocytopenia on day 8 or 15. Dose escalation was planned. RESULTS: Seventeen patients received a total of 115 (median, 6) cycles of chemotherapy. With carboplatin AUC 4, neutropenia prevented dose escalation of topotecan; hematologic toxicity caused 34/105 (32%) weekly treatments to be withheld. However, carboplatin could be dose escalated to AUC 5 when the day 15 dose of topotecan was withheld. In the intent-to-treat population, there were 4 (24%) complete and 9 (53%) partial responses, 2 (12%) patients (at the carboplatin AUC 4 dose) with stable disease, and 2 (12%) nonevaluable patients. CONCLUSION: Carboplatin (AUC 5) on day 1 in combination with topotecan 2.0 mg/m2 on days 1 and 8 of a 21-day cycle is well tolerated and active in patients with PS-OVCa/PCa. A phase II trial comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer is warranted.     

Phase II evaluation of topotecan in carcinosarcoma of the uterus: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the antitumor activity of topotecan in patients with persistent or recurrent carcinosarcoma (malignant mixed mullerian tumors) of the uterus and to determine the nature and degree of toxicity of topotecan in this cohort of patients. MATERIALS AND METHODS: Eligible patients had measurable advanced or recurrent carcinosarcoma of the uterus. Topotecan at a target dose of 1.5 mg/m(2) was administered IV daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. RESULTS: Twenty-seven member institutions entered 51 patients. Of the patients entered, 48 were eligible. Patient characteristics included a median age of 65, with 33% having prior radiation and 92% having prior chemotherapy. Twenty-six patients (54%) had a performance status (PS) of 0, 18 (38%) had a PS of 1, and four (8%) had a PS of 2. Patients received from 1 to 21 (with a median of 2) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 35 (73%) patients, leukopenia in 14 (29%), and thrombocytopenia in 10 (21%). Three (6%) patients developed neutropenic sepsis and died shortly after their first treatment cycle. There were five (10%) complete responses; 13 (27%) patients maintained stable disease, 26 (54%) experienced increasing disease, and reassessment did not occur in four (8%). CONCLUSION: Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent uterine carcinosarcoma previously treated with chemotherapy.     

Adenovirus-Mediated Thymidine Kinase Gene Therapy in Combination with Topotecan for Patients with Recurrent Ovarian Cancer: 2.5-Year Follow-Up

OBJECTIVE: Patients with recurrent ovarian cancer were treated intraperitoneally (ip) with a replication-deficient recombinant adenovirus (ADV) containing the herpes simplex virus thymidine kinase gene. Vector delivery was followed by intravenous administration of an antiherpetic prodrug and a topoisomerase I inhibitor. METHODS: Ten patients with stage IIIc epithelial ovarian cancer underwent secondary debulking to < or =0.5 cm residual tumor. Patients with normal ip flow received delivery of ip ADV. Two patients each were treated on dose level 1 (2 x 10(10) vector particles), dose level 2 (2 x 10(11)), and dose level 3 (2 x 10(12)); four patients were on dose level 4 (2 x 10(13)). Acyclovir and topotecan were started 24 h after vector delivery. Five patients underwent second-look surgery about 4 weeks after application of gene therapy (GT). RESULTS: At the time of the second-look surgery, two out of five patients were free of tumor. Four weeks after GT none of the peritoneal biopsies showed residual vector DNA. Patients pretreated with an average of three different chemotherapeutic drugs and two different chemotherapy regimens had a median overall survival (OS) of 18.5 months. Three patients are still alive 30, 30, and 31 months after GT. CONCLUSION: With the combination of secondary optimal debulking, GT, and topotecan, median OS was about one-third longer than in previously reported second-and third-line trials. Survival was comparable to that of patients of other studies with secondary cytoreductive surgery in combination with chemotherapy.     

Effectiveness of weekly topotecan in patients with recurrent epithelial ovarian cancer

The objective of this study was to investigate the effectiveness and toxicity of weekly topotecan in patients with recurrent epithelial ovarian cancer. Twenty patients were treated with topotecan at a dose of 4 mg/m(2) weekly. Efficacy was determined according to the Response Criteria in Solid Tumors (RECIST) Gynecologic Cancer Inter Group criteria. Median age was 62 years (45-78). Patients had received 1-7 (median 3) prior chemotherapy lines. A total of 203 weekly treatments were administered. In 13 patients (65%) treatment delay was necessary due to bone marrow toxicity. Grade 3/4 neutropenia occurred in 11 patients (55%) and grade 3/4 thrombocytopenia in four patients (20%). Six patients (30%) needed a dose reduction, and 42 cycles (21%) were given with dose reduction. No neutropenia, fever, or sepsis was observed. There was one complete response and one partial response (response rate 10%). All patients with response had platin-sensitive disease (three out of eight). Six patients needed blood transfusion. None of the patients required granulocyte/granulocyte-macrophage colony-stimulating factor. The median duration of response was 13 months. In addition, there were four patients (20%) with a stable disease lasting at least for 4 months. Based on the results of this Phase II study, the toxicity of weekly topotecan seems to be lower than with the 3-weekly topotecan. The response rate of 10% is low but was not expected to be higher as these patients were heavily pretreated.     

Phase I trial of escalating doses of topotecan in combination with a fixed dose of pegylated liposomal doxorubicin in women with müllerian malignancies

BACKGROUND: Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity. OBJECTIVES: Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m(2)) in a cohort of women with recurrent müllerian malignancies. METHODS: Topotecan dose was escalated from 0.5 mg/m(2)/day for 3 days in 0.2 mg/m(2)/day increments with treatment repeated every 21 days. Eligibility criteria required ECOG < or = 2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity. RESULTS: Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40-71) years. Patients received a median 1 (1-6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses. CONCLUSIONS: Doxil 30 mg/m(2) and topotecan 0.5 mg/m(2)/day by 72-h infusion (total dose 1.5 mg/m(2)), although a rational combination of cytotoxic therapies, have limited clinical activity.     

A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer

OBJECTIVES: To determine the safety and efficacy of a novel topoisomerase I inhibitor, liposomal lurtotecan, in patients with topotecan resistant ovarian cancer. METHODS: The trial was an open-label phase II study for patients stratified by resistance to either single agent topotecan or to a prior topotecan-containing regimen. Liposomal lurtotecan was delivered at a dose of 2.4 mg/m(2) on Days 1 and 8 of a 21-day cycle. Dose escalations and reductions were allowed based on hematologic toxicity. Patients were evaluated every two cycles for response to liposomal lurtotecan. RESULTS: Twenty-two women were accrued, with 16 women resistant to single agent topotecan and 6 women resistant to topotecan given in combination with a second chemotherapy agent. Hematologic toxicity consisted of mild to moderate thrombocytopenia, anemia, and neutropenia with mild to moderate gastrointestinal toxicity and fatigue. There were no responses, although eight patients had stable disease. CONCLUSIONS: Liposomal lurtotecan at this schedule demonstrates moderate hematologic toxicity and no evidence of clinical activity in a group of heavily pretreated women previously exposed to the topoisomerase I inhibitor topotecan. The study of this agent in alternative patient populations or with alternative schedules is ongoing.     

Effects of postpartum uterine curettage on maternal well-being in severe preeclamptic patients

PURPOSE: We assessed the effect of postpartum uterine curettage on maternal recovery time in severe preeclamptic patients. METHOD: Fifty-six pregnant women with the diagnosis of severe preeclampsia in their third trimester were enrolled in the study. Uterine curettage was performed in the early postpartum period on 31 randomly selected patients and curettage was not performed in the remaining 25 patients. Prepartum mean arterial pressure (MAP) values, quantitative platelet counts, presence of proteinuria tested semiquantatitively, lactic dehydrogenase (LDH), aspartate transferase (AST), alanine transferase (ALT), and uric acid levels were determined. FINDINGS: In the group that underwent curettage, we observed a faster drop in the mean arterial pressures monitored at two-hour intervals, especially after the sixth postpartum hour (p < 0.05). Average urine output recorded at four-hour intervals in the postpartum period was significantly higher in the curettage group compared to the non-curettage group (p < 0.05). The difference in the platelet counts of both groups was not significant at the 12th postpartum hour, however, at 24 hours, platelet counts in the curettage group were higher. In the postpartum period at the 12th and 24th hours there was no difference between the two groups with regard to LDH, AST, and ALT values (p > 0.05). RESULTS: In our study we have observed that uterine curettage performed in the postpartum period had favorable effects on blood pressure, platelet count, and urinary output and also helped in faster recovery from severe preeclampsia. We, therefore, consider that postpartum uterine curettage is useful for patients with severe preeclampsia that require faster recovery.     

Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: A Gynecologic Oncology Group trial

BACKGROUND: The aim of this study was to evaluate the efficacy of a more convenient topotecan administration schedule in the second-line treatment of advanced platinum-refractory ovarian cancer. METHODS AND MATERIALS: The Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional topotecan (8.5 mg/m(2)), repeated every 3 weeks in 26 patients with platinum-refractory ovarian cancer (failure to respond to initial platinum-based treatment or development of recurrent disease within 6 months of completion of chemotherapy). RESULTS: Grade 4 neutropenia (85% of patients) and thrombocytopenia (12%) were the major toxicities encountered. Of the 25 patients evaluable for response, only a single patient experienced an objective response (4%). CONCLUSIONS: When employed at this dose and schedule (24-h infusion every 3 weeks), topotecan has minimal second-line activity in platinum-refractory ovarian cancer.     

Rat liver regeneration after partial hepatectomy: effects of insulin, glucagon and epidermal growth factor.

This study evaluated the role of insulin, glucagon and the epidermal growth factor (EGF) on liver regeneration after partial hepatectomy. Male Wistar rats, weighing approximately 200 g, were used. A partial hepatectomy, with resection of the medial and left lateral lobes (67.31%), was performed on the control group and seven hormone-treated groups: insulin, glucagon, EGF, insulin plus glucagon, insulin plus EGF, glucagon plus EGF, and a combination of the three hormones. The hormones were administered subcutaneously two days prior to the partial hepatectomy. The groups administered insulin were allowed to drink 20% glucose in water. Another group of rats received simulated operations, i.e., only a laparotomy was performed. The rats were killed at six, 24, 48 and 72 hours after the operation. Remnant liver weight, deoxyribonucleic acid (DNA) content, rate of DNA synthesis, mitotic index, blood glucose and serum insulin levels were measured. The results showed that: 1) the effects of single hormone administration on posthepatectomy liver regeneration were not obvious; 2) combined administration of insulin and glucagon increased the weight of the remnant liver, the DNA content, and the rate of DNA synthesis; 3) the combined administration of insulin, glucagon, and EGF increased the regeneration based on the remnant liver weight and mitotic index; and 4) there was no concordance between the change in blood glucose levels and the effect of hormones during liver regeneration.     

Prostacyclin and thromboxane levels in women with severe preeclampsia undergoing magnesium sulfate therapy during antepartum and postpartum periods.

OBJECTIVE: To study effects of magnesium sulfate (MgSO(4)) on prostacyclin (PGI(2)) and thromboxane A(2) (TXA(2)) levels in women with severe preeclampsia during antepartum and postpartum periods. METHODS: Women with severe preeclampsia were randomized into two groups. Patients in Group A were continuously infused with MgSO(4) for 24 hours postpartum. In Group B, MgSO(4) administration was discontinued when urinary output was of > or =100 ml/hr for 2 consecutive hours. Patient demographic data were collected. Venous blood was drawn at time of MgSO(4) administration and 24 hours after delivery. Plasma levels of 6-keto-PGF1alpha and TXB(2), stable metabolites of PGI(2) and TXA(2), were measured by enzyme-linked immunosorbent assay (ELISA). Data are presented as mean +/- SE, and analyzed by paired t-test. RESULTS: A total of 50 patients were recruited, with 27 in Group A and 23 in Group B. There were no statistical differences for demographic data between the two groups with regards to maternal age; gestational age; systolic and diastolic blood pressures at admission, 12 hours postpartum, and 24 hours postpartum; and mode of delivery. Platelet counts were all within the normal range at the time of enrollment. MgSO(4) was administered for an average of 10 hours postpartum in Group B. Maternal blood pressures returned to normal or close to normal levels in both groups at 24 hours postpartum. 6-keto PGF1alpha levels were significantly decreased 24 hours after delivery compared with the levels at enrollment in both groups, (Group A: 98 +/- 13 vs. 180 +/- 28 pg/mL; Group B: 142 + 17 vs. 194 +/- 31 pg/mL, p < 0.05, respectively). However, there was no difference detected between the two groups. TXB(2) levels were not different between group A and Group B at the time of enrollment, 38 +/- 9 vs. 33 +/- 8 pg/mL, and 24 hours postpartum, 26 +/- 5 vs. 25 +/- 3 pg/mL, respectively. CONCLUSIONS: Administration of MgSO(4) does not affect prostacyclin and thromboxane levels in the maternal circulation in women with preeclampsia during antepartum and postpartum periods. We speculate that a higher level of prostacyclin before delivery may reflect compensatory effects of this vasodilator to offset increased maternal blood pressure during pregnancy.     

A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma

BACKGROUND: As suggested by preclinical trials, prolonged administration of topotecan, a reversible inhibitor of topoisomerase-I, may have a therapeutic advantage. Following a phase I trial of weekly 72-h topotecan infusion, we performed a phase II trial utilizing this schedule in ovarian carcinoma. METHODS: Eligibility included platinum-/paclitaxel-resistant ovarian carcinoma, measurable disease, and adequate hematologic, renal, and hepatic function. A dose of 2.0 mg/m(2) of topotecan was administered as a 72-h infusion weekly via an ambulatory pump. Plasma topotecan concentrations were determined prior to and at the completion of each weekly course. RESULTS: Twenty-four patients were entered and 23 patients were evaluable for toxicity and response. Two hundred eighteen weekly courses of therapy were administered (median 7 weeks, range 4-46 weeks). Toxicity was mild with grade 3 leukopenia, neutropenia, and anemia occurring in 13, 13, and 17% of patients, respectively. Two of 23 patients (9.1%) (CI 1-28%) had partial responses of 2 and 3 months' duration and 6 had stable disease. Steady state plasma topotecan lactone concentrations were a median of 1.2 ng/ml (range 0.4-8.00 ng/ml) following the first week of infusion. Steady state topotecan lactone concentrations after the first week of infusion were highest in 2 patients with partial responses. Mean steady state plasma topotecan lactone concentrations after the first week of infusion were 4.6, 2.0, and 1.3 ng/ml for partial response, stable disease, and progressive disease, respectively. An analysis of variance of steady state plasma topotecan concentrations after the first week of infusion over all administered cycles demonstrated a significant difference in steady state plasma topotecan lactone concentrations between patients with partial response and stable disease and between partial response and no response (significant at the 0.05 level after adjustment for multiple comparisons). Controlling for cycle number, steady state topotecan lactone concentrations are significantly greater for patients with responding or stable disease than those with progressive disease (P = 0.0003) and have a lower bound of > or = 1.9 ng/ml (95% confidence level). CONCLUSION: Steady state topotecan lactone concentrations are associated with responding or stable disease in platinum- and paclitaxel-resistant ovarian cancer. Steady state topotecan concentrations could potentially be utilized to modify tumor exposure and response.     

Magnesium sulfate effectively reduces blood pressure in an animal model of preeclampsia.

OBJECTIVE: We tested the ability of magnesium sulfate to reduce hypertension and neonatal growth retardation in an animal model of preeclampsia. STUDY DESIGN: On day 17 of pregnancy, osmotic minipumps were inserted subcutaneously to continuously deliver either vehicle (saline control group), or N-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day), or L-NAME (50 mg/kg/day) in combination with magnesium sulfate (60 mg/kg/day). Prior to insertion, blood pressure and heart rate were monitored with a pneumatic tail cuff device. Blood pressure measurements were repeated on days 18, 20, and 21 of pregnancy. Blood was obtained on days 17 and 21, along with urine, to assess magnesium levels and degree of proteinuria. Pups were weighed and measured at 48 hours postpartum. RESULTS: Rats receiving L-NAME developed hypertension within 24 hours of implantation (108 +/- 3.9 vs. 123 +/- 3.4 mmHg, p < 0.05). Magnesium sulfate, given along with L-NAME did not prevent mean blood pressure from increasing, but reduced it by day 21 compared to L-NAME given alone (107 +/- 3.4 vs. 122 +/- 8.7 mmHg, respectively, p < 0.05). Magnesium sulfate reduced neonatal growth retardation by improving the weight of the pups compared to pups from maternal rats given L-NAME alone (6.1 +/- 0.1 vs. 5.2 +/- 0.3 grams, respectively, p < 0.05). CONCLUSION: Maternal magnesium sulfate reduces blood pressure and increases neonatal size compared to L-NAME without magnesium. These findings support a beneficial effect of magnesium in preeclampsia.     

Effects of the antiprogesterone RU 486 in normal women. I. Single-dose administration in the midluteal phase

The response to a single oral dose of the antiprogesterone RU 486 was studied in the midluteal phase in 26 normal women. Each subject received a dose between 50 and 800 mg RU 486 on days 6 to 8 after the luteinizing hormone surge and blood samples were taken over the following 48 hours. Another group of five patients received a single oral dose of 200 mg RU 486 and blood sampling was extended for 14 days. Menses were induced in all women but one within 3 days after RU 486 administration. Two distinct patient populations emerged. In nine of the subjects, there was a single bleeding episode and the treatment cycle was significantly shorter (p less than 0.05) than the following cycle. In 16 of these 25 patients a second bleeding episode occurred 19.0 +/- 0.8 days after the luteinizing hormone surge. The total treatment cycle was significantly prolonged (p less than 0.05) when compared with the following cycle. In the group with a single bleeding episode, there was a significant decline in follicle-stimulating hormone, estradiol, and progesterone over the 48-hour sampling period, but there was no change in these values in the group with two bleeding episodes. These two groups could not be separated on the basis of RU 486 dose or serum levels. After the four higher doses, there was a dose-dependent rise in serum prolactin. There were no alterations in mean cortisol values with the three lower doses, but there was a significant increase at 24 and 48 hours after the higher doses. Serum levels of RU 486 were maximal between 1 and 4 hours and the half-life of serum RU 486 was determined to be 24 hours.     

Placental transfusion: umbilical cord clamping and preterm infants.

OBJECTIVE: To investigate the clinical effects of early versus late cord clamping in preterm infants. STUDY DESIGN: A total of 32 premature infants were prospectively randomized. The following parameters were measured: Initial spun hematocrit (Hct), hemoglobin (Hgb), red blood cell (RBC) counts, frequency of blood transfusions, peak serum bilirubin, mean blood pressure (MBP), oxygen index, intraventricular hemorrhage, and significant patent ductus arteriosus (PDA). RESULTS: Over the 4-week study period, the delayed cord clamping (DCC) group exhibited a decrease in the frequency of blood transfusion (p < 0.001) and also a decrease in albumin transfusions over the first 24 hours (p < 0.03). MBP in the first 4 hours was higher in the DCC group (p < 0.01), and there were statistically significant increases in Hct (21%), Hgb (23%), and RBC count (21%) compared with the early cord clamping group. The risks of patent ductus arteriosus, hyperbilirubinemia, or intraventricular hemorrhage were similar in both groups. Late clamping of the umbilical cord had little or no effect on the oxygen index. CONCLUSION: DCC significantly reduced the requirement for blood and albumin transfusion. It also increased the initial Hct, RBC count, Hgb levels, and MBP.