Pharmacokinetics of Ip cisplatin in refractory ovarian carcinoma

Four patients with small residual ovarian carcinoma following treatment with cisplatin, doxorubicin, and cyclophosphamide have subsequently received 57 courses of ip cisplatin. Cisplatin (120-270 mg in 2 L of Ringer's lactate) was administered via Tenckhoff catheter, with a dwell time of 15-20 mins. Courses were given weekly for 12 weeks, with response documented by laparoscopy or laparotomy prior to and following the trial. With a dwell time of 20 mins, 75% +/- 5% (mean +/- SD) of platinum was recovered. With 120 mg of cisplatin and a dwell time of 20 mins, total plasma platinum peaked at 1.23 +/- 0.42 microgram/ml and by 8 hrs decreased to 0.67 +/- 0.12 microgram/ml. Filterable (non-protein-bound) platinum peaked at 0.73 +/- 0.21 microgram/ml and by 8 hrs fell to 0.03 microgram/ml. Excretion rate paralleled the filterable plasma curve, peaking at 40 mins; 30% +/- 7% of absorbed drug was recovered in urine within 24 hrs. Renal clearance of filterable platinum was 106 +/- 20 ml/min. Creatinine clearance was 76 +/- 7 ml/min. Three responses, one complete and two partial, were noted. Zero to two episodes of vomiting occurred in each course. One patient had a creatinine clearance decrease to 40 ml/min, one had two episodes of thrombocytopenia, and one had mild abdominal pain with a cisplatin dose of greater than or equal to 210 mg. No neurotoxicity, catheter infection, or peritonitis was encountered.     

Efficacy of minimal dose aprotinin in open heart procedures

In a randomized double blind study, 30 patients posted for CABG surgery were assigned to 3 groups of 10 each. Group A received 140 mg (1,000,000 KIU) of aprotinin after induction of anaesthesia but before sternotomy, an equal amount in the pump prime and a maintenance dose of 70 mg/hr throughout cardiopulmonary bypass (standard dose). Group B received placebo after induction of anaesthesia, 70 mg (500,000 KIU) aprotinin in the pump prime with a placebo as a maintenance dose (minimal dose). Group C received a placebo after induction of anaesthesia, in the prime and as a maintenance dose (control group). The mean chest closure times were insignificantly lower in the aprotinin groups; 35.83 +/- 13.93 mins in group A and 37.5 +/- 10 mins in group B as against 57.25 +/- 26.54 mins in group C. Post-operative haemoglobin loss was significantly lower (P<0.01) in aprotinin groups, 5.42 +/- 1.6 gm in group A and 6.28 +/- 2.49 gms in group B, as against 39.77 +/- 27.51 gm in group C. Whole blood transfusion requirement was also significantly reduced from 4.12 +/- 1.79 units in the control group to 2.5 +/- 0.75 units in group A (p < 0.05) and 2 +/- 1.3 units (p<0.01) in group B. We conclude that a minimal dose of aprotinin 70 mg (500,000 KIU) is effective in reducing postoperative blood loss, blood transfusion requirement and is economical.     

Treatment of metastatic colorectal carcinoma with 5-FU, mitomycin, vincristine, and methotrexate

Fifty-three patients with advanced metastatic colorectal carcinoma were treated every 4-5 weeks with a chemotherapeutic regimen consisting of 5-FU (300 mg/m2 iv on Days 1-5), mitomycin (10 mg/m2 iv on Day 1 only [repeated every other course]), vincristine (0.75 mg/m2 on Days 1 and 5), and methotrexate (8.0 mg/m2 iv on Days 1 and 5). The overall response rate was 43.4%, with three patients (5.7%) achieving complete response (mean duration, 13.3 months) and 20 patients (37.7%) achieving partial response (mean duration, 6.3 months). Stable disease was not considered to be a response category in this report. The mean overall response duration was 7.8 months. The observed mean survival duration in responders was 15.2 months and in nonresponders was 8.9 months (P less than or equal to 0.01). Hematologic and subjective toxic effects are discussed.     

Prospective study of the pulmonary toxicity of continuously infused bleomycin

Bleomycin is an effective antitumor drug but must be used cautiously because of its pulmonary toxicity. We performed a prospective study of the effects on pulmonary function when bleomycin was given as a continuous iv infusion over a 7-day period. Bleomycin was administered at a dose of 15 units/m2 as an iv push followed by 15 units /m2/day as a continuous iv drip. Thirteen previously untreated patients completed the study after receiving a mean total dose of 228 units. Pulmonary function tests were performed before bleomycin treatment and periodically during the subsequent 6 months. There was a small mean increase in both vital and diffusing capacities after 6 months, which was not statistically significant. No patient had a serious loss in pulmonary function. We conclude that the risk of bleomycin toxicity is low when the drug is given at this dose by continuous infusion. The risk may be less than the risk of toxicity from bolus injection in this dose range.     

Phase I study of oral mitomycin C.

This study demonstrates that the gastrointestinal absorption of oral mitomycin C is variable and that myelosuppression correlates most closely with the peak serum concentration. The probable maximal-tolerated dose of oral mitomycin C is 45-50 mg/m2.     

Phase I clinical evaluation of cytarabine and cisplatin in patients with advanced cancer

Studies in cell culture systems and tumor-bearing animals have demonstrated synergistic cytotoxicity of cytarabine (ara-C) and cisplatin. We have conducted a phase I trial to assess the toxic effects and tolerable doses of these drugs in patients with advanced cancer. Forty-five such patients were treated with varying dosages of ara-C infused continuously during Days 1-3 of a 28-day cycle. Cisplatin at a dose of 100 mg/m2 was administered on Day 2 of the cycle. Using this schedule, the maximally tolerated dose of ara-C in previously untreated patients was 60 mg/m2/day (180 mg/m2). Hematologic toxicity was dose-limiting with median wbc and granulocyte count nadirs of 1800 and 168/mm3, respectively. Reduction of the cisplatin dose while maintaining the ara-C dose at 60 mg/m2/day resulted in less myelosuppression, suggesting that these drugs may have synergistic effects on the bone marrow. Objective responses were seen in six of 41 evaluable patients, including five of 12 patients with non-small cell lung cancer. The severe bone marrow toxicity observed at relatively low drug doses and the 42% response rate in patients with non-small cell lung cancer suggest that the combination of ara-C and cisplatin has substantial clinical activity. Phase II trials are warranted in non-small cell lung cancer and other tumors.     

Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers.

The effect of an infusion of two doses of peptide YY (PYY), a novel putative gastrointestinal hormone, has been assessed on mouth to caecum intestinal transit time and on the rate of gastric emptying after ingestion of an inert 200 ml liquid meal thought unlikely to interrupt fasting gastrointestinal motility patterns. A low dose of PYY was chosen to give plasma concentrations within the range seen postprandially in healthy subjects, while the high dose mimicked the raised levels seen in several malabsorptive conditions. During infusion of PYY at 0.18 pmol/kg/min plasma concentrations rose from a basal of 8 +/- 2 pmol/l to 38 +/- 5 pmol/l and at 0.51 pmol/kg/min to 87 +/- 10 pmol/l. Mouth to caecum transit time was delayed from 67 +/- 4 mins on the saline infusion day to 94 +/- 7 mins (p less than 0.01) on the low dose and 192 +/- 9 mins (p less than 0.001) on the high dose infusion day. Time to 50% gastric emptying was prolonged from 37 +/- 8 mins during saline infusion to 63 +/- 10 mins (p less than 0.05) during low and 130 +/- 12 mins (p less than 0.001) during high dose infusion. Thus the infusion of PYY shows a dose related inhibition of mouth to caecum intestinal transit time and of the rate of gastric emptying and suggests this novel hormonal peptide to be of importance in gastrointestinal physiology.     

Pharmacokinetics of carboplatin after i.v. administration

Pharmacokinetics of the cisplatin analog carboplatin were studied in ovarian cancer patients who received short-term iv infusions of 290-370 mg/m2. Platinum (Pt) was determined by atomic absorption spectrometry in plasma ultrafiltrate up to 24 hours and in plasma and urine up to 5 days following infusion. Carboplatin was determined in plasma ultrafiltrate and in urine by high-performance liquid chromatography with electrochemical detection. The final half-life of total Pt in plasma was 5.8 +/- 1.6 days. Pharmacokinetics of carboplatin and ultrafilterable Pt (free Pt) were similar with respect to alpha-half-life (16 +/- 6 and 23 +/- 8 mins), beta-half-life (118 +/- 15 and 120 +/- 11 mins), area under curve/dose (18 +/- 5 and 17 +/- 4 min/m2/L), total-body clearance (101 +/- 21 and 107 +/- 19 ml/min), and volume of distribution Vss (9.9 +/- 1.3 and 10.0 +/- 1.4 L/m2). After 6 hours the cumulative urinary excretion of carboplatin and Pt was 41% +/- 14% and 68% +/- 7% of the dose, respectively. After 5 days the cumulative urinary excretion of Pt was 84% +/- 6%. Renal and metabolic clearances of free Pt from plasma were 81 +/- 17 and 26 +/- 11 ml/minute, respectively. The first-order rate constant for metabolic elimination of free Pt (KM = CLM/Vss) was 1.5 X 10(-3) +/- 0.6 X 10(-3) min-1, which is ten times lower than the value calculated from literature data for cisplatin (15 X 10(-3) +/- 1 X 10(-3) min-1). This means that the overall in vivo reactivity of carboplatin is ten times lower than that of cisplatin.     

Plasma pharmacokinetics and tissue distribution of thiotepa in mice

We defined the plasma and tissue concentrations and pharmacokinetics of thiotepa in 22.8-29.3-g male Swiss-Webster mice injected iv with thiotepa at a dose of 5 mg/kg. Concentrations of thiotepa in ethyl acetate extracts of tissue and plasma were determined by gas chromatography. Plasma concentrations of thiotepa declined in a biexponential fashion that was well-described by the equation: Ct = 52.03e-3.36t + 3.10e-0.072t, indicating an alpha-half-life of 0.21 mins and a beta-half-life of 9.62 mins. Thiotepa was rapidly and extensively distributed through the tissues studied and was not concentrated in any particular tissue, although the liver consistently contained concentrations of thiotepa much lower than any other tissue studied. By 1 hr after injection, there was little thiotepa in plasma or any tissue.     

Intraarterial hepatic chemotherapy with fluorouracil,fluorodeoxyuridine, mitomycin C,cisplatin or methotrexate as single-agent anticancer drugs for a transplanted experimental liver tumor in rats

A prospective, controlled and standardized animal experiment was performed to study the influence of various anticancer drugs. The Novikoff hepatoma transplanted into male Spraque-Dawley rats was treated with fluorouracil (FUra), mitomycin C, methotrexate, cisplatin and fluorodeoxyuridine (FdUrd) at equi-effective dosage, in terms of side effects (weight loss), in comparison to a control group (0.9% saline solution) by locoregional application via the hepatic artery. The tumor multiplication factor (TMF = tumor volume day 12/tumor volume day 5) served as the parameter to compare the tumor growth of the various groups. All drugs showed a significant (P<0.05) effect on the tumor growth. In comparison to the control group (mean TMF 9.66), FdUrd (3.78) and FUra (3.03) only limited the tumor growth, mitomycin C (0.96) produced stable tumor, cisplatin (0.64) and methotrexate (0.15) significantly reduced (P<0.01) the tumor size. We suggest that, in addition to the established (FUra, FdUrd, mitomycin C) drugs, methotrexate and cisplatin should be considered in further studies of the treatment of primary and secondary liver malignancies.     

Effects of cardiovascular drugs on oxygen consumption/oxygen delivery relationship in patients with congestive heart failure.

The oxygen consumption (VO2)/oxygen delivery (DO2) relationship was analyzed in ten patients with severe congestive heart failure (CHF) and normal blood lactate levels. First dobutamine and then enoximone, after a washout period, were administered to each patient to increase cardiac output by at least 15 percent. Similar increases in DO2 were obtained with both drugs: from 285 +/- 46 to 393 +/- 87 ml/min/m2 for dobutamine, and from 285 +/- 54 to 392 +/- 99 ml/min/m2 for enoximone. However, while VO2 did not change (132 +/- 24 vs 132 +/- 21 ml/min/m2) (VO2/DO2 independency) with a dobutamine infusion (mean dose of 10 +/- 2 micrograms/kg/min), a significant increase in VO2 from 134 +/- 22 to 157 +/- 21 ml/min/m2 was observed with a bolus infusion of enoximone (mean dose of 1.7 +/- 0.5 mg/kg). These results, observed in patients with CHF without patent oxygen debt, suggest that an artefactual VO2/DO2 dependency might be induced by the cardiovascular drug used to elevate DO2, probably because of a drug-induced oxygen demand increase.     

Trial of the combination of mitomycin, vindesine, and cisplatin in patients with advanced non-small cell lung cancer

In prior trials, mitomycin, vindesine, and cisplatin have each been shown to have reproducible antitumor activity as single agents when used in the treatment of patients with non-small cell lung cancer. The two-drug combinations of vindesine plus high-dose cisplatin or mitomycin have shown an improved major response rate and manageable toxicity in prior trials. In this report, 90 patients with stage III non-small cell lung cancer were treated with the three-drug combination of mitomycin (8 mg/m2), vindesine (3 mg/m2), and high-dose cisplatin (120 mg/m2). Eighty-seven patients (97%) were adequate for both response and toxicity. Major objective responses occurred in 60% of the patients. The toxicity of this regimen was predictable and manageable when established supportive care measures were employed. Based on the response rate observed, the combination of these three agents merits further study in randomized trials against other chemotherapeutic regimens and consideration of its use in adjuvant and preoperative settings.     

Total ischaemic time in STEMI: factors influencing systemic delay

Total ischaemic time in ST-elevation myocardial infarction (STEMI) has been shown to be a predictor of mortality. The aim of this study was to assess the total ischaemic time of STEMIs in an Irish primary percutaneous coronary intervention (pPCI) centre. A single-centre prospective observational study was conducted of all STEMIs referred for pPCI from October 2017 until January 2019.There were 213 patients with a mean age 63.9 years (range 29–96 years). The mean ischaemic time was 387 ± 451.7 mins. The mean time before call for help (patient delay) was 207.02 ± 396.8 mins, comprising the majority of total ischaemic time. Following diagnostic electrocardiogram (ECG), 46.5% of patients had ECG-to-wire cross under 90 mins as per guidelines; 73.9% were within 120 mins and 93.4% were within 180 mins. Increasing age correlated with longer patient delay (Pearson’s r=0.2181, p=0.0066). Women exhibited longer ischaemic time compared with men (508.96 vs. 363.33 mins, respectively, p=0.03515), driven by a longer time from first medical contact (FMC) to ECG (104 vs. 34 mins, p=0.0021).The majority of total ischaemic time is due to patient delay, and this increases as age increases. Women had longer ischaemic time compared with men and longer wait from FMC until diagnostic ECG. This study suggests that improved awareness for patients and healthcare staff will be paramount in reducing ischaemic time.Key words: patient delay, primary PCI, STEMI, systemic delay, total ischaemic time     

VENO-OCCLUSIVE DISEASE OF THE LIVER FOLLOWING CHEMOTHERAPY WITH MITOMYCIN C AND DOXORUBICIN

Abstract A 54-year-old woman with metastatic breast cancer developed veno-occlusive disease of the liver following chemotherapy with mitomycin C and doxorubicin. The dose of mitomycin C received by this patient was much lower than that previously described to cause this complication. As both these drugs are used widely physicians should be aware of this complication.     

A phase I dose escalation study of multicyclic, dose-intensive chemotherapy with peripheral blood stem cell support for small cell lung cancer

A phase I dose-escalation study of multicyclic, ifosfamide, carboplatin, and etoposide (ICE) with sequential reinfusion of peripheral blood stem cells (PBSCs) was conducted to determine the maximum-tolerated dose (MTD) of ICE. Twenty-four patients with SCLC (LD: 6, ED: 18) were treated with ifosfamide (3000-9000 mg/m2, 24-h infusion), carboplatin (300-400 mg/m2), and etoposide (300 mg/m2) followed by subcutaneous filgrastim (75 microg/day) from day 4 to the day of PBSC collection. PBSC were harvested when the WBC count reached >/=5 x 109/l. The leukapheresis product was cryopreserved and reinfused on day 4 of the next cycle, which was started 48 h after the last PBSC collection. The ifosfamide dose was escalated as follows: 3000 mg/m2 (level 1), 5000 mg/m2 (level 2), 7000 mg/m2 (level 3), 9000 mg/m2 (level 4). Patients with LD were treated with concurrent radiotherapy at 1.5 Gy twice daily for the initial 3 weeks to a total dose of 45 Gy and MTD, defined separately. Patients were evaluated for hematologic and non-hematologic toxicity, actual dose intensities, as well as response to therapy. The maximum-tolerated dose (MTD) was defined as the dose level at which more than 5 days of grade 4 myelo- suppression or non-hematologic toxicity greater than grade 3 developed in two thirds of the patients. For ED cases, MTD was level 4 and the recommended dose of ifosfamide was 7000 mg/m2. For LD cases, the recommended dose of ifosfamide was 5000 mg/m2. The dose limiting toxicity of multicyclic ICE was hemato- logic toxicity and CNS toxicity which manifested as ataxia. Tumor responses were seen in all patients, with 14 patients showing a complete response. The actual total dose-intensity at the recommended dose level was 2.2 and 1.74, for ED and LD, respectively, compared with previously reported ICE regimens. PBSC support for dose-intensive ICE regimen permitted dose escalation of ifosfamide with a mean interval of 16-17 days. We conclude that this regimen is well tolerated, with acceptable hematological and non-hematological toxicity. Bone Marrow Transplantation (2000) 25, 5-11.     

High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: a dose finding study

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.     

113例冠脉造影和介入治疗被检者所受辐射剂量统计与分析

目的 通过对冠状动脉造影和介入治疗被检者所受辐射剂量值的统计、分析与评估,探讨如何降低其放射诊疗的风险度,避免确定性效应的发生。方法 收集113例受检者检查时在线记录的全部辐射剂量值及其相关的参数值,进行分类统计,对照国家相关文件要求比对、分析与评估。结果（1） 单纯冠脉造影（CA）69例,总累积剂量面积乘积（DAP） 均值为7257.8±7935.6μGy·m2 ;总累积皮肤入射剂量（ESD） 均值为865.5 ±418.87mGy,其中有6例＞2Gy,占9%;透视皮肤入射剂量率＞100mGy/min有24例,占35%。（2）冠脉造影 介入（I CA）44例,总累积剂量面积乘积（DAP） 均值为20811.8±11704.1μGy·m2 ;总累积皮肤入射剂量（ESD）,均值为2979.7±1625.1mGy,其中有42例＞2Gy,占95%;透视皮肤入射剂量率＞100mGy/min为33例,占75%;结论 I CA被检者所受辐射剂量约是CA的4.4倍。CA和I CA的透视皮肤入射剂量率超过指导水平的分别占到35%和75%;总累积皮肤入射剂量＞2 Gy者分别占到9%和95%,提示我们在医用放射诊疗防护中介入放射学的防护是重中之重,必须建立一套严格有效的管理机制。     

Hexamethylmelamine and cisplatin in advanced ovarian cancer after failure of alkylating-agent therapy

Thirty-eight women with advanced ovarian cancer resistant to alkylating-agent chemotherapy were treated with a combination of hexamethylmelamine and cisplatin. Hematologic toxicity was severe or life-threatening in seven of 13 patients treated with cisplatin at a dose of 100 mg/m2 but was acceptable in 25 patients treated at 75 mg/m2. Thirty-four percent of the combined group developed peripheral neuropathy and only 8% of those treated at 75 mg/m2 developed transient azotemia. Nine complete responses and 12 partial remissions were noted among 38 patients treated, with no obvious advantage for the higher dose of cisplatin. The median duration of remission was 8 months and the overall median survival was 9 months. The response rate of 55% is approximately twice that reported with either agent given alone in similar patient populations and is equal to or better than that reported for more complicated regimens containing these drugs together with other, less active drugs.     

Bleomycin, mitomycin, and cisplatin therapy for advanced squamous carcinoma of the uterine cervix: a phase II study of the Northern California Oncology Group

Twenty-eight patients with advanced squamous carcinoma of the uterine cervix received cisplatin, bleomycin, and mitomycin after failure of surgery and/or irradiation to control disease. Six patients (21%) achieved responses (two complete; four partial), ranging from 3 to 7+ months. Toxicity was acceptable for most patients; however, dose reduction because of myelosuppression was frequently required. Bleomycin was delivered by continuous iv infusion, and no significant pulmonary toxicity was observed. Although this combination of drugs has activity in advanced squamous carcinoma of the uterine cervix, the addition of cisplatin to bleomycin and mitomycin did not significantly increase the clinical response rate.     

Successful reduced-intensity SCT from unrelated cord blood in three patients with X-linked SCID

We describe three males with X-linked SCID (X-SCID) who were successfully treated by reduced-intensity SCT from unrelated cord blood (CB). Mean age at transplant was 5.7 months (range, 3-9 months). Pre-transplant conditioning for all patients consisted of fludarabine (FLU) (30?mg/m(2) per day) from day -7 to day -2 (total dose 180?mg/m(2)) and BU 4?mg/kg per day from day -3 to day -2 (total dose 8?mg/kg). All CB units were serologically matched at HLA-A, B and DR loci. Although two patients had suffered from fungal or bacterial pneumonia before transplantation, there were no other infectious complications during transplantation. All patients engrafted and achieved 100% donor chimerism. We also confirmed full donor chimerism of both T and B cells. Only one patient developed acute GVHD grade III, which was resolved by increasing the dose of oral corticosteroid. None of the patients has developed chronic GVHD during follow up for 21-77 months. None of the patient received i.v. Ig replacement post transplant, or showed delay in psychomotor development. Reduced-intensity conditioning consisting of FLU and BU and transplantation from unrelated CB was an effective and safe treatment for these patients with X-SCID.