A Phase II Trial of Etoposide, Leucovorin, 5-FU, and Interferon Alpha 2b (ELFI) + G-CSF for Patients with Pancreatic Adenocarcinoma: a Southwest Oncology Group Study (SWOG 9413)

Background. Chemotherapeutic treatments using combinationsof etoposide, leucovorin and 5-FU (ELF) have shown activity inthe treatment of gastrointestinal malignancies. Interferon alpha2b is known to have antiproliferative effects on several celllines and has well documented in vitro evidence ofsynergism with 5-FU. It was postulated that the combination ofELF and interferon alpha 2b would improve response rates andsurvival in patients with pancreas cancer. Methods. Fifty-five eligible patients with locally-advancedor metastatic pancreatic adenocarcinoma received a regimenconsisting of: IV leucovorin at 300 mg/m²/day on Days 1-3(of 28-day cycle), IV etoposide at 80 mg/m²/day on Days 1-3, IV 5-FU at 500 mg/m²/day on Days 1-3, subcutaneousinterferon alpha 2b at 3 million units TIW, and subcutaneousG-CSF at 5 g/kg/day on Days 4-14 (or until WBC exceeds10,000/l). Patients with no evidence of disease progressioncontinued on treatment for a total of 6 cycles. Results. Complete response was demonstrated in 1 patient,partial response in 5 patients (11% confirmed response rate).The median survival was 5 months, and the six-month survival ratewas 40%. Ten patients completed all 6 cycles of treatment.Toxicity-related dose delays and reductions were necessary formost patients. Conclusions. Although the combination of ELF and interferonalpha 2b (ELFI) has modest activity in pancreatic cancer, it isa toxic and complex regimen that is not superior to othercurrently available approaches for the chemotherapeuticmanagement of pancreatic cancer. ELFI cannot be recommended asa standard therapy.     

A phase II pilot study of high-dose 24-hour continuous infusion of 5-FU and leucovorin and low-dose PALA for patients with colorectal cancer: A Southwest Oncology Group study

PURPOSE: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients were required to have histologically confirmed colorectal cancer with distant metastases. The treatment regimen consisted of 5-FU 2600 mg/m(2) as a 24-hours continuous infusion given once a week, concurrently with leucovorin (LV) at 500 mg/m(2) as a 24-hour continuous infusion. PALA was administered 24 hours prior to 5-FU/LV at a dose of 250 mg/m(2) iv over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. RESULTS: This study accrued 28 patients and all were eligible and evaluable for toxicity. Four patients had inadequate assessment of response and are considered non-responders. There was one complete response and five partial responses for an overall response rate of 6/28 or 21% (95% confidence interval 8-41%). Estimated median survival was 17.4 months (95% confidence interval 13.3-20.5 months). One patient died of a treatment related infection. This patient also had grade 4 diarrhea and vomiting. CONCLUSION: The combination of 5-FU, leucovorin, and PALA in the doses and schedule used here, produces a response rate similar to other modulated schedules of 5-FU with similar survival and toxicity profiles.     

Phase II trial of 9-aminocamptothecin (NSC 603071) administered as a 120-hour continuous infusion weekly for three weeks in metastatic colorectal carcinoma

9-Aminocamptothecin (9-AC) is a camptothecin derivative with broad antitumor activity in preclinical studies. Prior investigations suggested that prolonged maintenance of 9-AC lactone plasma concentrations above 10 nmol/l and frequent administration of the drug are important determinants of antitumor activity. Our phase II study, therefore, examined a 5-day continuous infusion of 9-AC weekly for 3 weeks in patients with advanced colorectal cancer. Eighteen patients previously untreated for metastatic disease received 480 g/m²/day of 9-AC. No responses were observed in 17 evaluable patients. Severe toxicities included granulocytopenia, nausea, vomiting and diarrhea. The median absolute granulocyte count (AGC) nadir was 2,300/l (range 0–9,000/l) and occurred on day 10. Eight patients received an escalated dose of 600 g/m²/day. The median AGC nadir at the escalated dose was 1,500/l (range: 300–2,700/l) and occurred on day 22. The median number of courses given was 2 (range: 1–8); and the median time to disease progression was 8 weeks (range: 1–40 weeks). 9-AC administered by this schedule lacked antitumor activity in patients with advanced colorectal carcinomas.     

Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer

Summary The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m² was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m² as a bolus i.v. injection, and 5-FU 2300 mg/m² by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.     

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced biliary carcinoma

Precis: UFT 300 mg/m²/day and leucovorin 90 mg/day could be administered safely to patients with advanced biliary cancer with good performance status; however, this combination and schedule of 28-day administration has no activity in this disease.Purpose: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of patients with advanced biliary (gallbladder and bile duct) carcinoma.Patients and methods: Thirteen patients with advanced measurable biliary carcinoma were enrolled onto the trial. All patients had a Karnofsky performance status 60%, platelet count 75,000/L, total bilirubin 2.0× institutional upper limit of normal but otherwise normal liver and kidney function profile and bidimensionally measurable disease by CT scan or ultrasound examination. None of these patients previously received cytotoxic chemotherapy or radiation therapy for advanced disease. Patients received 300 mg/m²/d UFT plus 90 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days repeated every 35 days. Objective tumor response, the primary endpoint of this trial, was evaluated after two courses of therapy. Other endpoints included toxicity, time to progression, and overall survival.Results: All patients were evaluable for response and toxicity. No complete or partial responses were observed in this trial. Four patients had stable disease lasting 17, 30, 33, and 35 weeks, respectively. The median (range) time to progression and survival were 9 (1–35) and 28 (1–61) weeks, respectively. Treatment-related toxicity was mild with severe (grade 3 or 4) diarrhea seen in 2 (15%). Grade 3–4 hyperbilirubinemia (31%) and nausea/vomiting (31%) were observed and likely related to the underlying disease. Grade 1 and 2 toxic effects included mainly anorexia and fatigue.Conclusion: UFT 300 mg/m²/d plus oral leucovorin 90 mg/d administered for 28 days repeated every 35 days is ineffective in the treatment of advanced biliary carcinoma.     

Phase I trial of fluorouracil modulation by n-phosphonacetyl-l-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer

The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m² day 1, followed 24h later by MMPR 150 mg/m² as an iv bolus, and the initiation of a 24 hour infusion of 5-FU along with leucovorin 50 mg/m². This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m². Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m². There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.     

Phase II study of AMSA alone and in combination with DTIC in patients with metastatic melanoma

Summary A randomized phase II study of AMSA (amsacrine) alone and AMSA combined with DTIC (dacarbazine) was carried out in 31 and 39 patients with metastatic melanoma respectively. AMSA was used at a starting dose of 40 mg/m²/day × 3 days with escalation to 50–60 mg/m²/day × 3 days in 8 pts. For AMSA + DTIC the starting dose was: AMSA 30 mg/m²/day × 3 days; DTIC, 800 mg/m² × 1 day. Additionally, seven pts received AMSA in a similar dose schedule but DTIC was used in a 5-day schedule of 250 mg/m²/day. Twentyfive patients were evaluable for response in the AMSA group and 36 in the AMSA + DTIC group. The objective response to AMSA included 1(4%) partial response compared with 11 complete or partial responses (30%) with AMSA + DTIC therapy. The median lowest absolute granulocyte count was 1100/l in AMSA group compared with 1000/l in the AMSA + DTIC group. Severe neutropenia of < 500 granulocytes/l was observed in 5 pts in the AMSA group compared with 13 pts in the AMSA + DTIC group. We concluded that AMSA has no significant activity against melanoma, although the combination of AMSA + DTIC seemed to be more active than DTIC alone.     

Mitomycin C with weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract and periampullar carcinomas

We have reported a 33% partial response rate with acceptable toxicity using weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in patients with far advanced biliary tract cancers (BTC). In this study, we added mitomycin (MMC) to 5-FU and LV in an attempt to improve the response rate and survival. From July 1997 to September 1999, 25 chemotherapy-naive patients with pathology-proven far advanced BTC and periampullar cancers were enrolled. The regimen consisted of MMC 10 mg/m(2) every 8 weeks combined with 5-FU 2600 mg/m(2) and LV 150 mg at a schedule of 24-h infusion weekly for 6 weeks followed by a 2 week break. There were 10 males and 15 females with a median age of 57 years (range 40-76). The sites of primary tumor were 15 intrahepatic cholangiocarcinomas (CC), one perihilar CCs, three distal BTC, three gallbladder cancers (GB) and three periampullar cancers. A total of 148 sessions of chemotherapy were given with a mean of 8 (range 2-18). Nineteen patients were evaluable for response. The response rate was: 26% (five of 19) partial response, 42% (eight of 19) stable disease and 32% (six of 19) progressive disease. All of the patients were evaluable for toxicity. Toxicities more than grade III-IV were thrombocytopenia 16% (four of 25), leukopenia 12% (three of 25) and vomiting 4% (one of 25). There were four treatment-related deaths. The median time to disease progression was 3 months. The median survival was 6 months. A combination of MMC with weekly high-dose 5-FU and LV in patients with BTC did not improve the response rate, but produced more toxicity than weekly high-dose 5-FU and LV alone.     

A Bayesian method for predicting 5-fluorouracil pharmacokinetic parameters following short-term infusion in patients with colorectal cancer

The objective of this study was to develop a population pharmacokinetic model and validate it using a Bayesian approach for predicting, a priori and a posteriori, the individual volume of distribution (V(d)) and clearance (Cl) of 5-fluorouracil (5-FU) given as short-term intravenous infusion in weekly and multiple doses. Forty-four patients were divided in group A (5-FU weekly doses) including 27 patients with nonmetastatic colorectal adenocarcinoma treated with 450 mg/m(2) of 5-FU, 1 day per week for 48 doses, plus oral levamisol (50 mg/8 h) for 3 days, every 15 days and group B (5-FU multiple doses) including 17 patients with metastatic colorectal adenocarcinoma, receiving 5-FU (425 mg/m(2)) plus intravenous folinic acid (20 mg/m(2)) over 5 consecutive days, every 4 weeks for six cycles. In both groups 5-FU was administered as a 30-60-min infusion. A total of 176 plasma concentrations were analyzed using a NONMEM program according to a linear one-compartment model. In group A, 5-FU population pharmacokinetic parameters were obtained and the covariables studied were age, gender, weight, ideal body weight, height, body surface area, creatinine clearance, and hepatic function tests. A priori and a posteriori validation of this model was carried out with plasma concentrations obtained in day 1 in group B. In group B, population pharmacokinetic parameters of 5-FU following multiple doses were estimated using scale factors to identify differences in 5-FU V(d) and Cl between days 1 and 4, and the interindividual, interoccasion, and residual variabilities studied. V(d) was 0.266 L/kg of ideal body weight and Cl was 1.21 L/h. kg of total weight following weekly doses. The plasma sample obtained at 10 min gave the best accuracy and precision predictions. When 5-FU was administered in multiple doses, the Cl of the drug in day 4 is reduced by 30.14% compared to day 1. The interoccasion variability was lower than interindividual variability for both V(d) and Cl, suggesting that it could be feasible to individualise dosage of 5-FU for subsequent cycles from data obtained in a previous one in an attempt to improve the therapeutic index of colorectal cancer treatment.     

Does leucovorin alter the intratumoral pharmacokinetics of 5-fluorouracil (5-FU)? A Southwest Oncology Group study

Purpose and design: We previouslydocumented that there was an associationbetween the intra-tumoral pharmacokinetics(TPK) of 5-FU and response to therapy with5-FU and leucovorin (p < .0001). Since wehave shown that other modulators of 5-FU,such as methotrexate, interferon andneutrexin alter its TPK, it was of interestto determine if the modulating effect ofleucovorin would also alter the tumoral PKof 5-FU. In order to determine the effectof leucovorin on intratumoral 5-FUpharmacokinetics, 23 patients (21evaluable) underwent ¹⁹F magneticresonance spectroscopy ¹⁹F-MRS)twice. The first ¹⁹F-MRS was following5-FU 600 mg/m² alone, and the second¹⁹F-MRS was following by leucovorin500 mg/m² and then 5-FU 600 mg/m². Results: A comparison of theintratumoral 5-FU pharmacokineticsindicated that there was no general effectof leucovorin on the intratumoral half-lifeof 5-FU. In only two of these 21 patientswas the half-life of 5-FU altered, and inboth cases it was decreased by more than20%. Partial responses to 5-FU plusleucovorin therapy were seen only inpatients with a long intratumoral half-life(trapping) of 5-FU (3 PR in 11 patientswith T_1/2 20 minutes, comparedto 0 PR in 11 patients with T_1/2 <20 minutes). There was a statisticallysignificant correlation between tumorresponse and the intratumoral T_1/2 of5-FU, consistent with our prior results ina larger number of patients. However, therewas no statistically significantcorrelation of time-to-progression orsurvival with classification of thepatients into trappers or non-trappers,probably due to the small sample size inthis current study. Conclusion: The data reported hereare compatible with the hypothesis thatleucovorin enhancement of 5-fluorouracilantitumor responses is not mediated by thelevels of 5-FU in tumors, but rather, isdue to the modulation by leucovorin ofcellular metabolic processes that followthe uptake of free 5-FU into the tumorcell. The MRS technique may be useful inselected instances for elucidating thepossible metabolic interactions of drugsin vivo.     

Pharmacokinetics and biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Wistar rats were treated initially with very high single doses of ¹⁴C-2,3,7,8-TCDD (either 75 or 25 g/kg body wt) followed by weekly maintenance doses of 15 and 5 g/kg body wt, respectively. ¹⁴C-radioactivity was measured in various organs over a period of 22 weeks. 1) 75 g TCDD/kg body wt (followed by the maintenance doses) was lethal for all the rats within a period of 9 weeks. While the concentration of ¹⁴C-TCDD equivalents in liver and thymus stayed reasonably constant during this period in the surviving rats, the concentration in adipose tissue and kidneys clearly increased in the same animals. 2) The dose of 25 g TCDD/kg body wt (followed by weekly doses of 5 g/kg body wt) proved to be a just tolerable dose over a period of 22 weeks for our strain of rats. 3) Within the individual variabilities the TCDD concentrations in the investigated organs showed no clear-cut decline, indicating that the animals were exposed to fairly constant levels of TCDD throughout the study. Thus, this dosing regime is suitable for maintaining constant TCDD exposure during long-term studies.Abbreviations TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin     

Vasopressin has general rate-decreasing effects on schedules maintaining either high or low response rates

Male and female Wistar rats were treated with different doses of vasopressin (0.05, 0.25, 1.25, 3.75 and 6.25 g/kg) after responding had stabilized on either a differential reinforcement of low rate 15 s (DRL 15 s) or a differential reinforcement of high rate 0.75 s (DRH 0.75 s) schedule of reinforcement. Low to moderate doses of vasopressin did not affect response rates, response efficiency or the number of reinforcers obtained during vasopressin sessions on both the DRL and DRH schedules. Administration of 6.25 g/kg vasopressin reduced low response rates and the number of reinforcers obtained during vasopressin sessions, but increased response efficiency. High response rates and response efficiency were reduced after administration of 3.75 and 6.25 g/kg vasopressin, while the number of reinforcers obtained during vasopressin sessions was reduced at 6.25 g/kg. Sex differences in the effects of vasopressin were not observed on either schedule.     

Pharmacokinetic study of methotrexate,folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue

Summary The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g·m^–2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL).The median steady-state concentration of MTX was 66 mol·l^–1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg·m^–2·min^–1.The 7-OHMTX level increased during each infusion and a C_max of 19 mol·l^–1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8.The MTX metabolite APA was detected in concentrations less than 0.06 mol·l^–1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mol·l^–1 and 18 h following the last dose of LCV it was 0.44 mol·l^–1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mol·l^–1 with a median ratio of 5-MTHF to MTX of 2.Twenty infusions with 48 h MTX levels of less than 0.5 mol·l^–1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mol·l^–1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.     

Pharmacokinetics and cytotoxicity of B.3839, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea,in a mouse model

Summary B.3839 is the prototype compound in a series of novel molecular combinations of chloroethylnitrosoureas and 5-fluorouracil(5-FU) and has been tested against MAC tumours in mice. Previous studies have shown it is moderately active against MAC15A and highly active against MAC13 though this activity is dependent on route of administration. The aim of this study was to determine whether bioavailability could explain this difference in anti-tumour activity. Plasma levels of B.3839 and 5-FU after i.p. and oral administration were measured using HPLC. Non tumour-bearing and MAC26 bearing mice gave almost identical plasma profiles after i.p. administration with the C_max being 29.8 and 30.4 gml^–1 and t_1/2 16 and 15 min. The AUCs were 15.3 and 13.9g h ml^–1 suggesting tumour load had no influence over plasma levels. Oral administration gave a much lower C_max of 8.0g ml^–1 but an AUC of 15.2g h ml^–1 due to a longer terminal t_1/2 (94 min) giving 99% bioavailability. Levels of 5-FU release from B.3839 by either route were considered too small to influence anti-tumour activity. Cytotoxicity assaysin vitro against the MAC lines gave IC₇₀ values of 5.3, 13.8 and 8.6g ml^–1 for MAC 26,13 and 15A respectively after a one hour exposure. Bone marrow toxicity was shown to be less severe than that of TCNU which is currently in clinical trials. The results show bioavailability alone is not enough to explain tumour response. There appears to be a need for a threshold concentration (C) to be maintained for a period of time (t).Drs. M.C. Bibby and J.A. Double are members of the Screening and Pharmacology Group of the EORTC.     

A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion

Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokinein vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40g/m² and was ultimately escalated to 200g/m². A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160g/m² was defined as the MTD. At 160g/m² peak serum levels occurred within 5–20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80g/m². This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.     

A phase II study of rebeccamycin analog NSC 655649 in patients with metastatic colorectal cancer

The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated anti-tumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status 70%, age 18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500mg/m² by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1–6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/l (116–16,374/l) and 276×10³/l (5–769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.     

The effect of urapidil on responses to phenylephrine,angiotensin and isoprenaline in man

Summary Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg·h^–1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 g·min^–1 before to 685 g·min^–1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has ₁-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.     

Phase II trial of gemcitabine (2,2′-difiuorodeoxycytidine) in patients with adenocarcinoma of the pancreas

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m² was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 10³/l (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 10³/l (range 0.4–7.2). Thrombocytopenia - 100.0 × 10³/l was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.     

A phase II study of menogaril (NSC-269148) in colorectal carcinoma

Summary In this phase II trial, menogaril was administered to patients with metastatic colon cancer at a dose of 200 mg/m² IV over one hour with cycles repeated every 28 days provided the absolute granulocyte count was 2000 cells/l. Dose adjustments up or down were made depending upon nadir counts. Twenty-four patients were entered on this study with 21 eligible and evaluable for response. There was 1 CR lasting four and one-half months and 1 PR lasting three months for an overall CR \s&#x002B; PR rate of 10% with a 95% confidence interval of 1% to 30%. Six patients (29%) had stable disease and 13 (62%) progressed. Median survival is 13.1 months. Toxicity was primarily hematologic with two cases of life-threatening leukopenia (< 1000 cells/l) and one case of life-threatening granulocytopenia (< 250 cells/l) among the 21 eligible patients, and one case of life-threatening leukopenia and granulocytopenia in one ineligible patient. There were no deaths due to treatment.     

Monoamines modulate the electrically-evoked efflux of 3H-choline from slices of guinea pig nucleus basalis magnocellularis

The influence exerted by monoamines on acetylcholine release was studied in electrically stimulated slices of guinea pig nucleus basalis magnocellularis (nbM) prelabelled with ³H-choline (3H-Ch).Noradrenaline, 30 M, and clonidine, 1 M, reduced the evoked ³H-Ch efflux by about 50%, but phenylephrine, 100 M. did not; idazoxan, 0.1 M. but not prazosin, 1 M, antagonized these effects. pointing to the involvement of alpha₂ receptors. Apomorphine, 1 or 30 M. reduced ³H-Ch efflux from nbM slices as well. The effect was shared by quinpirole, 1 or 10 M, but not by 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benz-azepine (SKF 38393). 10 M, and was antagonized by sulpiride, 1 M, but not by R-(+)-8-chloro-2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390). 1 M, suggesting the involvement of the D₂ receptor subtype.5-hydroxytryptamine (5-HT) 0.3–30 M, and alphamethyl-5-HT, 10 M, significantly increased ³H-Ch efflux from nbM slices; the 5-HT₂ antagonist ritanserin, 1 M. prevented this response. 2-methyl-5-HT, 1–30 M, inhibited the evoked ³H-Ch efflux and its effect was prevented by the 5-HT₃ antagonist 1H,3,5H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222). 1 M.These findings indicate that i) catecholamines inhibit nbM neurons through alpha₂ and D₂ receptors and that ii) a complex serotonergic modulation of cholinergic function exists in the nbM, involving the activation of various receptor subtypes. which can mediate opposite responses. Correspondence to: A. Siniscalchi at the above address