Multicenter phase II study of chemoimmunotherapy in the treatment of metastatic melanoma

Combining chemotherapy and immunotherapeutic agents such as interleukin-2 and interferon alpha-2b might improve treatment results in metastatic melanoma (MM) patients compared with chemotherapy alone. This prospective study evaluated the potential efficacy of a biochemotherapy regimen followed by maintenance biotherapy for the treatment of MM. Twenty-two patients with stage IV melanoma were treated for 5 consecutive days with cisplatin at 20 mg/m, vinblastine at 1.6 mg/m, and dacarbazine at 160 mg/m. Pegylated interferon alpha-2b at a dose of 50 microg every week, subcutaneous interleukin-2, 1.8 MIU, and oral 13-cis-retinoic acid (13-cis-RA) at 0.5 mg/kg were given 5 days/week for 3 weeks each month during the period of chemotherapy administration. Maintenance biotherapy was continued in patients who had a complete or partial response or disease stability (clinical benefit) after six courses of biochemotherapy. The primary endpoint was response; secondary endpoints were the evaluation of the immunologic parameters, toxicity, progression-free survival, and overall survival. Twelve patients (54.5%) achieved a response, and seven (31.8%) maintained stable disease for at least 6 months with maintenance biotherapy. The median progression-free survival and overall survival were 23.3 and 45.7 months, respectively. The most important toxicities from chemotherapy were grades 3 and 4 neutropenia and thrombocytopenia in 41 and 18% of patients, respectively, whereas grade 2 autoimmune reactions were observed in 21% of patients after maintenance biotherapy. A prolonged enhancement of immunologic function was observed in the 19 patients treated with maintenance therapy. A regimen of six cycles of biochemotherapy followed by maintenance immunotherapy is well tolerated, and shows significant activity in patients with MM.     

Superiority of YM598 over atrasentan as a selective endothelin ETA receptor antagonist

The binding affinities of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598) for native human endothelin ETA and ETB receptors expressed in human coronary artery smooth muscle cells (CASMC) and a human melanoma cell line, SK-Mel-28, respectively, were examined, and the results compared with those for the endothelin receptor antagonists atrasentan and bosentan. The in vivo endothelin ETA receptor inhibitory activities of YM598 and atrasentan were also compared through the suppression of the big endothelin-1-induced pressor response in pithed rats. Ki values of YM598, atrasentan, and bosentan for native human endothelin ETA receptors were 0.772, 0.0551, and 4.75 nM, while those for native human endothelin ETB receptors were 143, 4.80, and 40.9 nM, respectively. The calculated selectivity ratios of YM598, atrasentan, and bosentan for endothelin ETA versus ETB receptors were 185, 87 and 8.6, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner on both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but closely similar on oral administration. These results suggest that YM598 has high selectivity for native human ETA against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist with regard to pharmacological bioavailability in rats.     

Coronary and aortic vasoreactivity protection with endothelin receptor antagonist, bosentan, after ischemia and hypoxia in aged rats.

This study investigated the effects of bosentan, a dual endothelin ET(A) and ET(B) receptor antagonist, during hypoxia-reoxygenation of senescent aorta and during ischemia-reperfusion of senescent heart. Isolated aortic rings and isolated hearts from adult and senescent rats were submitted, respectively, to hypoxia/reoxygenation (20/30 min) and to low-flow ischemia/reperfusion (45/30 min), without or with bosentan (10(-5) M). In the aorta, bosentan treatment prevented the impairment of relaxation in response to acetylcholine after hypoxia-reoxygenation at both ages. In the heart, coronary flow recovery during reperfusion, which is lower in senescents than in adults (48% vs. 76% of baseline value, respectively; P<0.05) was fully prevented by bosentan. Prevention of endothelial dysfunction during reoxygenation of hypoxic aorta and of coronary vasoconstriction during reperfusion of ischemic heart with a dual endothelin ET(A) and ET(B) receptor antagonist suggests a role of endothelin in the vulnerability of aorta to hypoxia-reoxygenation, and of coronary arteries to ischemia-reperfusion, especially during aging.     

Phase II study of epirubicin in advanced malignant melanoma

Summary Twenty patients with advanced malignant melanoma refractory to conventional chemotherapy, were entered into a Phase II study of epirubicin, one of the new doxorubicin analogues. The drug was given at a dose of 90 mg/m² IV every 3 weeks. One partial response and three disease stabilizations were observed. Nausea and vomiting and alopecia were common. Mild to moderate leukopenia occurred in 6 patients. Three cases of reversible ST-T changes were recorded. The observed response rate of 5% with a 39.2% probability of a true response rate 10%, does not suggest that epirubicin, in the dose and schedule chosen, is active in metastatic malignant melanoma.     

Bosentan

? Bosentan is a nonpeptide, specific, competitive, dual antagonist at both endothelin receptor subtypes (ET_A and ET_B). Orally administered bosentan effectively prevents endothelin 1-induced vasoconstriction in pulmonary vessels in patients with pulmonary arterial hypertension. ? Improvement in exercise capacity from baseline was significantly greater with bosentan than with placebo in two phase III trials in patients with WHO functional class III or IV pulmonary arterial hypertension (primary or associated with connective tissue disease) despite treatment with vasodilators, diuretics, anticoagulants, cardiac glycosides, or supplemental oxygen. The beneficial effects of bosentan on exercise capacity were maintained for at least 20 weeks. ? Compared with placebo, bosentan led to a significantly greater improvement from pretreatment values in secondary efficacy end-points such as the Borg dyspnea index, WHO functional class, and cardiopulmonary hemodynamic parameters (cardiac index, pulmonary vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure). ? Bosentan significantly reduced the incidence, and delayed the onset, of clinical worsening of pulmonary arterial hypertension compared with placebo. ? In published clinical trials, adverse events that occurred with similar or greater frequency with bosentan 125mg twice daily than with placebo included headache, syncope, flushing and abnormal hepatic function. Those that occurred less frequently with bosentan 125mg twice daily than with placebo included dizziness, worsening of symptoms of pulmonary arterial hypertension, cough and dyspnea.     

The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects

AIMS: To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS: This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings. RESULTS: Steady-state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady-state Cmax and Ctr were 2-2.1 microg l-1 and 0.65-0.69 microg l-1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0-23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 microg l-1 and a mean AUC (0, 12h) of 12 600 microg l-1 h. CONCLUSIONS: Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects     

Bosentan

Bosentan (Tracleer), an orally administered dual endothelin (ET)(A) and ET(B) receptor antagonist, is indicated in the treatment of pulmonary arterial hypertension (PAH).The efficacy of oral bosentan 125 mg twice daily in improving exercise capacity has been demonstrated in well designed trials in adult patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts, and in other trials in patients with idiopathic PAH or PAH associated with congenital heart disease or HIV infection. The beneficial effects of first-line bosentan treatment may be maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease. Despite the potential for treatment-related teratogenicity and hepatotoxicity, long-term data indicate that bosentan is generally well tolerated at the approved dosages. Although well designed trials are required to establish the efficacy of bosentan versus or in combination with other specific PAH therapies, especially sildenafil, the convenient oral administration and lack of serious injection-related adverse effects may render bosentan preferable to other PAH therapies. Preliminary data indicate that bosentan may be effective in pediatric PAH patients, although randomized trials are required. Furthermore, bosentan may be a useful option for the prevention of digital ulcer development in patients with systemic sclerosis. Thus, in accordance with current clinical guidelines, bosentan is a convenient, effective, and generally well tolerated agent for use in the first-line treatment of class III PAH or second-line treatment of class IV PAH.     

Effects of the non-peptide, non-selective endothelin antagonist, bosentan, on regional haemodynamic responses to NG-monomethyl-L-arginine in conscious rats.

1. Male, Long Evans rats (350-450 g) were chronically instrumented to allow monitoring of mean arterial blood pressure, heart rate and changes in renal, mesenteric and hindquarters haemodynamics. In the first experiment, animals (n = 8) were given a bolus i.v. injection of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine hydrochloride (L-NMMA; 30 mg kg-1) on four consecutive days. Fifteen min prior to L-NMMA administration on the fourth day, the endothelin, ETA-, ETB-receptor antagonist, bosentan, was injected (30 mg kg-1, i.v.). Relative to the response on the third day, bosentan caused 33 +/- 4%, 24 +/- 3%, 14 +/- 3%, and 18 +/- 5% inhibition of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of L-NMMA, respectively. 2. In the second experiment, bosentan was given 15 min before L-NMMA in a group of rats (n = 6) which had not received L-NMMA previously. Relative to the responses to L-NMMA on the first day in the previous experiment, bosentan caused a 30%, 24%, 18% and 27% inhibition of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of L-NMMA, respectively. 3. The results indicate a significant contribution from endothelin to the haemodynamic effects of L-NMMA in conscious rats. However, since our previous studies have shown the renin-angiotensin and sympathoadrenal systems are not involved, it is likely that the major component of the cardiovascular response to L-NMMA in conscious rats is due to loss of vasodilator action of endothelial nitric oxide.     

Phase II trial of escalated dose of tirapazamine combined with cisplatin in advanced malignant melanoma

A phase II study was undertaken to determine the efficacy of tirapazamine combined with cisplatin in patients with metastatic melanoma between April 1996 and April 1997. Tirapazamine 390 mg/m2, administered i.v. over 2 h, followed in 1 h by cisplatin 75 mg/m2 over 1 h, were used every 21 days to treat chemotherapy-naive patients with metastatic melanoma. Objective tumor measurements were used to assess efficacy of the regimen. NCI common toxicity criteria were used to grade toxicities. Forty-eight patients with metastatic melanoma of cutaneous or mucosal origin, none with symptomatic brain metastasis, were treated. Nine patients had a partial response, with an overall response rate of 20% (95% confidence interval: 9-33%). The median duration of response was 6 months. Grade 3 nausea, vomiting, anorexia, muscle cramps and fatigue occurred in fewer than 10% of patients. Neutropenia and thrombocytopenia were rare. This outpatient single-day administered tirapazamine-cisplatin regimen has definite activity in chemotherapy-naive patients with metastatic melanoma. Further studies in combination with other agents active against this disease are warranted.     

ADRENOCORTICOTROPHIC HORMONE-INDUCED HYPERTENSION IN THE RAT: EFFECTS OF THE ENDOTHELIN ANTAGONIST BOSENTAN

1. The effects of the endothelin antagonist bosentan on adrenocorticotrophic hormone (ACTH)-induced hypertension were examined in the conscious male Sprague-Dawley rat. 2. In order to confirm endothelin antagonism, 18 rats were randomly divided into two groups: receiving either (i) endothelin-1 (0.125, 0.25, 0.5 and 1 nmol/kg, i.v.); or (ii) endothelin-1 at these doses following bosentan (100 mg/kg gavage) and mean arterial pressure recorded (study A). Subsequently, 40 male rats (320 +/- 5 g) were randomly divided into four groups (n = 10): (i) Sham (0.9% saline, s.c.) + 5% acacia gum gavage; (ii) ACTH (500 micrograms/kg per day, s.c.) + 5% acacia gum gavage; (iii) Sham injection + bosentan (100 mg/kg per day) gavage; or (iv) ACTH + bosentan. Six control days (C1-C6) were followed by 11 treatment days (T0-T10). Systolic blood pressure, water intake, urine volume, food intake and bodyweight were measured every second day (study B). 3. Bosentan significantly attenuated the endothelin-1-induced blood pressure rise at 0.125 nmol/kg (P < 0.05), but not at higher doses. 4. Bosentan at a dose which attenuated endothelin-1-induced blood pressure increase had no effect on either blood pressure or metabolic parameters in ACTH-treated rats. 5. These results suggest that endothelin does not play a major role in ACTH-induced hypertension.     

Weekly paclitaxel, 5-fluorouracil and folinic acid with granulocyte colony-stimulating factor support in metastatic breast cancer patients: a phase II study

We conducted a phase II study to determine the activity and tolerability of weekly paclitaxel, 5-fluorouracil (5-FU) and folinic acid plus granulocyte colony-stimulating factor (G-CSF) support in anthracycline-pre-treated or -resistant metastatic breast cancer patients. The phase II study was designed following the Simon optimal-two stage method. Patients received paclitaxel 80 mg/m, folinic acid 10 mg/m and bolus infusion of 5-FU 300 mg/m every week plus G-CSF on day 3 for 24 consecutive weeks in the absence of disease progression. From May 1998 to May 2000, 51 patients entered the study. Patients received a median relative dose intensity of 97.5% (range 81-100%). No severe toxicities were observed. Seven patients (14%) experienced neutropenia grade 2. Seven patients (14%) experienced grade 2 anemia. Two patients (4%) experienced severe asthenia. Three out of 50 evaluable patients [6%, 95% confidence interval (CI) 2-12.6%] showed a complete response, whereas 23 (46%, 95% CI 32.2-59.8%) had a partial response, with an overall response rate of 52% (95% CI 38.2-65.8%). In addition, eight patients (15.7%) had stable disease. In the 13 patients untreated for metastatic disease, the overall response rate was 92.3% (CI 77.8-100), with one complete response and 11 partial responses (84.6% CI 65-100%). In the whole group, the median time to progression and overall survival were 8 (range 1-18) and 14 months (95% CI 11-17), respectively. Thus, in metastatic breast cancer patients pre-treated with anthracyclines, the weekly administration of paclitaxel, 5-FU and folinic acid with G-CSF support seems to be extremely tolerable and active.     

Treosulfan and gemcitabine in metastatic uveal melanoma patients: results of a multicenter feasibility study

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54-133 weeks], the progression-free survival was 28.5 weeks (95% CI 13-62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.     

The timing of endothelin and nitric oxide inhibition affects survival in a mice model of septic shock

The effect of endothelin and nitric oxide (NO) inhibition on survival from septic shock was investigated in male Swiss albino mice (20-40 g), with particular emphasis on the timing of the administration of their blockers after Escherichia coli endotoxin (lipopolysaccharide, O55:B5, 60 mg kg(-1), i.p.) challenge. Mice were injected with the endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 2 or 12 h after endotoxin) alone or in addition to the NO synthase blockers L-canavanine (100 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 3 mg kg(-1), i.p.) or aminoguanidine (15 mg kg(-1), i.p.), which were also given twice at 2 and 6 h after endotoxin. Control animals received saline, and survival rates in each group (n=10) were recorded over 24 h at 6-h intervals. At 24 h, the survival rate was 10% in controls, but 30% (n.s.) and 70% (P<0.05) in animals that received only bosentan at 2 and 12 h, respectively, indicating a relatively late involvement of endothelin in comparison to NO. In contrast, these figures were 70% (P<0.05) and 80% (P<0.05) at 12 h for L-NAME and L-canavanine, respectively, and 10% (n.s.) at 24 h, implying a relatively early involvement of NO compared to endothelin. Interestingly, survival in the aminoguanidine group (75% at 24 h, P<0.05 vs. controls) was markedly higher than that in the L-NAME and L-canavanine groups, an effect that was attributed to mechanisms other than NO inhibition. Survival was better (60%, P<0.05 vs. endotoxin alone) when bosentan was given at 2 h in combination with L-NAME, but the best outcome (90% survival, P<0.05) was observed in animals when bosentan was given at 12 h and L-NAME was injected twice at 2 and 6 h. However, the statistical analysis revealed no significant additional beneficial effect of L-NAME coadministered with bosentan. Therefore, we conclude that NO is involved during the earlier phases of septic shock in comparison to a relatively late involvement of endothelin peptides, and that bosentan alone appears to be beneficial when administered at least 12 h after the endotoxin challenge in our mice model of septic shock.     

Vindesine in advanced breast cancer,lymphoma and melanoma

Summary Fifty-six patients with advanced metastatic carcinoma of the breast, melanoma and lymphoma were treated with the new vinca alkaloid vindesine in a prospective Phase II study. The dose was 3 mg/M² by I.V. bolus once a week for a minimum of two doses. Patients who failed to respond to four I.V. doses were treated with 48-h intravenous infusions at a dose of 1.5 mg/M² per 24 h.Of the 26 evaluable patients with breast cancer, there were only two incomplete responses and four patients who experienced stabilization of disease. Of the 12 evaluable patients with melanoma, no responses were seen with four patients experiencing stabilization of disease. Of the 11 patients with non-Hodgkin's lymphomas, there was one complete remission which persisted for 26 months and two partial remissions. No additional responses were seen when the mode of administration was changed to 48-h infusion in three patients with breast cancer, five patients with melanoma and one patient with lymphoma. Significant toxicities included neutropenia in 24 patients and nausea and vomiting in two patients. There were no drug related deaths.Previously reported experience with vindesine in these tumors is reviewed as well.The views of the authors do not purport to reflect the positions of the Department of the Army or the Department of Defense.     

Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

PURPOSE: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. RESULTS: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. CONCLUSIONS: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.     

Does rapid dose titration affect the hepatic safety profile of Bosentan?

RATIONALE: Bosentan, a dual endothelin receptor antagonist, has proven efficacy in pulmonary hypertension. Due to an association with hepatic dysfunction, it is typically initiated at a sub-therapeutic dose for 4 weeks before titration to a therapeutic dose. At our institution some patients have undergone rapid titration, to potentially benefit from therapy earlier. This study assesses the impact of this practice on hepatic safety. METHOD: All patients initiated on bosentan therapy before April 2005 were included. Rapidly titrated patients achieved a therapeutic dose by 3 days, whereas standard titration patients were titrated at 4 weeks. All patients were monitored with monthly liver function tests. RESULTS: 149 patients commenced bosentan, of which 55 were rapidly titrated. At baseline, the two groups were similar in age, BMI, diagnosis, 6-min walking distance, alanine aminotransferase (ALT), cardiac index and pulmonary artery pressures. The rapid group had elevated right atrial pressures (9.7 mm Hg versus 7.4 mm Hg, p = 0.016) and worse WHO functional class (p = 0.008) and included less females (31% versus 69%, p = 0.024). The incidence of hepatic dysfunction in all patients was 12.8% at 12 months. There was no statistical difference in incidence between the rapid and standard groups (4% versus 11% at 3 months, p = 0.211 and 6% versus 15% at 12 months, p = 0.219). Of all patients on bosentan, hepatic dysfunction was most significantly associated with a higher baseline ALT (p = 0.021), female sex (p = 0.003) and underlying connective tissue disease (p = 0.025). Subgroup analysis suggested these factors were not confounders when comparing rapid and standard titration. CONCLUSIONS: Rapid and standard titration of bosentan resulted in similar hepatic safety profiles. Baseline ALT, female sex and the presence of connective tissue disease increased the risk of hepatic dysfunction independent of the titration method used.     

Pharmacological characterization of YM598, an orally active and highly potent selective endothelin ET(A) receptor antagonist

We describe here the pharmacology of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), a novel selective endothelin ET(A) receptor antagonist synthesized through the modification of the ET(A)/ET(B) non-selective antagonist, bosentan. YM598 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptor, with K(i) of 0.697 and 569 nM, and inhibited endothelin-1-induced increases in intracellular Ca(2+) concentration in human and rat endothelin ET(A) receptor. YM598 also inhibited endothelin-1-induced vasoconstriction in isolated rat aorta with a pA(2) value of 7.6. In vivo, YM598 inhibited the pressor response to big endothelin-1, a precursor peptide of endothelin-1. DR(2) values of YM598 in pithed rats were 0.53 mg/kg, i.v. and 0.77 mg/kg, p.o., and its antagonism in conscious rats was maintained for more than 6.5 h at 1 mg/kg, p.o. In contrast, YM598 had no effect on the sarafotoxin S6c-induced depressor or pressor responses. YM598 showed not only superior antagonistic activity and higher-selectivity for endothelin ET(A) receptor in vitro, but at least a 30-fold higher potency in vivo than bosentan. In conclusion, YM598 is a potent and orally active selective endothelin ET(A) receptor antagonist.     

Bosentan for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis of lung fibrosis, therefore it was hypothesized that the oral dual endothelin receptor antagonist bosentan may have efficacy for the treatment of IPF. The BUILD-1 study evaluated the efficacy, safety and tolerability of bosentan in patients with IPF. Bosentan was associated with a trend toward delayed time to disease progression or death and improvement in quality-of-life, both of which were more pronounced in patients with a biopsy-confirmed IPF diagnosis. These observations are being investigated in the ongoing BUILD-3 trial.     

Prospective multicenter phase II study of irinotecan as third-line therapy in metastatic colorectal cancer and progression after bolus and infusional 5-fluorouracil

Irinotecan has proven anti-tumor activity as induction treatment in combination with 5-fluorouracil (5-FU) or as second-line treatment after 5-FU in patients with metastatic colorectal cancer. The aim of the present phase II study was to evaluate irinotecan as third-line chemotherapy in patients with colorectal cancer after sequential treatment with bolus 5-FU followed by an infusional 5-FU regimen. Patients pretreated with bolus 5-FU/folinic acid and the infusional 5-FU/folinic acid regimen were treated with 350 mg/m irinotecan i.v. once every 3 weeks in a multicenter phase II study. Tumor size was measured every cycle and treatment with irinotecan was continued until the occurrence of progressive disease or unacceptable toxicity. A total of 50 pretreated patients were included. Of the 45 evaluable patients, 13.3% [n=6, 95% confidence interval (CI) 5.1-26.8] attained a response (complete/partial response) to treatment lasting 5.6 months (95% CI 4.2-6.3) and in four patients response has been confirmed (8.9%, 95% CI 2.5-21.2). Disease stabilization was noted in 51.1% of the patients (n=23, 95% CI 35.8-66.3). The median duration of response/disease stabilization was 4.2 months (95% CI 3.2-6.0). Median overall survival was 7.9 months (95% CI 6.1-11.1), corresponding to a calculated 1-year survival of 28.3% (95% CI 15.2-41.3). Severe neutropenia occurred in 14% (n=7) and anemia grade III in 6% of the patients (n=3). The most frequent non-hematological toxicity grade III/IV related to treatment was diarrhea in 24% of the patients (n=12), followed by vomiting in 8% (n=4) and constipation as well as infection in two patients each (4%) (evaluable n=50). We conclude single-agent irinotecan is an effective and well-tolerable treatment in pretreated patients with metastatic colorectal cancer after failure of bolus and infusional 5-FU/folinic acid regimens. Elderly patients had the same probability to respond.