Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

Summary Diaziquone, a new alkylating agent which crosses the blood brain barrier, has shown a 20% response rate in phase II studies in heavily pretreated patients. We have treated 23 patients at our institution as part of a multicentric phase II European trial of diaziquone. All had histologically proven malignant glioma unequivocally progressing on CT scan. Prior therapy had consisted of surgical excision (13 patients), cobalt radiotherapy to CNS (13 patients), and chemotherapy with nitrosourea derivatives (11 patients). Six patients had no prior therapy. Median age was 42 years (range 22–69) and performance status was 3+ or better. They were treated with monthly courses of diaziquone 5.5 mg/m² I.V. (10 min.) × 5 days. Dosage adjustments were made according to leucocyte and platelet nadirs. Thrombocytopenia was the dose limiting toxicity. Very mild gastrointestinal toxicity was observed. One patient developed hemolytic anemia. One complete response (clinical and CT scan), 7 partial clinical responses (3: > 50%, 4: 25–50%), and 1 disease stabilization (<25%) were documented. The longest response has now lasted over 26 months. These preliminary results show that chemotherapy with diaziquone can achieve a response rate as high as 35% in malignant glioma even in patients previously treated with a chemotherapy regimen including a nitrosourea (four of the seven objective responses were seen in such patients). Diaziquone is well tolerated and deserves further study in the management of malignant glioma. Address for offprints: Dr J Maral, Medical Oncology Service, Hôpital de la Salpetriere, 75651 Paris Cedex 13, France     

ENDOTOXIN ALTERS THE SYSTEMIC DISPOSITION OF NITRIC OXIDE SYNTHASE INHIBITORS IN THE AWAKE SHEEP

1. We evaluated the haemodynamic effects and systemic disposition of the nitric oxide synthase (NOS) inhibitor N^L-nitro-L-arginine (NOLA) after intravenous (i.v.) administration of two different doses (5 and 20 mg/kg) in awake healthy sheep and awake sheep given a continuous i.v. infusion of endotoxin (lipopolysaccharide, 12 ng/kg per h, i.v., for 18 h). In addition, we determined the systemic disposition of another NOS inhibitor, N^L-nitro-L-arginine methylester (L-NAME; 20 mg/kg, i.v.) in awake healthy sheep only. 2. A^rL-Nitro-L-arginine produced a dose-dependent decrease in heart rate (HR) and cardiac output (CO) together with a dose-dependent increase in mean arterial pressure (MAP) and peripheral vascular resistance (PVR) when compared to baseline. In endotoxic sheep NOLA produced a greater increase in MAP and mean pulmonary arterial pressure (MPAP). 3. In healthy sheep there was a dose-related increase in total body clearance (CI) of NOLA. The CI increased from 0.028 L/min after the lower dose to 0.032 L/min after the higher dose. The infusion of endotoxin caused an increase in CI of NOLA to 0.040 and 0.047 L/min, respectively, and a decrease in plasma slow half-life (t_1/2 from 825 to 546 min and from 780 to 453 min, respectively. 4. N^L-Nitro-L-arginine methylester was rapidly cleared from the plasma with a slow half-life of approximately 7.5 min and there was a simultaneous appearance of NOLA in the plasma. 5. These results support the view that nitric oxide has a significant role in regulating vascular tone in healthy and endotoxic sheep and indicate that the increases in CI of NOLA with an increase in its dose and the presence of endotoxin will be important in influencing appropriate dosage regimens in clinical studies.     

THE INCIDENCE OF FIRST-DOSE HYPOTENSION WITH QUINAPRIL IN PATIENTS WITH MILD TO MODERATE HYPERTENSION

SUMMARY A total of 2242 patients with mild to moderate hypertension (diastolic pressure 95–120 mmHg) were randomised on a double-blind basis to receive a single dose of placebo, 5 mg quinapril or 10 mg quinapril. Patients were identified who: (a) met the blood pressure (BP) criteria for first-dose hypotension (sitting or standing systolic BP <100 mmHg, or a fall in systolic BP ≥20 mmHg on standing); (b) had symptoms suggestive of hypotension; and (c) met the BP criteria and had symptoms. In all three classifications there were no statistically significant differences between the incidences in placebo and combined active treatment groups, or between those in the two quinapril groups. No associated serious adverse events were reported. In the low-risk population studied, it would appear that the incidence of first-dose hypotension with quinapril is similar to placebo and is not dose-related.