Michel Marty

Comparison of the 5-Hydroxytryptamine3 (Serotonin) Antagonist Ondansetron (Gr 38032F) with High-Dose Metoclopramide in the Control of Cisplatin-Induced Emesis

To compare ondansetron (GR 38032F), a 5-hydroxytryptamine3-receptor antagonist, with metoclopramide in the prophylaxis of acute cisplatin-induced emesis, we conducted a double-blind crossover study in 97 patients scheduled to receive cisplatin (80 to 100 mg per square meter of body-surface area) for treatment of cancer. None had received chemotherapy before this trial. Among the 76 patients who satisfactorily completed both parts of the study, complete or nearly complete control of emesis (i.e., no episodes of emesis occurred, or only one or two) was achieved in 57 of 76 treatments (75 percent) with ondansetron and in 32 of 76 treatments (42 percent) with metoclopramide (P less than 0.001). Ondansetron was also more effective in controlling acute nausea, as assessed with a visual-analogue scale (P = 0.019) or a graded scale (P = 0.024). There was a significant preference among patients for ondansetron (55 vs. 26 percent; P = 0.006). Dystonic reactions were observed during three treatments with metoclopramide; both agents were otherwise well tolerated. We conclude that ondansetron is more effective than metoclopramide in the control of cisplatin-induced nausea and vomiting, and that this suggests that serotonin is an important mediator of this side effect.

GR38032F, a 5HT3 receptor antagonist, in the prophylaxis of acute cisplatin-induced nausea and vomiting

SummaryA total of 28 patients receiving cancer chemotherapy with cisplatin-containing regimens (70–120 mg/m2) participated in an evaluation of the efficacy and safety of GR38032F for the prevention of acute nausea and vomiting. GR38032F, a 5HT3 receptor antagonist, was given 30 min prior to cisplatin as an 8-mg loading dose by i.v. infusion over 15 min, followed by continuous infusion at a rate of 1 mg/h for 24 h. Efficacy was assessed by measurement of the number of episodes of retching and vomiting occurring in the 24 h after cisplatin administration and by an assessment of nausea during the same period. In all, 26 patients were evaluable for efficacy: overall, complete control was achieved in 12 patients (46%), major control (1–2 emetic episodes), in 6 (23%); minor control (3–5 episodes), in 1 (4%); control could not be achieved (failure; >5 episodes) in 7 patients (27%). GR38032F was well tolerated, with no significant drug-related adverse events. These encouraging results should be confirmed in compariative trials.

Promyelocytic blast crisis of chronic myelocytic leukemia with both t(9;22) and t(15;17) in M3 cells.

A blast crisis with the features of promyelocytic leukemia (M3) occurred during the evolution of chronic myelocytic leukemia (CML) with the t(9;22) translocation. This rare form of transformation was confirmed by means of cytologic and electron microscopic examination. Cytogenetic studies showed two simultaneous translocations t(15;17) and t(9;22) in the promyelocytes. After intensive chemotherapy, a complete remission was obtained and only karyotypes with t(9;22) translocation were present. These data confirm the specificity of the t(15;17) translocation in malignant promyelocytic proliferation and provide evidence for a second genetic event in the genesis of blast crisis occurring in a committed cell belonging to the abnormal population defined by the Ph1 chromosome.

Human pharmacokinetics of N-L-leucyl-doxorubicin, a new anthracycline derivative, and its correlation with clinical toxicities.

A pharmacokinetic study of N‐l‐leucyl‐doxorubicin, a new derivative of doxorubicin, has been undertaken during a phase I trial in 19 patients with advanced cancer after intravenous bolus administration at doses ranging from 30 to 240 mg/m2. The pharmacokinetics of N‐l‐leucyl‐doxorubicin was linear with a total body clearance of 41.3 ± 25.7 L/hr/m2. N‐l‐Leucyl‐doxorubicin was extensively metabolized into doxorubicin, which appeared in plasma immediately after N‐L‐leucyl‐doxorubicin infusion. The mean molar doxorubicin/N‐l‐leucyl‐doxorubicin area under the curve (AUC) ratio was 0.49 ± 0.22 and was independent of the administered dose. A relationship has been established between the doxorubicin AUC (r = 0.74; p < 0.001) and the surviving factor in white blood cell counts. Other toxic side efects (thrombocytopenia or stomatitis) did not correlate with any pharmacokinetic parameter. These findings suggest that the degree of metabolization of N‐l‐leucyl‐doxorubicin into doxorubicin may be responsible for the toxicity, that is, N‐l‐leucyl‐doxorubicin may simply represent a pro‐drug for doxorubicin.

Combined modality in Hodgkin's disease: Comparison of six versus three courses of MOPP with clinical and surgical restaging

Between 1972 and 1979, 121 patients with Hodgkins disease (clinical Stages IInA, IB, IIB, and III) were treated by two different, successive, therapeutic protocols. The first group received six MOPP (mechlorethamine, vincristine, procarbazine, prednisone) cycles before radiotherapy, whereas the second group received only three MOPP cycles before irradiation. A total of 118 patients underwent surgical restaging with splenectomy before irradiation. Clinical criteria used in defining complete remission were verified by surgical restaging. Three MOPPs were just as effective as six MOPPs when combined with radiotherapy in achieving complete remission and in treating occult splenic disesae. Following extended‐field irradiation, complete remission rates were 96% for three MOPPs versus 94% for six MOPPs. The actuarial survival rates, 4 years after therapy completion, were 89% for three MOPPs and 94% for six MOPPs, with a relapse‐free survival rate of 88% and 96.6%, respectively.

Effect of combination chemotherapy, duration of methotrexate administration, and Patient's age on methotrexate pharmacokinetics

SummaryThe kinetics of methotrexate were studied in a group of 59 patients after infusion of high doses. From the triexponential analysis of the serum concentration curve, rate constants and relative concentrations in non-circulating pools were calculated, using a linear ‘mammillary’ three-compartment model. No significant variation as a function of dose (300–6,000 mg/m2) was observed. In circumstances the rapidly exchanging pool was a reflection of the circulating pool, suggesting that it is an extravascular, protein-bound pool of methotrexate. Considerable variations of the relative concentration and rate constants of the slowly exchanging pool were observed to be a function of the duration of methotrexate infusion, the presence of other drugs, and the patients age. If this compartment is assumed to include the target cells for methotrexate, then the large variations observed could be responsible for individual differences in toxicity and/or effectiveness.