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Biomedical subjects

P Ribaud

Publications and source records attributed to P Ribaud.

At least 91 records · Page 5Linked to original sources
PubMed1983

Kinetics and metabolism of a new fluoropyrimidine, 5'-deoxy-5-fluorouridine, in humans.

5'-Deoxy-5-fluorouridine (5'-dFUrd) is a new antineoplastic agent which possesses a higher therapeutic index in several experimental tumors compared to other fluoropyrimidines. During a Phase I trial, 5'-dFUrd, 1 to 15 g/sq m/week, was administered to patients as a 25- to 35-min i.v. infusion. Plasma kinetics and metabolism of 5'-dFUrd were investigated. The unmetabolized drug was measured by a high-performance liquid chromatography assay. 5-Fluorouracil and 5,6-dihydrofluorouracil, the two detected plasma metabolites, were quantitated by a gas chromatography-mass spectrometry methodology with a detection limit of 0.07 microM for both metabolites. The disposition of 5'-dFUrd in humans at therapeutic doses followed a nonlinear kinetic process. Plasma concentrations of 5-fluorouracil generated in vivo represented approximately 6% of 5'-dFUrd concentrations and the 5-fluorouracil half-life ranged from 8.8 to 27.1 min. High plasma values of 5,6-dihydrofluorouracil (14.5 to 30 microM) were observed in patients, indicating the importance of this pathway in humans.

Colonic Neoplasms↗
PubMed1982

[Treatment of acute myeloid leukemia with a protocol combining intensive induction chemotherapy, early consolidation treatment, splenectomy and long-term maintenance chemotherapy. Preliminary study].

Twenty-seven patients aged from 10 to 60 years (mean 34.4 +/- 13 years) in the first perceptible phase of acute myeloid leukemia were subjected to intensive induction chemotherapy consisting of adriamycin (ADM), vincristin (VCR) and cytosine arabinoside (ARA-C). Twenty-four patients (89%) attained complete remission (CR) after 1 to 3 cycles and were then given an early consolidation treatment with one of the previous cycles. This was followed by long-term continuous maintenance chemotherapy with 6-mercaptopurine (6-MP) and methotrexate (MTX) alternatively and 3-monthly reinforcement courses of donaurubicin (DNR) and VCR. Twenty of these 24 patients were splenectomized soon after the consolidation treatment. None of the spleens were enlarged, and histological sections of the spleens, liver biopsies and mesenteric lymph-nodes stained with routine dyes and by the naphthol AS-D chloroacetate esterase method revealed mature granulocytes but no demonstrable leukaemic cells. In the group of splenectomized patients, the probabilities of staying in complete remission at 27 and 44 months were 70 +/- 12.6% and 52 +/- 18.5% respectively, and the probabilities of remaining alive at 32 and 55 months were 79 +/- 11% and 57 +/- 19% respectively. Age over 40 and evidence of extramedullary infiltration at presentation appeared to leave little hope of disease-free survival. The rationale for the present therapeutic study is discussed.

Adolescent↗
PubMed1982

[Aclacinomycin-A in acute leukaemias and leukaemic non-Hodgkin lymphomas (author's transl)].

Aclacinomycine-A (ACM), a new anthracycline derivative, was administered intravenously to 50 patients in doses of 10-30 mg/m2/day for periods of 6 to 30 days. Among the 45 patients who could be assessed, 17 were suffering from acute myeloid leukaemia, 19 from acute lymphoid leukaemia and 9 from non-hodgkin lymphoma. The results confirmed those first published by the authors in 1978 and led them to propose new measures aimed at reducing the toxicity of ACM. Depending on the dosage, complete or partial (more than 50%) remissions were obtained in patients with acute myeloid leukaemia. In the 19 patients with acute lymphoid leukaemia, complete remission was observed in 2 and partial remission in 2. Among the 9 patients with non-hodgkin lymphoma, there was 3 complete and 1 partial remissions. ACM did not produce alopecia and, as predicted by the authors' experimental study on hamsters, did not have major cardiac toxicity. The gastrointestinal toxicity, which had forced a reduction of the total dose in the first trial, proved moderate, even with normal dosage.

Aclarubicin↗
PubMed1982

[Treatment of leukemias and lymphomas with interferons: I. Trial of myeloma therapy with human beta-interferon].

Eighteen patients with malignant gammapathies (16 with myeloma and 2 with Waldenström's disease) for a short time because in a phase II-I trial were treated with human (IF beta) given i. v. 6 X 10(6) units weekly (7 patients) or 3 X 10(6) units twice weekly (11 patients) during at least 3 months if tolerated. Treatment was discontinued because of side-effects in three patients. Reduction of the M component of at least 25% from the initial value was obtained in 3 patients. In one case, was also observed in disappearance of the urinary Bence-Jones protein, in 4 cases a significant reduction of bone marrow infiltration by plasma cells and, in 5 cases, major alleviation or disappearance of bone pain. Length of treatment seems an important factor for activity. Immune monitoring with currently available tests, mainly NK cell activity, yielded no correlation with therapeutic effect in these patients. This very preliminary study demonstrates the effect of fibroblastic interferon in myeloma, but further studies are mandatory to determine the population of patients likely to benefit from treatment, the best modalities, possible special indication, dose schedule and duration of treatment. Interferon, however, already appears in this population of patients as giving results similar to those of single agent chemotherapy. As it is not myelosuppressive, it could be indicated in that frequent situation of advanced myeloma with bone marrow failure contra-indicating combination chemotherapy.

Clinical Trials as Topic↗
PubMed1982

[Treatment of leukemias and lymphomas with interferons: III. Trial treatment of meningeal localizations of acute leukemia and non-Hodgkin's lymphomas with beta interferon administered by the intrathecal route].

Six patients with pure meningeal relapse of acute lymphoblastic leukemia (ALL) (5 patients) or leukemic lymphosarcoma (LS) (non Hodgkin's lymphoma) (NHL) (1 patient) were treated with intrathecal (I.T.) human fibroblastic interferon (IF beta), one vial (1.3 million units) every other day or every day up to remission or failure. Tolerance was excellent in all six patients with no local or general side effects. 5 patients had no improvement of their meningeal blast infiltrations after 5 to 8 injections and were given IT chemotherapy. The sixth patient achieved a complete remission (CR) after 11 injections, and was maintained in CR for eleven months under systemic and IT chemotherapy. IF cannot be proposed as standard treatment for meningeal leukemia, but we may be able to select a population of patients in which it could be indicated. Its combination with methotrexate and arabinoside cytosine, the two agents used IT which are S-dependent, has to be studied for a possible potentiation. Moreover, its good tolerance would permit its use in severe meningeal viral diseases.

Acute Disease↗
PubMed1982

[Treatment of leukemias and lymphomas by interferons: II. Phase II of the trial treatment of chronic lymphoid leukemia by human interferon alpha+].

Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon alpha (IF alpha). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with a rising dose in the same patient from cycle to cycle, if tolerance permits, from 1.5 to 6 X 10(6) units daily. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who had previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10(6) units daily. Tumor mass reduction was seen in only three patients, but significant decrease in peripheral lymphocytosis was seen in 7 patients sustained in the continuous treatment group with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed, in this population of patients, a very good correlation between NK cell activity and clinical response. Further studies are warranted to determine the best modalities of treatment as well as the population of patients likely to benefit from it, and the possible special respective indications of IF, and of the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.

Drug Evaluation↗
PubMed1982

Correlation between precancerous bronchial metaplasia and cigarette consumption, and preliminary results of retinoid treatment.

Vitamin A and its derivatives, so-called retinoids, can prevent squamous metaplasia induced not only by vitamin A deficiency but also by carcinogenic hydrocarbons. An aromatic retinoid, such as ET1, has been shown to prevent chemically induced papillomas in mice and to amplify certain immunologic reactions. Heavy smokers, 106 volunteers, were submitted to fibrobronchoscopy with bronchial biopsies. An index of metaplasia (IM) was calculated on the basis of microscopical examination of a total of 9,633 sections of 1,010 biopsies. Despite the subjectivity of the estimates of cigarette consumption, this was significantly (P less than 0.02) and positively correlated to the IM. Eighty-five percent of the women had a low IM as compared to only 42% of the men (P less than 0.01), although there was no significant difference in the reported cigarette consumption. Fifty-two subjects had an IM greater than 15% and were given 25 mg ET1 orally daily for 6 months. The bronchoscopy was repeated in 30 patients following completion of the 6-month treatment. The IM was significantly (P less than 0.01) reduced after treatment.

Adult↗
PubMed1981

Clinical pharmacology and pharmacokinetics of cis-platinum and analogs.

cis-Platinum (DDP), the first metal coordination complex introduced into clinical trials, is remarkable for its therapeutic index. A short review of the numerator of this index, ie, the clinical activities of DDP given as a single agent or in combination therapy is presented. Toxicity of DDP, the denominator of the index, is given more attention, particularly nephrotoxicity, whose cumulative character and molecular mechanism are still in question and which can most often be prevented by following certain safety rules that are detailed in this paper. Pharmacokinetics data of free and filterable platinum are reviewed and discussed according to the different modalities of administration of DDP, and to what is known about its toxicity and its mechanism of cell kill. The rationale for using DDP in combination treatment is presented and the question of possible long-term toxicities is raised. cis-platinum analogs are sought for the purpose of enlarging the spectrum of activity, increasing selectivity and diminishing toxicity. Malonato-platinum has been shown not to be cross-resistant with DDP and to be clinically effective in adult acute leukemia. In a phase I study, malonato-platinum, which is poorly soluble, was administered in 6-24-hour infusions to 49 patients in doses ranging from 3 to 32 mg/kg. GI toxicity was universal. Hematological toxicity appeared to be mild and not clearly dose-related (the 3-32 mg/kg patients were not yet evaluable). Platinum pharmacokinetics in urine and plasma were performed using flameless absorption spectrophotometry. Preliminary results have suggested that malonato-platinum presented several pharmacokinetic features in common with DDP. Minor responses were seen in four solid tumor patients, three of whom were refractory to DDP. Other analogs soon to be introduced into clinical trials are listed.

Animals↗
PubMed1981

Pharmacokinetics of Malonato (1,2 diaminocyclohexane) platinum.

Malonato-(1,2 diaminocyclohexane) platinum (MP) is a new platinum analog currently undergoing phase I clinical trials. Using flameless atomic absorption spectrophotometry, the pharmacokinetics of MP were studied at five dosage levels. The drug was given as a prolonged intravenous infusion, lasting from 6 to 24 hours. Peak plasma platinum concentrations (Pt) were seen at the end of the infusion, and ranged from 1.1 microgram/ml when 3 mg/kg was given to 14-20.5 micrograms/ml at the 24-mg/kg level. Following completion of the infusion, a prolonged T1/2 beta (mean 63.5 hours) was noted. The percentage of free:total platinum was high (90-95%) at the beginning of the infusion but fell rapidly, to only 15-21% at the end of the 24-hour infusions. Urinary excretion accounted for 16-37.5% of the total administered dose. MP appears to have several pharmacokinetic features in common with cisplatin: rapid binding to protein, a prolonged terminal phase half-life involving primarily bound platinum, and incomplete excretion by the kidney.

Dose-Response Relationship, Drug↗
PubMed1980

Vindesine: a new vinca alkaloid.

Vindesine (VDS) is an analogue of the vinca alkaloids. Its spectrum of antitumoral activity is similar to that of vincristine (VCR), but with milder experimental neurotoxicity, and it inhibits the polymerization of tubulin. Its terminal half-life is 24 h and its plasma clearance is intermediate between those of vinblastine (VLB) and VCR. The maximal tolerated dose is 4-5 mg/m2/week, the dose-limiting toxicity being myelosuppression (nadir by days 7-8 and recovery by days 11-13). It has already been demonstrated as efficient in childhood acute lymphoid leukemia (ALL), non-Hodgkin's lymphoma, blastic crisis of chronic myeloid leukemia, and esophageal carcinoma. It has also shown activity in Hodgkin's disease, breast and germ cell carcinomas, and melanoma. Intolerance is mainly neurologic, with paresthesias, without motor impairment, or hematologic, with leukopenia, and sometimes alopecia, asthenia, and muscle pains. The results are better if the patients have not been treated previously; continuous infusion could be of interest and there appears to be no cross-resistance with its parent VCR, as documented in ALL.

Animals↗
PubMed1980

Cisplatinumdiamminodichloride (CPDD) in chemotherapy of cancers: a phase II therapeutic trial.

We have conducted a phase II trial of cisplatinumdiamminodichloride (CPDD) which not only demonstrated its remarkable activity in embryonic carcinoma of the testes, but also in ovarian carcinoma, in melanoma, and in epidermoid carcinoma, especially of the head and of the uterus cervix. Its toxicity, manifested mainly in the digestive and renal tracts, confines its administration to hospitalized patients only. This compound is now indicated in combination therapy for the above-mentioned tumors.

Adolescent↗
PubMed1980

Preclinical and phase I studies of malonatoplatinum.

After preclinical toxicologic study in baboons, we are conducting a phase I trial of malonatoplatinum, starting with 3 mg/kg and now reaching 1 mg/kg. Toxicity, mainly hematologic, was mild and our study was mainly limited by poor solubility. Regressions, which have been rare in the advanced-tumor patients, have been observed in three patients considered as clinically resistant to cisdichlorodiammino-platinum (DDP). Malonatoplatinum pharmacokinetics appeared similar to those of DDP as far as total platinum is concerned.

Adolescent↗