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Biomedical subjects

F Muggia

Publications and source records attributed to F Muggia.

At least 37 records · Page 2Linked to original sources
PubMed1996

Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies.

AD-32 (N-trifluoroacetyladriamycin-14-valerate), an analogue of doxorubicin, was examined for intraperitoneal (ip) administration in a phase 2 trial involving 25 patients with advanced gynecologic malignancies. At an AD-32 dose of 600 mg/m2, the limiting toxicity was grade 4 neutropenia (64% of patients), while severe abdominal pain was relatively uncommon (12%). Intraperitoneal AD-32 administration was associated with a 200-fold pharmacokinetic advantage for cavity exposure, compared to the systemic compartment. At the 600 mg/m2 dose level, 4 of 9 patients (44%) with ascites experienced control of malignant fluid reaccumulation. Based on the results of this phase 1 trial, further exploration of a possible role for the ip administration of AD-32 in individuals with gynecological malignancies appears indicated, particularly in patients with either small volume residual disease after initial systemic chemotherapy or in those with intractable ascites.

Aged↗
PubMed1996

Saline MR peritoneography.

OBJECTIVE: Our objective was to describe a new method for the evaluation of peritoneal surfaces in patients with intraperitoneal carcinomatosis and sarcomatosis. CONCLUSION: Fast spin-echo T2-weighted imaging in conjuction with intraperitoneally instilled saline permits detailed evaluation of peritoneal surfaces, omentum, and mesenteries. The detection of tumor implants is facilitated by their visualization against the saline background. Additionally, normal and abnormal saline distribution patterns can be identified. This technique may also be useful in predicting response to intraperitoneally instilled chemotherapy.

Female↗
PubMed1995

High-performance liquid chromatographic method for the determination of a novel thymidylate synthase inhibitor, AG 331, in human serum.

AG 331 is a novel thymidylate synthase inhibitor currently in Phase I clinical trial. To determine the pharmacokinetic parameters of AG 3331 in human subjects, a suitable analytical method was developed using high-performance liquid chromatography. Serum and urine samples were prepared using both solid-phase extraction and solvent extraction. Either 4,4'-diaminodiphenyl sulfone or benz[cd]indole-2(1H)-one were used as internal standards for the method. A reversed-phase C18 analytical column completely resolved the drug and internal standard peaks from non-specific substances present in biological matrix. The method was validated for precision, accuracy, and reproducibility in serum and was linear over a concentration range of 50-2000 ng/ml, with a limit of detection of 20.0 ng/ml and a quantifiable limit of 50 ng/ml.

Chromatography, High Pressure Liquid↗
PubMed1995

Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.

PURPOSE: Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposi's sarcoma (AIDS-KS). PATIENTS AND METHODS: Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation. RESULTS: The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02). CONCLUSION: DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Preclinical pharmacokinetics and stability of isophosphoramide mustard.

Stability and preclinical pharmacokinetics of isophosphoramide mustard (IPM), an active metabolite of ifosphamide, were investigated using analytical methods developed in this laboratory. For stability evaluation of IPM we used a rapid, high-pressure liquid chromatographic (HPLC) method by which IPM is analyzed directly from aqueous solutions without derivatization on a 10-microns C-18 reversed-phase column with theophylline as the internal standard. IPM in sodium phosphate buffers was found to undergo pH-dependent first-order degradations. At pH 7.4 and 38 degrees C, the IPM solution showed a half-life of 45 min. A gas chromatographic-mass spectrometry (GC/MS) method for the analysis of IPM in plasma was also developed. This method utilized solid-phase extraction with deuterium-labeled IPM as the internal standard. The routine detection limit for the assay was 50 ng/ml with within-run and between-run coefficients of variation of 6% and 11%, respectively. By this method, stability of IPM in plasma and in RPMI 1640 tissue culture medium was evaluated, and its pharmacokinetics in the Sprague-Dawley rat following i.v. administration at 40 mg/kg were investigated. IPM was found to be more stable in these media, with half-lives in the range of 100 min. IPM plasma pharmacokinetics were found to decline monoexponentially with terminal half-lives ranging from 6.8 to 18.7 min and total clearance between 6.0 and 18.3 ml/min. Plasma protein binding of IPM was found to be 55%, and the partition ratio between plasma and red blood cells of 4.9 to 1, respectively. Cytotoxicity of IPM to L1210 cells was evaluated, and the results indicated that the IC50 with 1-h and 4-h exposure was 33 and 15 microM, respectively. Based on these data, IPM plasma levels in the rat declined below the IC50 in about 1 h at this dose. More frequent dosing or infusion may be necessary to maintain adequate drug levels for antitumor activity when IPM is administered directly.

Animals↗
PubMed1994

Phase I and pharmacologic study of liposomal daunorubicin (DaunoXome).

We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial dose-escalation steps from 10 to 60 mg/m2. At 80 mg/m2, two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m2. Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m2 in previously treated and 120 mg/m2 of DaunoXome in previously untreated patients with solid tumors.

Adult↗
PubMed1994

Paclitaxel (Taxol) in heavily pretreated ovarian cancer: antitumor activity and complications.

OBJECTIVE: To analyze the efficacy and toxicity of Taxol in patients with ovarian cancer who had failed at least two previous chemotherapy treatment regimens. PATIENTS AND METHODS: Sixty-eight patients with advanced pretreated ovarian cancer, with either measurable or evaluable disease who were shown to have disease progression were entered on a National Cancer Institute sponsored 'compassionate' treatment referral center protocol and received intravenous infusion of Taxol over 24 hours 135 mg/m2, (after steroid-containing premedication) repeated every 3 weeks and continued while showing no evidence of progression. RESULTS: Of the 68 patients enrolled, 10 patients (15%) had a partial response and one assessable by marker only had improvement of disease. In addition, 27 others (40%) were stable on continued Taxol for a median time of 6.4 months and CA-125 decreased in 20 patients out of 59 patients with elevated baseline CA-125s. Twenty-seven patients progressed while receiving 1-6 cycles of treatment. Three patients were not evaluable for response. Neutropenia and its complications occurred primarily during the first two cycles of Taxol treatment. Febrile episodes requiring antibiotic treatment occurred in 44% of patients which is a higher incidence than in prior series. CONCLUSIONS: Taxol as a single agent has modest activity in heavily pretreated ovarian cancer patients but appears to be useful and is subjectively well tolerated by many. The high incidence of infection in comparison with other series of patients with ovarian cancer treated with chemotherapy suggests this pretreated patient population has enhanced susceptibility to develop complications from neutropenia. Safer treatment in this advanced setting should include more aggressive use of cytokines and/or less myelosuppressive regimens (e.g. shorter Taxol infusions).

Adult↗
PubMed1991

Phase II trial of carboplatin or iproplatin in cervical cancer.

From July 1984 to November 1987, 89 patients with recurrent measurable squamous-cell cancer of the uterine cervix were randomized in a single institution to receive treatment with either carboplatin (CBDCA) or iproplatin (CHIP). Objective response rates were similar: 2 complete regressions (CRs) and 10 partial regressions (PRs) were recorded both in the 46 evaluable patients treated with CBDCA (response rate, 26.1%; 95% confidence interval, 15-41%) and in the 40 evaluable patients treated with CHIP (response rate, 30%; 95% confidence interval, 17-47%). The median duration of response was 5.5 months for CBDCA and 6 months for CHIP; the median survival was 7.5 and 7.6 months, respectively. Both drugs were given in an outpatient setting and myelosuppression (thrombocytopenia) was the predominant toxicity. Analysis of all toxic events yielded additional interesting observations: the occurrence of moderate to severe platelet nadirs beyond cycle 1 was confined to CHIP, a higher incidence of gastrointestinal toxicity during treatment with CHIP, and five moderate to severe complaints of asthenia (recorded as neurologic events) during CHIP therapy versus only one during treatment with CBDCA. Because of its antitumor activity and its toxicologic advantage, a future role for CBDCA in the treatment of cervical cancer appears likely.

Antineoplastic Agents↗
PubMed1990

Good tolerance of weekly oral idarubicin: (4-demethoxydaunorubicin): a phase I study with pharmacology.

Idarubicin (4-demethoxydaunorubicin) is an orally active anthracycline. We treated 26 patients with 37 courses of the drug on a schedule of oral administration weekly x 3 followed by a 3-week rest period. The maximum tolerated dose on this schedule was 22.5 mg/m2 weekly x 3 every 6 weeks, with consistent myelosuppression being the dose-limiting toxicity; other toxicity was minimal. Pharmacologic studies showed a mean alpha half-life of 1.6 +/- 0.3 h and a beta half-life of 39 +/- 8.4 h for idarubicin. This schedule was well tolerated, with consistent toxicity patterns seen. Pharmacologic studies confirmed prolonged exposure to the drug and its active metabolite. In comparison with other schedules, this one may offer advantages in terms of consistent hematologic toxicity and prolonged exposure to both the parent compound and its active metabolite. Dose intensity was comparable with that on other schedules.

Adult↗
PubMed1990

Phase I toxicity and pharmacology study of trimethylcolchicinic acid in patients with advanced malignancies.

A phase I study of trimethylcolchicinic acid (TMCA) given orally once daily for 5 days every 3rd week was performed in 19 patients with advanced malignancies. Myelosuppression and mucositis were the major toxicities observed. Serum TMCA levels were monitored and appear to be useful in predicting toxicities. A partial response was seen in one lymphoma patient and stabilization of disease was noted in one patient each with prostatic and ovarian cancer.

Administration, Oral↗
PubMed1990

Biological modification of protracted infusion of 5-fluorouracil with weekly leucovorin. A dose seeking clinical trial for patients with disseminated gastrointestinal cancers.

A clinical trial was designed to find the maximally tolerated dose of weekly leucovorin (LV) that could be combined with 4 weeks of protracted infusion (PI) of 5-fluorouracil (5FU) at a fixed dose of 200 mg/m2. A total of 36 patients with disseminated gastrointestinal malignancies were treated; 9 either progressed or died before receiving 4 weeks of treatment leaving 27 patients evaluable for toxicity and response. 5FU was given as a protracted infusion using an ambulatory infusion pump and indwelling venous access. LV doses included 20, 25, 50, and 75 mg/m2 given as an i.v. push at the time of weekly pump fill with 5FU. In all, 72% of the patients tolerated LV at 20 mg/m2 for 4 continuous weeks, whereas the higher doses required treatment rests prior to 4 weeks. The dose-limiting toxicity at all doses was stomatitis. No significant myelosuppression was seen; diarrhea was infrequent. Overall, 40% of the patients with measurable cancer had partial responses. In view of evidence of biologic and therapeutic effects of these weekly doses of 20 mg/m2 LV with 200 mg/m2 5FU per day given as a protracted infusion over 4 weeks, phase II trials and multimodality studies for patients with gastrointestinal malignancies are being initiated at our institution using this dose and schedule.

Aged↗
PubMed1989

Phase II trial of ICRF-187 in patients with acquired immune deficiency related Kaposi's sarcoma (AIDS-KS).

Thirteen patients with AIDS related Kaposi's Sarcoma were entered on a phase II trial of ICRF-187, 1000 mg/m2 IV daily for 3 days every 3 weeks. Eight patients had received prior chemotherapy for AIDS-KS. Six patients had prior opportunistic infection. There were no complete responses; one partial response lasting six months was seen. Toxicity was significant, and of the first 5 patients treated, 3 out of 5 had grade III or IV neutropenia. Because of this, subsequent patients received 800 mg/m2 IV days 1-3 if previously untreated or 600 mg/m2 if previously treated. Overall 4 of 13 patients had Grade IV neutropenia and 5 of 13 had Grade III neutropenia. One patient had Grade IV thrombocytopenia. ICRF-187 at a daily x 3 schedule has some efficacy in the treatment of AIDS related KS, future trials should evaluate lower doses or alternate schedules of administration.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Advanced ovarian cancer: three-year results of a 6-8 month, 2-drug cisplatin-containing regimen.

Fifty-two patients with advanced (stage III and IV) ovarian cancer were treated with a regimen of cisplatin (100 mg/m2 over 5 days) and cyclophosphamide (600 mg/m2/day 4). Treatment was repeated every 3-4 weeks for 6-8 months and followed by second look surgery. The median follow up for this single institution study (1980-1984) is 36 months. The median progression-free survival (projected) is 24 months and the median overall survival (projected) is 37 months in this group of patients with unfavorable pretreatment characteristics: median age: 61, median performance status (ECOG) 2, poorly-differentiated tumors: 60%, extensive residual tumors (greater than 2 cm): 65%. Pretreatment performance status was the only independent predictor for prolonged survival. Pathologically documented complete responses were observed in 23% of all patients and 43% of the patients who underwent second-look surgery (28 patients). Neurotoxicity from this regimen was substantial: it occurred in 65% of cases, was severe in 17% and was often not entirely reversible. The results with this intensive 2-drug cisplatin-containing regimen compare favorably to other more complex regimens in the literature. It is possible that the 'dose intensity' of cis-platinum may be the most important element of current therapeutic regimens in ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗