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Biomedical subjects

G Milano

Publications and source records attributed to G Milano.

At least 181 records · Page 10Linked to original sources
PubMed1989

5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer.

This 4 year study reports on a pharmacokinetic study for the widely used regimen of cis-platin plus continuous 5-day 5-FU as first-line chemotherapy of head and neck cancer, and the benefit of such data for real-time therapy management. Pharmacokinetic analysis of 177 cycles for 77 patients from a group of 89 patients (group 1; 228 cycles) revealed that both the time-concentration product (AUC) for the entire cycle and the half-cycle AUC (AUC0-3 days) were predictive of cycle toxicity. Real-time analysis of individual AUC0-3 days was used to decide whether to reduce the dose during the second half of the cycle for a total of 249 cycles (81 patients; group 2). The dose in the second half of the course was reduced in 40% of the group 2 courses. There was a statistical difference in complete response rates between group 1 (31%) and group 2 (47%), (0.02 less than P less than 0.05) and a statistically significant reduction was observed in the incidence of toxic cycles (greater than grade 2, group 1 = 20% versus group 2 = 12.4%; 0.02 less than P less than 0.05). Pharmacokinetic follow-up of these patients has proved to be an objective means to improve therapeutic index significantly.

Adult↗
PubMed1988

Dose versus pharmacokinetics for predicting tolerance to 5-day continuous infusion of 5-FU.

This non-randomized study reports pharmaco-clinical data on 5-FU administered by the widely used 5-day continuous infusion schedule to 42 patients with metastatic colorectal cancer; 5-FU was given by hepatic intra-arterial route (h.i.a.) at doses ranging from 800 to 1,450 mg/m2, and by a systemic intravenous route (i.v.) at doses ranging from 650 to 1,300 mg/m2. 5-FU blood levels were available for a total of 179 cycles. Toxicity was dose-dependent during h.i.a. cycles but not during i.v. cycles. For h.i.a. cycles, 1,000 mg/m2/day represented the threshold dose for tolerance. The individual total cycle drug concentration-time product might predict toxicity for both i.v. and h.i.a. cycle when the threshold is set at 30,000 ng/ml.hr. These data may be of practical value for improving the therapeutic index of 5-day continuous treatment by 5-FU given by i.v. or h.i.a. routes.

Adult↗
PubMed1988

Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients.

A circadian rhythm in the plasma concentration of 5-fluorouracil (5-FUra) is demonstrated in seven patients receiving this drug as a continuous venous infusion at a constant rate for 5 days. All patients had stage C bladder carcinoma and received cis-diamminedichloroplatinum(II) (45-91 mg/m2) on day 1 as a 30-min venous infusion at 5 p.m. Continuous venous infusion of 5-FUra (450-966 mg/m2/day) was started on day 2 at 8:30 a.m. via a volumetric pump and lasted for 5 days (until day 6). Blood samples were obtained on EDTA every 3 h on days 2, 4, and 6 on each patient (20 samples/patient). 5-FUra plasma concentration was determined by high performance liquid chromatography. Data were analyzed by both multiple analysis of variance and cosinor. Mean lowest and highest values (+/- SEM) were, respectively, 254 +/- 33 ng/ml at 1 p.m. and 584 +/- 160 ng/ml at 1 a.m. (F = 2.3; P less than 0.03). Because of large intersubject differences in 24-h mean plasma concentration, data were also expressed as percentages of each patient's 24-h mean. Both analysis of variance and cosinor analysis further validated (P less than 0.0001) a circadian rhythm with a double amplitude (total extent of variation) of 50% of the 24-h mean and an acrophase located at approximately 1 a.m. (estimated time of peak). Such findings warrant a thorough scrutiny at the chronopharmacology of anticancer drugs when designing continuous infusion schedule. A circadian modulation of the infusion rate of this drug may further optimize the therapeutic index of such treatment modality.

Aged↗
PubMed1988

Orosomucoid:prealbumin ratio--a marker of the host-tumor relationship in head and neck cancer.

The OPR was studied in 203 patients with squamous cell carcinoma of the head and neck at the time of diagnosis, before any specific treatment. The mean initial OPR value was significantly higher in cancer patients than in 63 healthy controls: 5.29 +/- 3.09 vs. 2.63 +/- 1.07; P less than 0.001. There was no significant difference by anatomic site, but the OPR was significantly lower in stage I-II disease than in stage III-IV: 5.10 +/- 3.85 vs. 3.23 +/- 1.99, P less than 0.001. An initial OPR under or over 6 seems to be an important prognostic factor: at 2 years, 51% of patients with an OPR less than 6 were alive vs. only 24.5% of those with an OPR greater than 6, P less than 0.001. The difference was also noted in patients with stage III-IV disease (mean survival: 16 months vs. 7 months, P less than 0.001) and in 89 of the patients who received chemotherapy (mean survival 16 months vs. 6 months, P less than 0.001) whatever the response to chemotherapy. The OPR index, which explores nutritional and acute phase reactant proteins, seems to reflect the host-tumor relationship. Its initial value is strongly related to prognosis at 2 years.

Adult↗
PubMed1988

Hexadecane-induced skin hyperplasia in the hairless rat: time course of histological and biochemical events related to the synthesis of polyamines and DNA.

Several biochemical parameters including ornithine decarboxylase activity (ODC) and tissue polyamine levels were measured during the hexadecane-induced epidermal hyperplasia of hairless rat skin. Animals received three applications of 200 microliters pure n-hexadecane on day 1. ODC activity and polyamine levels (putrescine, spermidine and spermine) in the epidermis were significantly increased and reached maximum elevations at 12 h after the start of n-hexadecane treatment with DNA synthesis peaking at 24 h. Histological studies confirmed a significant cellular edema at 24 h after the beginning of the treatment followed at 48 h by an epidermal hyperplasia which was maximum at 72 h. These data support the view that ODC activation, increased biosynthesis of polyamines and DNA are early events in epidermal cell hyperproliferation.

Alkanes↗
PubMed1988

Value of urinary hydroxyproline and bone isoenzyme of alkaline phosphatase in the early detection and follow-up of bone metastasis in breast cancer patients.

A multiparametric biological study of 178 evaluable breast cancer patients was performed to evaluate the usefulness of individual parameters for the prediction, diagnosis and follow-up of bone metastasis (BM) as compared to physical tests. Serum and urinary calcium and phosphorus were of little discriminative value. The sensitivity and specificity for the urinary hydroxyproline/creatinine ratio (UHP/creat.) were respectively 75% and 81.4% versus 43.2% and 91.4% for the bone isoenzyme of alkaline phosphatase in serum (BIE). During an average follow-up of 14.3 months for 51 patients with bone metastasis, variations in UHP-creat. and BIE correlated with clinical and physical findings; the best correlation was given by UHP/creat. Twenty patients who were initially free of bone metastasis were followed-up for a mean metastasis-free interval of 14 months; UHP/creat. predicted the appearance of bone metastasis in 50% of cases with a lead time of 5.5 months versus 40% and 8.5 months for BIE. Combined use of UHP/creat. and BIE gave a prediction rate of 70% and a mean lead time of 7 months, and this combination of markers thus merits consideration in the management of breast cancer patients.

Alkaline Phosphatase↗
PubMed1987

Relationship between systemic 5-FU passage and response in colorectal cancer patients treated with intrahepatic chemotherapy.

The study described herein was conducted to analyze the relationship between tumor exposure to 5-FU and clinical response. Six patients were placed on continuous 5-day intrahepatic 5-FU chemotherapy for colorectal cancer metastasized to the liver. The starting dose was 600-800 mg/m2 per day; cycles were repeated at 4-week intervals. The 5-FU dose was increased by 250 mg/day at each cycle. All six patients received 3 or more cycles, for a total of 37 cycles. Response was evaluated after each cycle by ultrasonography or computed tomography (CT). Pharmacokinetic data revealed a high individual cycle-to-cycle variability for all six patients in the 5-FU area under the curve (AUC day 1 to day 5) corrected for the dose. These variations in drug biodisposition, reflecting hepatic 5-FU uptake, were significantly related to measurable modifications in the tumor mass in 71% of cycles. The correlation between the reduction in local drug exposure and tumor regrowth was better than that between the increase in local drug exposure and tumor reduction. These findings constitute an original illustration in humans of the experimental concept of the drug exposure/tumor response relationship for 5-FU.

Aged↗
PubMed1987

HPLC micromethod for simultaneous measurement of estradiol, progesterone, androgen and glucocorticoid receptor levels. Application to breast cancer biopsies.

Estradiol (ER), progesterone (PR), androgen (AR) and glucocorticoid receptor (GR) levels were assayed in 25 breast cancer tumors. The tissue was pulverized and homogenized in buffer, then divided into two parts: one was assayed by the standard dextran-coated charcoal method (DCC), with Scatchard plot analysis, the other was assayed by a micromethod developed in our laboratory, as described below: --incubation of the cytosol with several ligands (labelled and unlabelled) selected to avoid unwanted cross-reactions --DCC separation, followed by extraction of all receptor-bound steroids by precipitation of proteins with methanol/TCA --separation of these steroids on a high pressure liquid chromatography (HPLC) column using a methanol/water solvent --collection of the fractions of the column outlet and counting. Use of three labelled ligands and appropriate unlabelled ligands allowed assays of the four receptors. This micromethod was highly correlated with the standard method: ER = 0.985 (P less than 0.001); PR = 0.999 (P greater than 0.001); AR = 0.989 (P less than 0.001); GR = 0.867 (P less than 0.001). Thresholds of positivity were not modified. This micromethod allowed simultaneous measurement of several receptors in 40 mg biopsy specimens and can be applied to other hormone-dependent tissues.

Breast Neoplasms↗
PubMed1987

Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies.

This pharmacokinetic study examined the relationship between methotrexate (MTX) dose and drug concentrations in blood and cerebrospinal fluid (CSF) during repeated 24 hr infusions. Two regimens were used: an intermediate dose (ID) of 0.5 g/m2 (7 patients, 23 cycles) and a high dose (HD) of 2.5 g/m2 (8 patients, 39 cycles). Inter-patient variability in the drug concentration was apparent in serum and CSF for both doses. The dispersion was particularly wide in CSF for HD MTX. Considering median values, serum and CSF MTX were linked to dose escalation. Individual CSF/serum drug ratios were not modified by the dose (1.1% for ID MTX versus 1.4% for HD MTX). A potentially cytotoxic drug level in CSF (10(-6) M) was never obtained for ID MTX cycles, but was achieved in 44% of HD MTX cycles: for HD MTX, this corresponded to 88% of patients (7/8). Total body clearance did not modify the degree of CSF MTX passage. A positive, significant correlation (r = 0.62, P less than 0.05) was observed for ID MTX between individual serum and CSF MTX; no such relationship was seen with HD MTX. Individual cycle-to-cycle variations in the MTX concentration were particularly marked in CSF and for HD MTX, without strict concordance with blood levels.

Adolescent↗
PubMed1987

Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours.

Recent biochemical and pharmacological findings concerning tamoxifen (TMX) have proven that both the unchanged drug and the main metabolites, N-desmethyltamoxifen (NDT) and 4-hydroxytamoxifen (4OHT) are biologically active. An HPLC method based on on-line post-column UV irradiation with fluorescence detection is described. Optimized conditions allowed complete and rapid separation of TMX 4OHT, NDT and two other recently reported metabolites, Y and Z. This method was applied to plasma and cytosol drug and metabolite analyses. In plasma, from the moment of initial drug administration until the steady state (after 1 month or more of continuous oral TMX treatment), the values of NDT to TMX ratios were completely reversed: 22 to 215 in mean %, P less than 0.01. The presence of metabolites Y and Z is significant. 4OHT, hardly detectable at the first dose, was measured at the steady state with high interpatient variability. It is hypothesized that metabolite evolution with time may be due to auto-induction of drug metabolism. In cytosols, which were all obtained during continuous TMX treatment, the ratios between TMX and metabolites were comparable to those observed in plasma, but with greater interpatient variability. Metabolite Y was not detectable in cytosols. This variability was not linked to the levels of cytosolic oestradiol receptors before initiation of treatment.

Breast Neoplasms↗
PubMed1986

Radiosensitization of human tumor cells by alpha-difluoromethylornithine.

The effect of polyamine depletion on the radiosensitivity of a human tumor cell line was investigated. CAL 18 A cells, derived from a breast carcinoma, were incubated with alpha-difluoromethylornithine (DFMO)--a specific and irreversible inhibitor of ornithine decarboxylase (ODC)--at a 1 mM or 10-mM concentration for either 1 hr or 24 hr and irradiated thereafter. Survival curves of exponentially growing cells revealed a moderate but significant enhancement of radiosensitivity as compared to untreated irradiated cells. Maximum radiosensitization was observed at a concentration of 10 mM after 1 hr incubation. Plateau-phase cells were used to study the effect of polyamine inhibition on repair of radiation-induced potentially lethal damage (PLD). DFMO enhanced the radiation response and significantly inhibited PLD repair in these cells. Measurement of ODC indicated that this enzyme was markedly inactivated upon brief incubation of CAL 18 A cells with DFMO, reflecting a depletion of polyamine synthesis. These results extend findings that have demonstrated enhancement of drug-induced cytotoxicity, and raise the possibility of clinical use of this substance for potentiation of radiation response.

Breast Neoplasms↗
PubMed1986

Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen.

Co-administration of ketoprofen was found in 4 of 118 cycles of high-dose methotrexate (MTX) analysed retrospectively in thirty-six patients. All 4 cycles were characterised by severe MTX toxicity, which was fatal in three cases. Simultaneous administration of ketoprofen was associated with prolonged and striking enhancement of serum MTX levels. There were no abnormalities in MTX kinetics or evidence of MTX toxicity when ketoprofen was given at least 12 h after completion of high-dose MTX infusion. The kidney may be the site of drug interaction. This high-risk association between MTX toxicity and ketoprofen may also apply to other non-steroidal anti-inflammatory drugs.

Adolescent↗
PubMed1986

Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer.

Twenty-nine previously untreated patients with head and neck carcinoma received a total of 63 cycles of an initial chemotherapy protocol combining cis-platinum (100 mg/m2 on day 1) and continuous 5-day infusion of 5-FU (1000 mg/m2/24 h) from day 2 to day 6. This protocol was repeated on day 16 and day 31. Two daily blood samples obtained from all patients every day during 5-FU administration were analyzed by HPLC to determine the 5-FU concentrations. In the majority of cases a constant elevation was observed in total 5-FU cycle exposure (C X T) from cycle to cycle. A close relationship was demonstrated between elevated 5-FU C X T values (over 30 000 ng h ml-1) and the frequency of cycles in which signs of toxicity (myelosuppression, mucositis, diarrhea) were observed. By contrast, no obvious association was noted between response to treatment and systemic 5-FU exposure.

Adult↗