Biomedical subjects

J Robert

Publications and source records attributed to J Robert.

At least 19 recordsLinked to original sources

PubMed1992

Haematological profile of healthy elderly Australians.

OBJECTIVE: To determine normal values for haematological parameters in healthy elderly persons, and document any changes in these over a 12 month period. DESIGN: The study was conducted as part of a randomised controlled trial of low-dose aspirin for primary prevention of cardiovascular disease in the elderly. All participants (380) had a full blood examination performed at entry, which was repeated after 12 months. The baseline results for all patients and the 12 month findings in a cohort of 162 persons allocated placebo were used in the present study. SETTING: Community-based (general practices and residential retirement villages). SUBJECTS: Persons aged 70 years and over (53% females) who were ambulatory, living independently, and volunteered to participate. None had significant vascular disease, peptic ulceration, haemorrhagic symptoms or were currently taking non-steroidal anti-inflammatory drugs. MAIN OUTCOME MEASURES: Full blood examination (excluding white cell differential counts) performed with a Technicon H1 analyser. RESULTS: The mean haemoglobin level +/- standard deviation (SD) was 14.69 +/- 1.10 g/dL (for men) and 13.72 +/- 1.05 g/dL (for women). Significant differences (P less than 0.001) in packed cell volume, red cell and platelet counts were observed between the two sexes. No clinically significant change was observed in any of the parameters over a 12 month period. CONCLUSIONS: Haematological reference values for healthy elderly Australians are consistent with normal values reported in younger populations for both sexes. As a result recommendations are provided for normal reference values among this group in an Australian setting.

Aged↗

PubMed1992

Right ventricular overload and induced sustained ventricular tachycardia in operatively "repaired" tetralogy of Fallot.

The aim of the study was to evaluate the main predictors of the inducibility of sustained ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot. Thirty-five patients (age 12 +/- 6 years) underwent right-sided cardiac catheterization, echocardiography, radionuclide angiography and ventricular stimulation; 10 had (group 1) and 25 had no (group 2) sustained VT. Group 1 patients were significantly older at the time of surgery and had longer follow-up periods (7 +/- 3 vs 4 +/- 4 years, p less than 0.02; and 12 +/- 4 vs 5 +/- 2 years, p less than 0.001, respectively). Right ventricular (RV) systolic pressure, end-systolic and end-diastolic normalized RV volumes were higher in group 1 (48 +/- 14 vs 38 +/- 11 mm Hg, p less than 0.05; 1.23 +/- 0.2 vs 0.86 +/- 0.17, p less than 0.001; and 2.35 +/- 0.37 vs 1.70 +/- 0.22, p less than 0.001, respectively). RV end-diastolic pressure, left ventricular and RV ejection fractions were similar in the 2 groups. A stepwise discriminant analysis was made to predict patients with inducible sustained VT (group 1): Time period from surgery to follow-up (p less than 0.001), normalized RV end-systolic volume (p less than 0.002) and RV systolic pressure (p = 0.01) were higher in group 1 and allowed classification of 90% of patients in group 1 and 96% in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1992

Changes in calcium uptake by liver induced by ferric lactate.

In vitro and in vivo Ca(2+)-uptake by the liver is increased by ferric lactate. In vitro albumin and deferoxamine inhibit ferric lactate effects. Electrophoresis demonstrates the binding of ferric lactate to albumin. In vivo, ferric lactate induces a significant increase of Ca(2+)-uptake by liver, with a maximum of 2.9 nmol/g against 0.66 nmol/g for control livers (P less than 0.005) between 5 and 24 h after administration. This uptake modification is reversible, while the amount of iron (measured as 59Fe taken up) remains constant throughout the experiment. The affinity of ferric lactate for protein and the iron mass-dependence of Ca(2+)-uptake increase support for the hypothesis of a ferric lactate-cell membrane interaction rather than an iron-catalyzed cell injury by lipid peroxidation as the major event leading to an increased Ca(2+)-uptake.

Animals↗

PubMed1992

Prognostic factors from computed tomography in acute left colonic diverticulitis.

This prospective study examined factors which may predict a poor outcome (complications and recurrence) after a first attack of diverticulitis which has been successfully managed conservatively. Twenty-four of 107 patients who entered the study had a poor outcome: persistent diverticulitis (nine cases), recurrence (seven cases), colonic stenosis (six cases), residual parasigmoid abscess (one case) and colovesical fistula (one case). Eight of the 18 men aged 50 years or less had a poor outcome compared with 16 of the remaining 89 patients (P = 0.032). Twelve of 76 patients (16 per cent) with mild findings on computed tomography (CT) (localized thickening of colonic wall and inflammation of pericolic fat) had a poor outcome compared with 11 of 23 patients (48 per cent) whose CT was estimated as severe (abscess and/or extraluminal air and/or extraluminal Gastrografin) (P = 0.004). These results suggest that elective colectomy can be proposed after a first attack of acute left diverticulitis in men up to 50 years of age and/or in patients whose initial CT reveals findings of severe diverticulitis.

Acute Disease↗

PubMed1992

Elective hepatic resection in the elderly.

This retrospective review assessed the safety and validity of elective liver resection in patients older than 64 years of age. In all, 293 patients underwent elective liver resection over a 23-year period (1967-1990). Fifty-two patients (18 per cent) were older than 64 (maximum 84, mean 70.4) years and all but four of these did not have cirrhosis. In this older subgroup, indications for resection were liver metastases in 30 patients, primary malignancy in 16, benign tumours in five and multiple abscesses in one. There were 21 major resections, with two deaths from hepatic failure, and 31 minor resections, with one death from cardiac failure (total mortality rate 6 per cent). During the same period, there were seven deaths after elective resections performed in 222 patients without cirrhosis who were younger than 64 years (P = 0.39). Mortality rate and duration of postoperative hospital stay were not related to the extent of liver resection nor to patients' grading according to the American Society of Anesthesiologists' criteria. Intraoperative blood loss was the only parameter found to influence mortality rate (P = 0.008) and duration of hospital stay (P = 0.04). Elective liver resection can be safely undertaken in elderly patients without cirrhosis, provided that intraoperative blood loss is minimized.

Age Factors↗

PubMed1992

Results of surgical palliation for cancer of the head of the pancreas and periampullary region.

Between 1977 and 1986, 101 patients underwent surgical bypass for periampullary carcinoma. The hospital mortality rate was 18 per cent and the morbidity rate 43 per cent. Mortality was not influenced by the extent of the tumour. Survival rates at 1,2 and 3 years were 28, 9 and 4 per cent, respectively. The median survival time was 17 months for localized tumours, 10 months for those that had invaded surrounding tissues, 6 months in the presence of lymph node involvement and 3 months with distant metastasis. The quality of survival was good for most patients with localized tumours but poor for those with parenchymal metastasis, in whom palliation was transient for 85 per cent and effective for less than half of their survival time for 60 per cent. These results suggest that patients with distant metastasis but without impending duodenal obstruction should undergo palliation by endoscopic or percutaneous routes while those with less advanced disease or with duodenal involvement remain candidates for surgical bypass.

Adenocarcinoma↗

PubMed1992

Variability in the pharmacokinetics of epirubicin: a population analysis.

Population pharmacokinetic analysis of the anticancer agent epirubicin was carried out using the program NONMEM. Data were available from 36 patients aged 20-73 years, of whom 23 were women. All subjects exhibited normal liver and renal function. Epirubicin was given as a short-term i.v. infusion over the dose range of 25-100 mg/m2, and an average of 11 plasma samples/subject were taken for a period of up to 72 h after each dose. A Two compartment model was fitted to the data, characterised by the parameters clearance, volume of the central compartment, alpha and beta. Clearance was tested as a linear function of various demographic and/or biochemical features. A significant proportion of the variability in clearance could be attributed to sex, and also to age in women. For example, a 25-year-old man would display an average clearance of 95 l/h, whereas a 70-year-old woman would exhibit an average clearance of 64 l/h. Such differences in clearance might be important in the selection of epirubicin dose regimens.

Adult↗

PubMed1992

Drug resistance in oncology: from concepts to applications.

The complex problem of drug resistance is discussed with respect to host toxicity, to tumor characteristics (kinetic resistance, heterogeneity of cell subpopulations, hypoxia, mutation and gene amplification), and to the medication itself (pharmacokinetic and pharmacodynamic resistance: cell membrane, intracellular metabolism, intracellular target). After detailing each type of resistance, the possibilities of fighting against drug resistance are explored (dealing with host toxicity, tumor characteristics and drugs--intensifying therapy, multiple drug therapy, biochemical modulation, particular modalities of drug administration). Finally, perspectives of research and development of new drugs are summarized.

Animals↗

PubMed1992

Incidence, outcome, and proposed management of isolated abscesses complicating acute left-sided colonic diverticulitis. A prospective study of 140 patients.

In a prospective evaluation of 140 consecutive patients with acute left-sided colonic diverticulitis demonstrated by computerized tomography (CT) in all cases, 22 (16 percent) were found to have an associated abscess without peritonitis. Thirteen of these 22 required surgery (seven during the first stay and six from 2 to 11 months after the acute episode; median, three months). Nine patients were treated conservatively, eight of whom are now totally asymptomatic 24 months after the initial attack (range, 10-47 months). There were 10 mesocolic abscesses (seven treated with antibiotics alone), nine pelvic abscesses (seven requiring surgery), and three intra-abdominal abscesses, all operated upon. These results suggest that mesocolic abscesses can usually be managed conservatively without drainage; should surgery be necessary, en bloc resection with immediate anastomosis can usually be safely performed. Pelvic and intraabdominal abscesses behave more aggressively and usually require a two-stage surgical procedure when initial percutaneous drainage cannot be performed or is felt to be hazardous.

Abdomen↗

PubMed1992

Measurement of doxorubicin-induced lipid peroxidation under the conditions that determine cytotoxicity in cultured tumor cells.

We have investigated doxorubicin-induced lipid peroxidation by the measure of malondialdehyde (MDA) formation in rat glioblastoma cells and human breast carcinoma cells in culture. There was a significant production of MDA when the cells were incubated with pharmacologically relevant doxorubicin concentrations, i.e., concentrations that produce a significant cytotoxicity (0.1 micrograms/ml). At equitoxic doses, vincristine provided no lipid peroxidation, indicating that MDA formation is not a consequence of cell death. Doxorubicin-induced lipid peroxidation was maximal 24 h after incubation of the cells with doxorubicin, indicating that a delay was necessary for the free radical-mediated membrane damage induced by doxorubicin. In the presence of alpha-tocopherol in the culture medium, the doxorubicin-induced MDA formation was inhibited. The development of this method will help in defining the role of free radicals and lipid peroxidation in the cytotoxicity of doxorubicin.

Animals↗

PubMed1992

P-glycoprotein overexpression cannot explain the complete doxorubicin-resistance phenotype in rat glioblastoma cell lines.

We have associated pharmacological studies to a semi-quantitative evaluation of P-glycoprotein(s) expression, to establish if classical multidrug resistance (MDR) could account for the complete resistance phenotype exhibited by progressively doxorubicin-resistant rat glioblastoma cells. Three resistant variants (C6 0.001, C6 0.1 and C6 0.5) of the C6 glioblastoma cell line (C6 S) were selected by long-term culture in the presence of three concentrations of doxorubicin (0.001, 0.1 and 0.5 microgram.ml-1 respectively). The degree of doxorubicin resistance was respectively 7, 33 and 400, and all the cell variants were cross-resistant to m-AMSA, etoposide and vincristine. Doxorubicin incorporation was reduced similarly in all resistant cells, irrespective of the level of resistance. When exposed to their respective doxorubicin IC50, the 7-fold resistant cells had the same intracellular drug incorporation as the sensitive cells, whereas the 33-fold and 400-fold resistant cells could incorporate respectively 3.7 and 17 times more drug. The ratio of doxorubicin exposures required for 50% DNA synthesis inhibition and 50% growth inhibition was dependent on the degree of resistance; this ratio was 12.8 in C6 S, 11.6 in C6 0.001, 6.3 in C6 0.1 and 1.8 in C6 0.5. P-glycoprotein(s) overexpression was of the same magnitude as the resistance factor in variants C6 0.001 and C6 0.1, but was lower than resistance factor in variant C6 0.5. Reversal of drug incorporation by verapamil was complete in all resistant cell lines; however, reversal of doxorubicin cytotoxicity was complete only in the 7-fold resistant line and was only partial in the most resistant lines, which remained 10-fold and 20-fold resistant to doxorubicin. These results suggest that classical MDR was the first phenotype selected by doxorubicin in C6 0.001, whereas mechanism(s) of doxorubicin resistance other than classical MDR are added in the most resistant lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

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 less than 0.001) and the surviving factor in white blood cell counts. Other toxic side effects (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.

Dose-Response Relationship, Drug↗

PubMed1992

Pharmacokinetics and metabolism of epirubicin administered as i.v. bolus and 48-h infusion in patients with advanced soft-tissue sarcoma.

We have studied the pharmacokinetics of epirubicin after its administration in sarcoma patients either as an i.v. bolus or as a 48-h infusion (5 courses each; 9 patients in total). Bolus injection was followed by a three exponential decay in plasma, with half-lives of 2.43 min, 1.95 h and 21.7 h; 48-h infusions were characterized by the very rapid establishment of a plasma plateau concentration followed by a biexponential decay after stopping the infusion. Pharmacokinetic parameters such as total plasma clearance, total volume of distribution, mean residence time and elimination half-life were similar, irrespective of the duration of the administration. In contrast, the relative amounts of the metabolites of epirubicin were reduced when the drug was administered over 48 h; in particular, the plasma levels of epirubicin glucuronide never exceeded those of epirubicin, which always occur after bolus injection. This may result from a lower availability of epirubicin for metabolism. These results now require validation in a larger group of patients using a cross-over design.

Adolescent↗

PubMed1992

Respective effects of malnutrition and phosphate depletion on endurance swimming and muscle metabolism in rats.

To examine the respective roles of malnutrition and phosphate depletion on muscle exercise capacity and bioenergetics, phosphate-depleted, either underfed or partly refed rats; phosphate-supplemented, either underfed or partly refed rats; and well-nourished control animals were studied, using swim time to exhaustion and 31P NMR spectroscopy measurements of muscle phosphocreatine, inorganic phosphate, adenosine triphosphate and intracellular pH. Only partly refed rats displayed hypophosphataemia. Swim time to exhaustion was lower in non-refed rats than in controls. Among the four groups, both refeeding and phosphate depletion positively affected swim time to exhaustion (both with P less than 0.02), and swim time to exhaustion was negatively correlated with phosphataemia (P less than 0.05). At rest, the ratio of muscle phosphocreatine/inorganic phosphate was lower in the phosphate-supplemented rats than in controls, whereas muscle phosphocreatine/adenosine triphosphate and intracellular pH were comparable. After non-tetanic stimulation, the muscle phosphocreatine recovery was slower in the four groups than in controls and closely correlated with exhaustion (P less than 0.01). These findings suggest that malnutrition alters the capacity of muscular work, mainly because of a reduced cell oxidative energy availability. These patterns are improved by partial refeeding and clearly influenced by the level of phosphorus intake, whether depletion is capable of improving metabolic alterations or uncontrolled supplementation is deleterious in malnourished animals.

Animals↗

PubMed1992

Nuclear magnetic resonance spectroscopy of excised human hearts.

BACKGROUND: Phosphorus nuclear magnetic resonance spectroscopy has been proposed as a method of studying the metabolism of the myocardium in patients. Little is known about 31P nuclear magnetic resonance spectroscopy of diseased human hearts. METHODS: Two donor hearts meeting the requirements for heart transplantation and 11 diseased hearts were removed during a transplantation procedure and were studied in a horizontal 2.35 T superconducting magnet. Spectra were obtained at 0 degrees C about 30 minutes after the excision. The areas of the inorganic phosphate peak (Pi) and of the phosphocreatine peak (PCr) were summed and expressed as a ratio with respect to the area of the beta ATP peak. RESULTS: The ratio (Pi + PCr)/beta ATP was found to be significantly lower in five hearts with a myocardial infarct (0.77 (0.18)) than in hearts with dilated cardiomyopathy (1.25 (0.29)) and in normal hearts (1.69 (0.11)). The area of the phosphodiester peak was expressed as a ratio with respect to the area of the beta ATP peak: no differences were found between the three groups. CONCLUSIONS: These results suggest that the phosphocreatine concentration is lower in ischaemic heart disease than in dilated cardiomyopathy and that the phosphodiester peak is probably not useful in distinguishing between these two types of heart disease.

Adenosine Triphosphate↗

PubMed1992

In vitro growth of thymic tumor cell lines from Xenopus.

A spontaneous lymphoid thymus tumor was discovered in a male Xenopus of the MHC ff genotype. The tumor cell can be transplanted in histocompatible larval ff hosts, but not in ff adults unless irradiated (3000 rad). The tumor is rejected by allogeneic hosts. The tumor cells express neither markers of the B-cell lineage nor MHC encoded molecules; they express only markers of the T-cell lineage. Its lymphoid population is clonal as revealed by the existence of a stable rearrangement pattern of the immunoglobulin genes. Cell lines growing continuously in vitro have been derived from the tumor.

Animals↗

PubMed1992

Role of imaging technics in the classification of acute pancreatitis.

This paper is a review of some aspects of acute pancreatitis (AP) (definition criteria, outcome, and prognostic factors) and a reminder of the invaluable contribution of computed tomography (CT) in confirming the diagnosis of AP, distinguishing between edematous and necrotizing forms, and in providing prognostic information via detection of possible extrapancreatic spreads (EPS). The Geneva experience (510 cases of AP over a 9-year period) has shown that no fatalities occurred when no EPS were found on CT performed within 48 h of admission; mortality was 1.5% in the case of 1 or 2 EPS and 19% in the case of 3 EPS or more.

Acute Disease↗

PubMed1992

Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

PURPOSE: 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS: The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS: Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS: Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Blood Platelets↗