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Biomedical subjects

N Simon

Publications and source records attributed to N Simon.

At least 37 records · Page 2Linked to original sources
PubMed1998

Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences.

BACKGROUND: Coenzyme Q10 or ubiquinone is a redox component of the respiratory chain, which may be involved in the pathogenesis of cancer. METHODS: In order to better understand the role of this vitamin in the pathogenesis of breast cancer, a clinical trial including 200 women hospitalized for the biopsy and/or the ablation of a breast tumor was conducted. Ubiquinone plasma concentrations were determined simultaneously with vitamin E plasma concentrations (as antioxidant reference) by HPLC. RESULTS: A coenzyme Q10 deficiency was noted both in carcinomas (80 patients) and non-malignant lesions (120 patients), while vitamin E concentrations were within the normal range. A correlation was shown between the intensity of the deficiency and the bad prognosis of the breast disease based on high TNM and SBR values or the lack of estrogen receptors. However, neither cathepsin D level nor adenopathy invasion was related to ubiquinone levels. CONCLUSIONS: Since prooxidants may promote tumorigenesis, ubiquinone supplementation in breast cancer could be relevant.

Adult↗
PubMed1997

Population pharmacokinetics of high-dose thiopental in patients with cerebral injuries.

Thiopental monitoring was performed in 95 critically ill patients hospitalized for neurologic damage, High-dose thiopental was infused during long-term treatment. Total dose of 333 +/- 144 mg/kg (449 +/- 185 mg/kg for females and 302 +/- 113 mg/kg for men) were given in 125 +/- 43 hours. Plasma concentration-time data were analyzed according to a population pharmacokinetic approach with an initial group of 65 patients. Clearance (CL) and central volume of distribution (Vc) were modeled alone and under the influence of demographic covariates, assuming a two-compartment open model with first-order elimination. The final population models were as follows: CL (L/hr) = 11.7.weight (kg).age (yr)/(2136 + age2) and Vc = 1.52.weight (kg) + 44.8. Mean CL and Vc mean population estimates were 8.01 L/hr (133 ml/min or 2.02 ml/min/kg) and 145 L (2.19 L/kg). The predictive performance of the population modeling and parameters was evaluated with a bayesian fitting procedure in an independent validation set of 30 patients with similar physical and clinical characteristics. There was no statistically significant bias or imprecision between measured and predicted thiopental plasma concentrations in this validation group. Moreover, there was a good adequation (r = 0.939) between individual CL values predicted from the population formula and estimated with the bayesian approach.

Adolescent↗
PubMed1997

Prednisolone and azathioprine worsen the cyclosporine A-induced oxidative phosphorylation decrease of kidney mitochondria.

We investigated the effects of cyclosporine A, prednisolone and azathioprine on respiration rates, Ca2+-induced swelling and Ca2+ fluxes of rat kidney mitochondria. The three drugs significantly decreased the succinate induced-respiration rates according to concentration-dependent processes. Each drug inhibited about 10% of the respiratory control ratio, with EC50 of 3.7 x 10(-7) M, 5.8 x 10(-9) M for cyclosporine A and azathioprine respectively. Prednisolone was the most effective (19.2%) acting by a two-step process with EC50 of 9.2 x 10(-12) M and 1.9 x 10(-8) M. The combination of the three drugs developed a higher significant decrease of respiratory control ratio than that of each drug but lower than the sum of their respective effects. Inhibitions of swelling and Ca2+ fluxes through mitochondrial membrane due to the combination were not different from those induced by cyclosporine A alone. The action mechanisms of cyclosporine A and prednisolone were total and partial Ca2+ dependent respectively. Azathioprine appears to act by a Ca2+-independent one. It is concluded that azathioprine and prednisolone may worsen cyclosporine A-induced renal mitochondrial alteration of oxidative phosphorylation.

Animals↗
PubMed1997

[The Cochrane Collaboration, support of therapeutic information].

Today, prescribers need to distinguish between the clinical practices based on randomized clinical trialing information and those based on animal physiological data or theory. Now the information on therapeutics is becoming more dense, more complex and less available to the clinicians. Information sources are numerous and varied, including data whose quality differs. These data are unhierarchised in terms of methodological quality and clinical relevance. It will be optimal if each prescriber could himself collect and analyse scientific information. In fact this situation cannot be effective in private physician's practices. An international collaboration, the Cochrane Collaboration, including volunteers, university researchers, and clinical investigators has the following objective: to prepare, maintain and disseminate systematic reviews of the effects of health care. The Cochrane Collaboration is thus the most adapted intermediairy between scientifically actualized data and clinical practitioners.

France↗
PubMed1997

pH dependent binding of ligands to serum lipoproteins.

PURPOSE: The binding interactions of binedaline, nicardipine and darodipine with lipoproteins (HDL, LDL, VLDL) were examined as a function of pH in order to evaluate the role of lipoprotein components and ligand protonation in the binding process. METHODS: Binding studies were performed by equilibrium dialysis with radiolabeled ligands and differential UV-visible spectroscopy. RESULTS: Deprotonated ligands had a markedly higher affinity for lipoproteins than the protonated forms, resulting in a concomitant decrease in the pKa of bound ligands, i.e., a decrease in the basicity of the ligand in the bound state. The UV-visible difference spectra generated upon binding of auramine O to lipoproteins also showed that there was a contribution to the binding arising from the deprotonation of the ligand. Ligand binding was related to the phospholipid and cholesteryl ester content and to a lesser degree to the free cholesterol and protein content of lipoproteins, therefore to the surface monolayer components of lipoproteins. This relationship was even more accurate for the deprotonated, high-affinity, than for the protonated species. CONCLUSIONS: It is suggested that among other possible interactions, ligand binding to lipoproteins involves proton exchange between the reactants and that the high affinity ligand species interact more specifically with the phospholipids of the lipoprotein surface monolayer.

Hydrogen-Ion Concentration↗
PubMed1997

Blood-to-brain transfer of various oxicams: effects of plasma binding on their brain delivery.

PURPOSE: The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. METHODS: The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-l-acid glycoprotein (AAG) solutions at various concentrations. RESULTS: All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction. CONCLUSIONS: Except for piroxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of meloxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall.

Adult↗
PubMed1997

In vitro targeting and specific transfection of human neuroblastoma cells by chCE7 antibody-mediated gene transfer.

We developed a new vector for gene targeting of neuroblastoma (NB) cells, based on the utilization o a monoclonal antibody (chCE7) covalently linked to polylysine (PL). In the presence of chloroquine, chCE7-PL-DNA complexes transfected NB cells as efficiently as DOTAP, transfectam, TF-X50, or lipofectamine. This was demonstrated by transfection of the luciferase or beta-galactosidase reporter genes in three different NB cell lines. This transfection was specific, since it was inhibited in the presence of competing unconjugated chCE7 antibody (Ab), and was not observed in cell lines negative for the CE7 antigen. We tested the potential biological activity of a plasmid coding for gamma-interferon (gamma IFN) transfected with chCE7-PL. HLA ABC expression on NB cells was induced after transfection with pCMV-gamma IFN at a higher level than after incubation with 1000 IU/ml of purified gamma IFN. Moreover, these HLA ABC-positive NB cells were able to activate autologous cytotoxic T lymphocytes in vitro. Thus chCE7-PL is able to target a plasmid to NB cells and to allow the expression of the transfected gene in a biologically active form.

Antibodies, Monoclonal↗
PubMed1997

Trimetazidine does not modify blood levels and immunosuppressant effects of cyclosporine A in renal allograft recipients.

AIMS: In renal allograft recipients, trimetazidine (Vastarel) was proposed to be associated with the classic immunosuppressant treatments because it displays anti-ischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, Sandimmun, and trimetazidine. METHODS: Twelve renal transplant patients were selected on the basis of the stability of their cyclosporine A blood concentrations for the previous 3 months. They received trimetazidine, 40 mg twice daily orally for 5 days. Other coadministered drugs were kept unchanged during the study. Before and after trimetazidine administration, cyclosporine A blood concentrations, plasma interleukin-2 and soluble interleukin-2 receptor levels were measured. RESULTS: The data showed that neither cyclosporin A blood pharmacokinetic parameters, Cmax, tmax, AUC, nor the concentrations of interleukin-2 and soluble interleukin-2 receptors were significantly modified. CONCLUSIONS: Therefore, it was suggested that trimetazidine may be coadministered with cyclosporine A without cyclosporine A dosage adjustment.

Adult↗
PubMed1997

Melatonin high-affinity binding to alpha-1-acid glycoprotein in human serum.

The binding of 3H-melatonin to human serum proteins was investigated by equilibrium dialysis at 37 degrees C and pH 7.4. The binding to serum was moderate (53%) for physiological melatonin concentrations below 1 nmol/L. alpha 1-Acid glycoprotein and albumin bound melatonin with high 27 +/- 3 and low 1.5 +/- 0.1 (mmol/l)-1 affinity, respectively. Melatonin binding to other serum proteins, gamma-globulins and lipoproteins was not significant. The serum binding was characterized by a saturable and a nonsaturable component. The saturable component resulted from the high-affinity binding to alpha 1-acid glycoprotein and the nonsaturable component resulted from the low-affinity binding to albumin. The number of binding sites was 0.36/molecule of alpha 1-acid glycoprotein, when either pure alpha 1-acid glycoprotein or serum were studied, indicating that only a fraction of alpha 1-acid glycoprotein bound melatonin. The observed binding parameters did not enable simulation of the observed serum binding, and melatonin binding to an alpha 1-acid glycoprotein-albumin mixture was higher than that expected from the binding to each isolated protein. The high-affinity melatonin binding to alpha 1-acid glycoprotein might result from a potentiation of the binding interaction by albumin and the amount of melatonin bound in plasma might vary according to the alpha 1-acid glycoprotein concentration.

Blood Proteins↗
PubMed1997

Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.

Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection.

Adenosine Triphosphate↗
PubMed1996

[Evaluation of pediatric advise asked by telephone in emergency units].

BACKGROUND: Telephone calls for advice are common in pediatric emergency departments. This study was conducted to determine the nature of these calls and the answers provided. METHODS: From 24 April through 24 July 1994, all telephone calls requesting pediatric advice in the emergency department of the Poissy Hospital were independently analysed by two pediatricians from forms prospectively filled in for each call by the resident or the attending people who answered the call. RESULTS: Of the 239 registered calls, 186 could be analysed. They represented, in number, 15.25% of the children seen at the same emergency department during the study period. Weekend and holiday calls accounted for 35.5% of calls. 7.8% of calls were received from 0.01 am to 8.00 am, 28.7% from 8.01 am to 4.00 pm, and 63.5% from 4.01 pm to 12.00 pm. Thirty-seven percent concerned children under one year of age. The caller was one of the parents in 93% of cases. The four most frequent complaints were fever (26.5%), requests for information (17.2%), rash (12.3%), and vomiting (10.2%). The review of calls by two pediatricians determined that 67% of children did not need to be seen by a physician within six hours; 28% needed to be seen within 6 hours, and 5% needed to be seen within one hour. The advice given was followed in 88% of cases; 96% of callers were satisfied with their calls management. CONCLUSIONS: Telephone advice constitutes an important part of the activity in the pediatric emergency department. Instructional programs in telephone management are necessary for physicians. These programs should include communication skills and familiarization with protocols concerning the most frequent complaints, especially those regarding children under one year of age.

Adolescent↗
PubMed1996

[Telephonic advice by an emergency department given in a simulated pediatric case].

BACKGROUND: Emergency departments (ED) are requested everyday to dispense medical telephone advice for children. To evaluate the quality of telephone management, a mock scenario simulating a febrile 4 month-old-girl with signs compatible with septicemia was used. METHODS: One hundred randomly selected French emergency departments were called on. Half of the hospitals had a pediatric department with more than 20 beds; the other half did not have a pediatric department. A research technician called and said: "My baby has got fever and I do not know what to do". Additional information was given only on request. RESULTS: Ninety-four ED gave medical advice by telephone: 65% of the cases by a physician, 24.5% by a nurse, 9.5% by a nurse technician and 1% by a secretary. In hospitals without a pediatric department, physicians took calls in 76.5% of the cases, whereas in hospitals with a pediatric department they only took calls in 53% of the cases. The mean number of questions asked per ED was 3.1. The age of the child was requested by 87.2% of the respondents. Advice was given by 36.1% of the ED without asking either the age of the patient or grade of the fever. The advice given by the respondents was: come to the ED immediately (30.9%), see a community physician immediately (51%), come to the ED tomorrow (2.1%), see a community physician tomorrow (8.5%), and manage at home (7.5%). CONCLUSIONS: This study has shown important inadequacies in pediatric telephone advice given by some ED. It suggests that the respondents do not use a protocol to handle the calls; development of such protocols to guide the histories taken and advice given for the most common telephone queries is urged.

Attitude of Health Personnel↗
PubMed1996

Early inflammatory response correlates with the severity of injury.

OBJECTIVE: To determine if the early inflammatory response correlates with the severity of injury in a blunt trauma model in rats. DESIGN: Prospective, randomized, controlled trial. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats, weighing 250 to 400 g. INTERVENTIONS: Twenty-two male Sprague-Dawley rats were divided randomly into single hindlimb fracture, bilateral hindlimb fracture, and no fracture groups. At 90 mins, all animals underwent midline laparotomy and aspiration of blood from the inferior vena cava. Venous blood gas, plasma lactate, and plasma concentrations of tumor necrosis factor (TNF), prostaglandin F(6-keto-PGF1 alpha), and interleukin (IL)-6 were sampled. Statistical analysis was done via one-way analysis of variance and Scheffé post hoc analysis. In a second part of this experiment, the effect of hemorrhage on the release of IL-6 was evaluated. Animals in this group were compared with control and bilateral hindlimb fracture animals, using the Student's t-test. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in venous pH or base deficit among the groups. Oxygen saturation was significantly decreased in the bilateral hindlimb fracture group when compared with the control group. In the hemorrhage plus bilateral fracture group, oxygen saturation was significantly decreased when compared with the bilateral fracture group. lactate concentrations in plasma were increased in both fracture groups as well as the hemorrhaged groups. Plasma TNF concentrations were increased in the injured groups but there was no significant difference between single and bilateral hindlimb fracture groups. The 6-keto-PGF1 alpha concentrations were increased in both of the fracture groups when compared with the control group and there was a significant difference between single and bilateral hindlimb fracture groups. Similarly, circulating IL-6 concentrations were significantly higher in the bilateral fracture group than in the single fracture group; both fracture groups were significantly higher than the control group. Hemorrhaged animals had even higher IL-6 concentrations. CONCLUSIONS: Plasma lactate and TNF concentrations were affected by injury, however their concentrations did not correlate with degree of injury. IL-6 concentrations were increased early postinjury and correlated with severity of injury. The 6-keto-PGF1 alpha concentrations in plasma also correlated with the severity of injury and this phenomenon may represent early endothelial activation which may be the source of IL-6 release.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Inhibition of rat cerebral mitochondrial respiration by cyclosporins A, D, and G and restoration with trimetazidine.

The aim of this work was to investigate possible inhibitory effects of Ca+ and different cyclosporins (Cs) on the rat brain mitochondrial respiratory control ratio (RCR) and whether or not these effects could be antagonized by trimetazidine (TMZ). The RCR was evaluated as the state 3/state 4 ratio of oxidative phosphorylation. CsA, D, and G inhibited about 10% of RCR in a concentration-dependent manner with EC50 of 57, 19 and 7 nM, respectively, whereas CsH did not modify RCR. TMZ was able to fully antagonize this inhibitory effect in a concentration-dependent manner with EC50 of 5,200, 180, and 1 nM, respectively. The Ca2+ added to the mitochondrial preparation decreased RCR in a concentration-dependent manner with a maximal effect of 46% obtained with 100 microM Ca2+. In the presence of TMZ (100 microM), the inhibitory effect of Ca2+ was partly reversed (9%). TMZ alone showed no inhibitory or stimulant effect on RCR. These results show that restoration of RCR by TMZ is due to a Ca(2+)-dependent mechanism, promoting Ca2+ efflux from the mitochondrial matrix. However, Ca2+ efflux is only partial in case of Ca2+ overload. These data suggest that TMZ may restore ATP synthesis in circumstances where neither Ca2+ overload, nor a prooxidant have generated a RCR decrease.

Analysis of Variance↗