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P Chatelain

Publications and source records attributed to P Chatelain.

At least 127 records · Page 7Linked to original sources
PubMed1992

In vitro and in vivo enhancement of ricin-A chain immunotoxin activity by novel indolizine calcium channel blockers: delayed intracellular degradation linked to lipidosis induction.

With regard to increasing the clinical potential of ricin A-chain immunotoxins (RTA-ITs), a novel class of calcium channel blockers, indolizines SR33557 [2-isopropyl-1-[4-(3-N-methyl-N-(3,4-dimethoxy-beta- phenethyl)amino)propyloxy)benzenesulfonyl))indolizine] and SR33287 [isopropyl-2-((1-butylamino-3-propyl)oxy-4-benzoyl)-3-indolizine], were evaluated for their ability to enhance RTA-IT activity in vitro and in vivo. Five microM SR33287 and 5 microM SR33557 were potent enhancers of both anti-Thy 1.2 AT15E RTA-IT (84- and 64-fold, respectively) on T2 cells and anti-CD5 T101 (622- and 538-fold) and T101 F(ab')2 RTA-IT (34- and 28-fold) on CEM III cells. This was superior to the effect achieved by both 10 microM verapamil and 10 mM NH4Cl, albeit slightly inferior to that of 50 nM monensin and 5 microM perhexiline. Murine T2 lymphoma cells bearing the Thy 1.2 antigen were injected i.v. in Thy 1.2 (-) BL. 1.1 mice (median survival time, 17.7 days). Intravenous treatment with 10 micrograms of AT15E RTA-IT prolonged the survival of mice (median survival time, 26.8 days). When 400 micrograms of SR33287 were coinjected i.v. with 10 micrograms of AT15E RTA-IT, mouse survival was further increased, with 5 of 6 mice surviving, disease free, over 42 days. SR33287 had a significant impact on the intracellular routing of 125I-AT15E RTA-IT, which induced a greater than 2-fold increase in intracellular intact AT15E RTA-IT at 90 min. This effect on RTA-IT half-life was distinctly different from that observed with either NH4Cl or monensin and may be linked to the inhibition of acid lysosomal sphingomyelinase by SR33287, leading to cellular lipidosis. In conclusion, indolizines appear to be promising agents not only for immunotoxin enhancement but also for increasing the activity of any number of targeted therapeutic agents where modifying either the intracellular routing or increasing the intracellular half-life of the ligand would be beneficial to its cytotoxic activity.

Ammonium Chloride↗
PubMed1992

Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of type 1 (insulin-dependent) diabetes mellitus in high risk individuals.

The prevalence of glutamic acid decarboxylase autoantibodies was determined with an immunotrapping enzyme activity assay in newly-diagnosed Type 1 (insulin-dependent) diabetic patients as well as in first-degree relatives using rat brain homogenate as a source of glutamate decarboxylase. Twenty-six out of 86 islet-cell cytoplasmic auto-antibody positive and one out of 24 islet cell autoantibody negative patients of recent onset, had autoantibodies to glutamate decarboxylase above the upper 99% confidence limit obtained from 89 control sera. Among 27 islet cell autoantibody positive relatives including 19 siblings and 8 parents, antibodies to glutamate decarboxylase were found in 8 of 9 (89%) relatives and 7 of 8 (87.5%) siblings with islet cell auto-antibody titres above 20 JDF units, in 1 of 19 (5.2%) relatives with islet cell autoantibody titres between 2 and 5 JDF units, in 2 of 263 (0.7%) siblings and 1 of 139 parents without islet cell autoantibodies. In first-degree relatives, high titre islet cell autoantibodies and autoantibodies to glutamate decarboxylase were tightly associated (X2 = 182, p = 0.0001). None of the relatives with low genetic risk (n = 64), i.e. HLA-different to the diabetic proband, was found to be antibody positive. Antibodies to glutamate decarboxylase were present only in those relatives sharing at least one haplotype with the diabetic proband, including two islet cell autoantibody negative but HLA-identical siblings. Autoantibodies to glutamate decarboxylase were present in 7 of 9 (77%) relatives who developed the disease, including one islet cell autoantibody negative sibling.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Treatment with growth hormone-releasing hormone (GHRH) 1-44 in children with idiopathic growth hormone deficiency: a randomized double-blind dose-effect study. The GHRH European Multicenter Study (GEMS) Group.

One hundred and eleven pre-pubertal children (70 boys, 41 girls, aged 2.5 to 14.3 years) with growth failure (height 2 SD below the mean for chronological age (CA) and height velocity (HV) below the 10th percentile for bone age) due to idiopathic growth hormone deficiency (peak plasma GH < 20 mUI/1 to two standard provocative tests) were treated with GHRH 1-44 NH2. Patient stratification in two classes was performed according to body weight; in each class, patients were randomly allocated to one of seven GHRH doses, from 30 to 300 micrograms/day. GHRH was injected subcutaneously, every evening, for six months in a double-blind fashion. No relationship was found between the absolute or incremental HV during treatment and the dose (range from 1.3-23.1 micrograms/kg/day) of GHRH. However, HV (cm/year) increased from 3.8 +/- 0.1 (mean +/- SEM) before treatment to 6 +/- 0.2 during six months treatment and 47 patients (42%) increased their HV up to at least the mean normal HV for bone age (catch-up growth). Low titer antibodies to GHRH were found in 19 patients (17.1%) at six months; no adverse effect was observed. Our results suggest that patients showing catch-up growth were older, had a height closer to the mean for chronological age and a slower pre-treatment height velocity. Failure to demonstrate a relationship between GHRH dose and changes in growth velocity might be explained by the combination of a placebo effect, insufficient frequency of GHRH administration and heterogeneity of the population.

Adolescent↗
PubMed1992

Effects of the divalent cations nickel and cadmium on contractions of rat aorta to endothelin-1.

1. The effects of inorganic and organic calcium channel antagonists on the contractile responses of rat isolated aortic rings to endothelin-1 (ET-1) were studied. 2. ET-1 (0.1-100 nM) evoked concentration-related contractile responses of the rat aorta (EC50 1.65 +/- 0.22 nM, Emax 125.8 +/- 4.5 %KClmax, n = 20). In Ca(2+)-free modified Krebs solution (containing 1 mM EGTA) aortic rings failed to contract to ET-1 (0.1-30 nM). 3. Nickel chloride (0.2-0.8 mM) attenuated the ET-1 (1-100 nM)-induced contraction of rat aorta (response (%KClmax) to 10 nM ET-1: control 132.0 +/- 8.7 and after 0.2 mM Ni2+ 90.3 +/- 14.8, 0.4 mM Ni2+ 54.7 +/- 12.3, 0.8 mM Ni2+ 10.3 +/- 4.4, n = 6/group). Cadmium chloride (10-30 microM) depressed the maxima of the concentration-response curves to ET-1 with an IC50 of 15.4 +/- 1.5 microM (n = 6). 4. The ET-1 evoked contractile responses were not modified by the dihydropyridine calcium channel antagonist, nicardipine (0.1 microM), or by omega-conotoxin (1.0 microM). Cinnarizine (10 microM), however, significantly attenuated the maximum response to ET-1 (96.9 +/- 6.0 vs 128.0 +/- 5.8 %KClmax for control), but failed to modify the EC50 value. 5. Amiloride, a Na(+)-Ca2+ exchange inhibitor, also depressed the maxima of the concentration-response curves to ET-1 with an IC50 of 0.45 +/- 0.05 mM (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1992

Prevention of calcium overload and down-regulation of calcium channels in rat heart by SR 33557, a novel calcium entry blocker.

The effect of SR 33557, a novel calcium entry blocker, on calcium overload, and regulation of calcium channels and beta-adrenergic receptors was investigated in the rat heart. Calcium overload and infarct-like lesions were produced by a large dose of isoproterenol (40 mg/kg, subcutaneously) to rats. Calcium overload was maximal 8 hours after administration of isoproterenol (control: 5.7 mmol Ca2+/kg dry weight, isoproterenol: 34.9 mmol Ca2+/kg dry weight). At that time, a decrease in the total number of beta-adrenergic receptors (-27%) and calcium channels (-20% and -23%) was observed. Intravenous injection of SR 33557 (0.5-10 mg/kg), 30 minutes before administration of isoproterenol, attenuated the increase in calcium content in a dose-related manner, such that 5 mg/kg SR 33557 reduced calcium overload by 50%. At this dose, SR 33557 had no effect on the number of beta-adrenergic receptors but prevented the decrease in the number of calcium channels. The total number of binding sites and the dissociation constants of each radioligand were estimated from saturation isotherms. The dissociation constants were unchanged when animals given isoproterenol or SR 33557 and isoproterenol were compared to the control group. The results indicate that SR 33557 is able to protect against the calcium overload induced by sympathetic over-stimulation. This over-stimulation of the sympathetic system causes a down-regulation of the number of active beta-adrenergic receptors and calcium channels. The down-regulation of calcium channels is selectively reduced by earlier administration of SR 33557.

Animals↗
PubMed1992

Increase of circulating insulin-like growth factor-I in chronic renal failure is reduced by low-protein diet.

We performed a nutritional trial to assess the variations of circulating insulin-like growth factor-I (IGF-I) in chronic renal failure (CRF). Eight patients suffering from mild renal failure (SCr = 374 +/- 52 mumol/l) were prescribed a standard diet for 1 month followed by 1 month of protein restriction. Mean protein intake was 0.77 and 0.46 g/kg BW/day, mean caloric intake 25 and 24.7 kcal/kg BW/day for the first and the second month, respectively. After each period of diet, nitrogen balances were negative (-1.2 +/- 1.6 and -1.6 +/- 0.9 g/N/day). Despite these low-caloric conditions, mean serum IGF-I level was at the upper level of normal (358 +/- 136 ng/ml) after 1 month of standard protein intake, and statistically reduced (289 +/- 122 ng/ml, p < 0.002) by the low-protein diet. No correlation was observed between serum IGF-I levels and protein, caloric intake, and nitrogen balances for the two periods. Estimation of the IGF-I binding by the ratio of extracted to nonextracted IGF-I value suggested abnormal binding in CRF. This binding was modified by reduced protein intake. In conclusion, larger studies are needed in CRF to assess the significance of IGF-I variations and the IGF-I binding proteins which modulate the bioactivity of this growth factor.

Adult↗
PubMed1991

Reversal of multidrug resistance by calcium channel blocker SR33557 without photoaffinity labeling of P-glycoprotein.

The altered pharmacology of drugs in multidrug-resistant cells (decreased accumulation and retention) appears to be mediated by a high molecular weight integral membrane protein, called P-glycogprotein (P-gp). Agents known to reverse this pleiotropic drug resistance (chemosensitizers) have been shown to interact with P-gp; and as such, the inhibition of photoaffinity labeling by P-gp probes (such as [3H]azidopine) has been proposed as a basis for mass screening of chemosensitizers. In this study, we provide direct evidence that a novel calcium channel blocker (SR33557), which was 4.5 times more potent in sensitizing P388/ADR cells to doxorubicin as compared to verapamil (while inducing a similar increase in uptake and decrease in efflux of [14C]doxorubicin, did not compete for the [3H]azidopine-binding site on P-gp, whereas verapamil did. Moreover, SR33557, which is inherently photoactivable, did not photolabel P-gp, but a 65-kDa protein did appear to be an acceptor; and this binding was displaced by diltiazem and nifedipine, but not by verapamil. Finally, the implication for the participation of a sphingomyelin/sphingosine cycle (as a potential lipid second messenger system) in the chemosensitization of P388/ADR cells was investigated. 30 microM SR33557 induced a 72% inhibition in acid lysosomal sphingomyelinase activity, a 5-fold increase in sphingosine levels, and a 75% inhibition in intracellular protein kinase C activity. Although no direct link is established between these observations and P-gp activity, further studies on a possible sphingosine-mediated regulation of P-gp may yield information on the involvement of this second messenger system in the action of SR33557.

Animals↗
PubMed1991

A conformational analysis study of the interaction of amiodarone and cholesterol with lysophosphatidylcholine.

The spatial configuration of amiodarone (in both its protonated and neutral forms) and a hydroxylated analog was studied using conformational analysis in a simulated membrane-water environment. The three compounds and cholesterol were studied as isolated molecules and in interaction with lysophosphatidylcholine. The association of the molecules with lysophosphatidylcholine was further characterized by incorporation in a phosphatidylcholine matrix. Calculation of the mean interaction energy, the surface charge density and the hydrophilic and hydrophobic mean molecular areas showed that the protonated form of amiodarone, and to a lesser extent cholesterol form a stable association with lysophosphatidylcholine. This association was further stabilized when incorporated into a phosphatidylcholine matrix so that the mean interaction energy increased to -96.1 kJ/mol (i.e. 60% higher than the mean lipid-lipid energy of interaction). Lysophosphatidylcholine was shown to possess a cone-shaped structure whilst amiodarone was shown to be in the form of an inverted cone. This association of the two cones forms a stable cylindrical structure.

Amiodarone↗
PubMed1991

Autoantibodies and genetic factors associated with the development of type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients.

Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type 1 diabetic patients. Relatives were prospectively followed for 2,304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas other remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Near normalization of adolescent height with growth hormone therapy in very short children without growth hormone deficiency.

Ten prepubertal children with stature at or below the 1st percentile for height and without growth hormone deficiency received 0.3 U recombinant growth hormone per kilogram daily for 2 years before puberty. Their growth velocity increased from 4 +/- 0.3 cm/yr before treatment to 10.7 +/- 0.6 and 8.8 +/- 0.6 cm, respectively, during the first and second years of treatment, and then remained at 5.7 +/- 0.7 cm the year after the end of growth hormone administration. This resulted in a near normalization of adolescent height. Bone maturation paralleled chronologic age, and therefore the expected final height of the children increased by approximately 10 cm. Administration of growth hormone induced a reversible hyperinsulinemia, with moderate and transient changes in glucose metabolism. A prospective, randomized study, including an untreated cohort, will be needed to confirm the effects on final height and to determine the magnitude of the response in familial short stature.

Adolescent↗
PubMed1991

[Preparation of leukocyte-depleted human platelet concentrates by centrifugation and filtration of a pool of sterilely connected buffy-coats].

We describe a new method for the preparation of standardised therapeutic doses of leukocyte depleted platelets. The first step is to remove the buffy-coat from whole blood units drawn on triple Siamese ACD/SAGM bags (Maco-Pharma) by means of a Compomat (NPBI). The second step is to connect (SCD Haemonetics) six buffy-coats and one plasma to a special kit (Maco-Pharma) including a PALL PL 100 filter; after centrifugation, the supernatant platelet concentrate is extracted, filtered and recovered in a 2 litre TOTM PVC bag. The volume, the number of platelets and leukocytes of these pools are measured. A comparison of these parameters is made with therapeutic doses prepared in the same way without filtration. Besides, pH measurements up to the 6th day of storage and bacteriological checks are carried out. The results show: no platelet loss related to filtration; a synergy between the preparation process out of buffy-coats and the filtration: so each dose contains less than 10(6) leukocytes; a good pH level allowing the storage for five days as it is associated to the bacteriological safety of the functionally closed system. This technique makes it possible to transfuse only leukocyte depleted platelet concentrates. In addition, it offers new prospects for standardisation and quality improvement.

Blood Transfusion↗
PubMed1991

Dramatic early postnatal growth failure in children with early onset growth hormone deficiency. The International Board of the Kabi Pharmacia International Growth Study.

From the large group of patients included in the Kabi Pharmacia International Growth Study, 58 were studied who were treated with growth hormone (GH) before the age of 2 years, after diagnosis of GH deficiency (GHD). The growth parameters calculated from these infants indicate dramatic early postnatal growth failure, thus suggesting that GH could participate in early postnatal growth. The intensity of growth failure in these infants with GHD suggests that early screening on clinical grounds is possible.

Body Constitution↗
PubMed1991

Stenting of superior vena cava and inferior vena cava for symptomatic narrowing after repeated atrial surgery for D-transposition of the great vessels.

Double venous stenting of the superior vena cava and inferior vena cava was successfully performed after failed balloon angioplasty in a young woman who had venoatrial narrowing and kinking after repeated Mustard procedure for D-transposition of great vessels. Self-expanding metallic stents were used. Angiography showed that the first stent was fully patient after six months when a second stent was implanted. This operation was followed by sustained clinical improvement. The present report shows the feasibility and success of stenting of the great veins when postoperative narrowing or kinking is unresponsive to balloon angioplasty alone.

Adolescent↗
PubMed1991

Effect of increasing degrees of ischemic injury on myocardial oxidative metabolism early after reperfusion in isolated rat hearts.

The present investigation studied the effect of increasing severities of ischemic injury on recovery of oxidative metabolism after reperfusion in isolated rat hearts perfused retrogradely with erythrocyte-containing medium. Hearts subjected to 60 minutes of low-flow ischemia (5% of control perfusion) exhibited delayed but sustained recovery of left ventricular pressure development during reperfusion and preservation of ultrastructure delineated with electron microscopy. Immediately after reperfusion, myocardial oxygen consumption returned to control values, well before left ventricular pressure development recovered. Early after reperfusion release of 14CO2 from [1-14C]palmitate was reduced (-53%, p less than 0.01). Conversely, release of 14CO2 from [U-14C]glucose was increased (+131%, p less than 0.05). After 60 minutes of reperfusion 14CO2 release had completely returned to normal for both labeled substrates. Pulse-labeling experiments indicated that during transient depression of [1-14C]palmitate oxidation more tracer was incorporated into myocardial lipid esters, primarily triglycerides. In contrast to hearts subjected to low-flow ischemia, hearts subjected to 60 minutes of no-flow ischemia exhibited poor recovery of contractile function during the reperfusion period. Electron microscopic examination of reperfused hearts showed advanced myocyte damage consistent with irreversible injury. Interestingly, myocardial oxygen consumption in this group also recovered to control values. The substrate pattern during the early reperfusion period was similar to that of hearts subjected to low-flow ischemia. After 120 minutes of no-flow ischemia, recovery of oxidative metabolism was virtually absent. The results indicate a pronounced dissociation between recovery of oxidative metabolism and of contractile function in reperfused myocardium. The oxidative metabolic rate was disproportionately high compared with contractile function, not only in reversibly "stunned" hearts, but also in severely damaged hearts exhibiting signs of irreversible injury.

Acetates↗
PubMed1991

Characterization of the slow calcium channel binding sites for [3H]SR 33557 in rat heart sarcolemmal membranes.

SR 33557 represents a new class of compounds (indolizine sulfone) that inhibit L-type Ca2+ channels. [3H]SR 33557 has been shown to bind with high affinity (Kd congruent to 0.36 nM, calculated from saturation isotherms and association/dissociation kinetics) to a single class of sites in a purified preparation of rat cardiac sarcolemmal membranes. The binding was found to be saturable and reversible. The maximal binding capacity was in approximately 1:1 stoichiometry with that of other Ca2+ channel antagonists. Various divalent cations (Mg2+, Mn2+, Ca2+, Ba2+, and Cd2+) were shown to inhibit specific [3H]SR 33557 binding, with Cd2+ being the most potent. Among several receptor or channel ligands (including omega-conotoxin and Na+ and K+ channel modulators), only the L-type Ca2+ channel antagonists were found to displace [3H]SR 33557. However, dihydropyridines, phenylalkylamines, benzothiazepines, and diphenylbutylpiperidines were found to inhibit [3H]SR 33557 in a noncompetitive manner as demonstrated by displacement and saturation experiments in addition to dissociation kinetics. From these results, we suggest that SR 33557 binds with high affinity to a unique site on the L-type Ca2+ channel found in rat cardiac sarcolemmal membranes.

Animals↗
PubMed1991

[Endocrine complications of treatment of brain tumors in children].

The recent treatment protocols used in the management of children with brain tumors have greatly improved the survival rate in these patients. The authors present a review of the endocrine dysfunctions associated with the different types of treatment. Cranial irradiation is the first cause of endocrine disorders, growth failure being the main risk. A simplified protocol for endocrine evaluation and treatment of the disorders is suggested.

Adolescent↗