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Biomedical subjects

C Lambert

Publications and source records attributed to C Lambert.

At least 73 records · Page 4Linked to original sources
PubMed1996

Direct chronotropic effects of atrial and C-type natriuretic peptides in anaesthetized dogs.

1. The chronotropic effects of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) were investigated using injections (50 micrograms in 1 ml of Tyrode solution as bolus over 1 min) directly into the sinus node artery of 21 anaesthetized and vagotomized dogs which had been pretreated with a beta-adrenoceptor antagonist. The injections were also repeated following: (a) alpha-adrenoceptor antagonism (prazosin) and muscarinic receptor antagonism (atropine); (b) inhibition of prostaglandin synthesis (indomethacin); (c) angiotensin II AT1 receptor antagonism (losartan); (d) histamine H1 (mepyramine) and H2 (cimetidine) receptor antagonism. 2. The results obtained indicate that ANP had no significant effect on the basal sinus rate, whereas CNP produced a slight but significant increase of 12 +/- 2 beats min-1. The effect of CNP was long-lasting (return to pre-injection levels after maximum effect in 17 +/- 3 min) and was not influenced by the various antagonists mentioned above. 3. During in vitro experiments on spontaneously beating right atria isolated from 6 dogs, the injection of CNP (50 micrograms in 1 ml of Tyrode solution) into the sinus node artery produced an increase in atrial rate of 14 +/- 1 beats min-1. 4. The results of this work indicate that CNP exerts a significant and prolonged positive chronotropic effect both in vivo and in vitro. Other studies are required to elucidate the mechanism of action of CNP on the heart conduction system, to ascertain the presence of natriuretic peptide receptor B in the region of the sinoatrial node and to determine the role of CNP in the control of heart rate.

Adrenergic beta-Antagonists↗
PubMed1995

High frequency of IL-10-secreting CD4+ graft-infiltrating T lymphocytes in promptly rejected kidney allografts.

IFN-gamma and IL-10 secretion by sorted T cell subsets of irreversibly rejected kidney graft-infiltrating cells (GIC) and normal PBMC was studied by ELISPOT. The low spontaneous frequency of IFN-gamma-producing cells (IFN-gamma-PC) was strongly increased by anti-CD3 activation within unsorted, CD3+CD4+, and CD3+CD4- subsets of GIC and PBMC. In contrast with PBMC, IL-10-PC from GIC were at higher frequency within CD4+ cells than among CD4- ones (P < 0.03). Four kidneys removed after 3.7 +/- 0.8 months showed acute vascular rejection, high frequency of activated CD4+ IL-10-PC (118 +/- 68 per 10(4) cells), and high percentage of anti-class II antibody reactivity (87.6 +/- 6.3%). In contrast, four patients with kidneys removed later (53.7 +/- 1.6 months, P = 0.02) displayed chronic rejection with superimposed acute cellular rejection, low frequency of CD4+ IL-10-PC (7.0 +/- 3.0 per 10(4) cells, P = 0.02), and low percentage of anti-class II antibody reactivity (12.9 +/- 6.1%, P = 0.02). Thus, accelerated vascular rejection appears to be associated with preferential production of IL-10 by activated CD4+ GIC, which may act by shifting the effector arms of alloreaction toward humoral responses.

Acute Disease↗
PubMed1995

Release of 5-ASA from Pentasa in patients with Crohn's disease of the small intestine.

BACKGROUND: Pentasa is a controlled-release tablet made from semipermeable microspheres and designed to continuously deliver therapeutic quantities of 5-ASA (5-aminosalicylic acid) throughout the gastrointestinal tract. Scintigraphic studies in healthy subjects have documented that 5-ASA release could occur in the small intestine. We tested here the disintegration of Pentasa in the digestive tract of nine patients with Crohn's disease of the small intestine. MATERIALS: Each patient was given, after breakfast, a 250 mg tablet of Pentasa containing samarium-153 oxide. For 8 h the progression of the isotope in the gastrointestinal tract was followed using gamma camera scintigraphy. Plasma measurement of 5-ASA and acetylated 5-ASA was used to verify the liberation and absorption of 5-ASA. RESULTS: The Pentasa tablet appeared completely dissolved in the stomach by 117 +/- 18 min. Samarium oxide was first detected in the small intestine 60 +/- 5 min after its ingestion; it reached the colon after 280 +/- 13 min and it was completely absent from the small intestine at 360 +/- 26 min. Plasma concentrations of 5-ASA started to rise after 67 +/- 7 min and were maximal at 222 +/- 25 min. CONCLUSION: In patients with Crohn's disease of the small intestine, Pentasa microgranules start releasing 5-ASA in the proximal small intestine, acting locally to exert its beneficial effect.

Adult↗
PubMed1995

Mechanisms of angiotensin II chronotropic effect in anaesthetized dogs.

1. The chronotropic effect of angiotensin II (5 micrograms in 1 ml of Tyrode solution), injected directly into the sinus node artery of 24 anaesthestized and vagotomized dogs pretreated with a beta-adrenoceptor antagonist, was evaluated before and after the administration of: (a) an angiotensin II AT1 receptor antagonist (losartan, 50 micrograms kg-1 min-1 infused i.v. for 120 min), (b) an alpha-adrenoceptor antagonist (prazosin, 1 mg kg-1 i.v. bolus injected), (c) a Ca2+ channel blocker (nifedipine 50, 100 and 200 micrograms kg-1 i.v. bolus injected) and (d) a protein kinase inhibitor (staurosporine, 800 nM infused via the sinus node artery at 0.6 ml min-1 for 15 min). 2. Losartan and staurosporine by themselves had no effect on basal systemic arterial pressure and heart rate, whereas prazosin and nifedipine caused significant diminutions of both parameters. 3. Angiotensin II induced significant increases in heart rate, the mean augmentations being 29 +/- 2 beats min-1. Losartan, nifedipine and staurosporine significantly decreased the chronotropic effect of angiotensin II, the mean respective diminutions being 65 +/- 8, 40 +/- 9 and 64 +/- 10%, whereas prazosin had no effect. 4. This work has demonstrated that angiotensin II exerts in vivo a significant positive chronotropic effect that is mediated via AT1 receptors located in the region of the sinoatrial node. This effect is independent of the adrenergic system. It is decreased by the inhibition of the production of protein kinases, most probably of protein kinase C, and by the blockade of the voltage-sensitive L-type Ca2+ channels. Other studies are obviously needed to ascertain the role of angiotensin II in the control of heart rate and/or the genesis of arrhythmias.

Adrenergic alpha-Antagonists↗
PubMed1995

Upregulation of cardiac angiotensin II AT1 receptors in congenital cardiomyopathic hamsters.

Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathic x control) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar1,Ile8]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic animals. Competition curves using specific receptor subtype antagonists revealed that 125I-sarile binding sites were exclusively of the AT1 subtype in both groups of animals. Importantly, the density of AT1 receptors was found to be significantly increased (90% augmentation at 70 to 75 days) in the ventricles of cardiomyopathic hamsters. This augmented expression was observed in all adult groups and was already present at 25 days, when no histological lesions were visible. The affinity of the receptor for losartan did not vary significantly between adult normal and cardiomyopathic animals (mean Kd, 19.6 and 16.7 nmol/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Induction of rodent hepatic drug-metabolizing enzyme activities by the novel anticonvulsant remacemide hydrochloride.

Remacemide hydrochloride [FPL 12924AA; 2-amino-N-(1-methyl-1,2-diphenylethyl) acetamide hydrochloride] is being evaluated as a novel neuroprotective treatment for epilepsy and stroke. Preliminary safety evaluation studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic enzyme induction. To examine this further, the levels and activities of the major drug metabolizing cytochrome P450 (CYP) subfamilies (CPY1, CYP2, and CYP3) were monitored in microsomal samples from male Sprague-Dawley rats dosed by gavage with FPL 12924AA (250 mg base.kg-1.day-1 for 28 days) or an equivalent volume of vehicle (controls). The interpretation of the findings was aided by comparison with the effects of phenobarbitone (75 mg.kg-1.day-1 ip for 4 days) and beta-naphthoflavone (a single intraperitoneal dose at 80 mg.kg-1.day-1). No significant changes in total hepatic P450 levels (1.44 +/- 0.40 nmol.mg-1 vs. 1.31 +/- 0.19 nmol.mg-1 in controls) or ethoxyresorufin O-deethylase activity (a CYP1A induction probe) were observed after remacemide treatment. The pattern of induction produced by remacemide was very similar to that observed with phenobarbitone. The nonspecific CYP-dependent reaction ethoxycoumarin O-deethylation was induced approximately 2-fold. The specific CYP2B markers pentoxyresorufin O-depentylase and 16 beta-hydroxytestosterone production were both increased markedly by FPL 12924AA (approximately 100- and 20-fold, respectively). 2 beta- and 6 beta-Hydroxytestosterone production were also elevated, indicating the induction of CYP3A1/2. Similar effects on isoform-selective P450-dependent activities were observed in male and female mice treated with remacemide as part of a dose-ranging study.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗
PubMed1994

Conformational changes of lipoxygenase (LOX) in modified environments. Contribution to the variation in specificity of soybean LOX type 1.

The addition of water-soluble cosolvents in the reaction medium of type 1 soybean lipoxygenase can modify the selectivity of the enzyme in the hydroperoxide synthesis reaction. This also results in changes in secondary reactions such as carbonyl compound formation. The possibility of a conformational change of the enzyme due to variations in its microenvironment was considered. Using enzyme immobilization and laser visible Raman spectroscopy, both indirect and direct observations of such a protein conformational rearrangement are described. Subtle modifications in the secondary and/or tertiary structures, for example in microenvironments of Tyr and Trp residues, in orientations of lateral side chains were evidenced, and their importance to enzyme specificity is discussed.

Linoleic Acid↗
PubMed1994

Negative chronotropic effect of the atrial natriuretic peptide in an anesthetized dog model.

The effects of atrial natriuretic peptide (ANP) on heart rate and on the chronotropic response induced by angiotensin II were evaluated. The action of angiotensin II, injected into the sinus node artery, on heart rate was determined in anaesthetized and vagotomized dogs pretreated with beta-adrenoceptor antagonist (n = 9), before and after the infusion of physiological and pharmacological doses (10 and 50 ng/kg per min) of ANP. ANP plasma concentrations were determined by radioimmunoassay. Compared to the baseline concentration values (117 +/- 3 pg/ml), a slight increase was produced by the lower dose (293 +/- 45 pg/ml), whereas a significant augmentation was noted with the higher dose of ANP (1024 +/- 255 pg/ml). The basal heart rate and mean systemic arterial pressure were decreased (26.3 and 13.5%) during the intravenous infusion of the physiological dose of the peptide and were significantly reduced (32.5 and 29.2%, P < 0.05) by the administration of the pharmacological dose of ANP. Angiotensin II had a positive chronotropic effect (29 +/- 3 beats/min) that was significantly inhibited by the pharmacological dose of ANP. Our results suggest that ANP might have a role in the control of heart rate.

Adrenergic beta-Antagonists↗
PubMed1994

Emerging standards for diabetes care from a city-wide primary care audit.

Aggregated data from Manchester practices participating in the Diabetes 2000 project were used to develop peer group standards of mean performance and of excellence. The crude prevalence of known diabetes mellitus was 1.21% of which 20.2% had Type 1 diabetes. The aggregated mean of patients who had the following examinations performed in the preceding year were: glycated haemoglobin 56.8%; weight or body mass index 67.8%; foot pulses 37.3%; ankle reflexes 31.3%; proteinuria 60%; fundoscopy 48.2%; blood pressure 81.1%; serum cholesterol or lipids 34%. The percentage of patients referred to or seen by health care professionals in the preceding year were 14.4% to diabetes specialist nurses; 22.1% to opticians or ophthalmologists; 25% to chiropodists; and 21.5% to dietitians. The best performing practices examined 79% of patients fundi in the preceding year, 84% of their foot pulses, 74% of their ankle reflexes, and gave appropriate smoking advice in 65% of cases. These standards were fed back to the participating practices so that they could compare their own performance with that of the city-wide mean, and with the best performing practices. From these data practices have then been able to set themselves realistic targets for improved performance in the following year.

Diabetes Mellitus↗
PubMed1994

Atypical case of Becker's muscular dystrophy. Early identification and management.

A case of a child with Becker's muscular dystrophy is presented. Because of the genetic and clinical similarity with the more common Duchenne muscular dystrophy, these two diseases are compared. Since muscular dystrophy often initially presents with toe walking, flat-foot, and waddling gait, podiatrists may be the first physicians to see the child and provide early diagnosis.

Adolescent↗
PubMed1994

Natural serum TNF antagonists in end-stage renal failure and following renal transplantation.

TNF is clearly involved in allograft rejection but measurement of serum cytokine levels do not reflect reliably the rejection crisis. TNF induces release of soluble receptor parts that are more stable, are catabolized by kidneys and have inhibitory activity. Thus it is crucial to analyse their kinetics during renal function recovery after transplantation to forecast their potential clinical use in rejection monitoring or treatment. A sequential study was performed in 61 patients undergoing kidney graft, compared to 60 graft patients with long follow-up and 15 healthy controls. Soluble TNF and Il2 receptors were measured by ELISA and TNF was measured by RIA. The sTNF-Rs were markedly increased in renal failure, much more than another soluble cytokine receptor, the sIl2-R. Levels progressively decreased with the recovery of renal function and became directly correlated to the renal function. Normal levels were only reached after some weeks. No significant changes were observed during graft rejection at that stage of renal function but p75 were higher after antilympocyte antiserum and tubular necrosis. High sTNF-R did not seem to minimize rejection risk or gravity. In long-standing recipients, sTNF-R rose in some patients, particularly with glomerulonephritis, and may help in monitoring chronic rejection activity. sTNF-R but not sIl2-R markedly accumulate in ESRF and mask any changes that could be helpful in the monitoring of early graft events. However, increased levels above renal impairment (sTNF-R/SCr) may be clinically relevant in late rejection or glomerulonephritides.

Adult↗
PubMed1994

Effects of procainamide and propafenone on the composition of the excitable gap in canine atrial reentry tachycardia.

The effects of procainamide and propafenone on the composition of the excitable gap (EG) were studied in a canine model of atrial flutter (AFI) around the tricuspid valve. In 14 open-chest, chloralose-anesthetized dogs, a Y-shaped incision was made in the intercaval area extending to the right atrial appendage. Atrial effective refractory period (ERP) was measured at constant stimulation cycle lengths (CLs) (200 and 300 msec) at each of five recording sites around the tricuspid valve. The EG as defined by the reset-response curve was determined by introducing premature stimuli during AFI induced by burstpacing. Seven dogs each received procainamide or propafenone as a bolus followed by infusion. At constant plasma levels, both drugs increased ERP at constant paced CL and prolonged the reentry CL. In the absence of drug, reset-response curves were mixed, demonstrating an EG composed of both partially (increasing portion) and fully (flat portion) excitable tissue. Procainamide and propafenone shifted the curve upward and to the right and prolonged ERP during AFI, but did not change the duration of the EG. On procainamide, fully excitable tissue was preserved, but on propafenone, in some cases, the fully excitable part of the gap was reduced markedly or even eliminated. In conclusion, both drugs can prolong AFI CL by a direct effect on conduction velocity in fully excitable tissue. In addition, propafenone's effect on refractoriness can contribute significantly in some cases to slowing of AFI.

Action Potentials↗
PubMed1993

Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers.

Cardizem SR and Bi-Tildiem were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatogrpahic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p < 0.01) differences in AUC0-12 with means (+/- SD) of 519.2(+/- 172.8) and 429.6(+/- 147.2) ng h ml-1, AUC0-36 of 835.6(+/- 281.6) and 730.9 (+/- 271.5) ng h ml-1 and Cmax of 89.1(+/- 30.3) and 61.1(+/- 21.2) ng ml-1 for Cardizem SR and Bi-Tildiem, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+/- SD) change in AUC0-12 of -13.6(+/- 20.8) and +8.4(+/- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+/- 43.7) and -0.3(+/- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively. These findings suggest that assessment of efficacy of sustained-release formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.

Adult↗