PubMed Health⌕ Search

Biomedical subjects

C Lambert

Publications and source records attributed to C Lambert.

At least 145 records · Page 8Linked to original sources
PubMed1988

A comparative study of the formation of chemically reactive drug metabolites by human liver microsomes.

1. The metabolism of amodiaquine (A), ethinyloestradiol (E), mianserin (M), phenytoin (Ph), sulphanilamide (S) and paracetamol (Pa) to both stable and chemically reactive, i.e. irreversibly protein bound, metabolites was investigated using microsomes prepared from histologically normal human liver obtained from eight kidney donors. 2. All drugs, except amodiaquine, were metabolized by NADPH-dependent microsomal enzymes to chemically reactive metabolites. The degree of NADPH-dependent binding varied between drugs (E, 11.5 +/- 5.8% incubated drug; M, 3.0 +/- 1.9%; Ph, 0.10 +/- 0.09%; S, 0.57 +/- 0.38%; Pa, 1.2 +/- 1.2%; mean of eight livers +/- s.d.). 3. Inclusion of glutathione (1 mM) or ascorbic acid (1 mM) in the incubation reduced the NADPH-dependent binding for all substrates, indicating the involvement of electrophilic oxidation products. 4. Binding of M and Pa correlated with each other (Spearman's r = 0.86) and with total cytochrome P-450 content (r = 0.76 and 0.78 respectively). E binding also correlated with the binding of M (r = 0.79) and Pa (r = 0.81) but not with cytochrome P-450. Binding of Ph and S did not correlate with any of the other measured metabolic parameters.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil and mianserin.

1. The cytotoxicity of metabolites generated from phenytoin, sorbinil and mianserin by human and mouse liver microsomes was assessed by co-incubation with human mononuclear leucocytes as target cells. Cytotoxicity was determined by trypan blue dye exclusion. 2. Phenytoin and sorbinil were metabolised by NADPH-dependent murine microsomal enzymes to cytotoxic metabolites. Cytotoxicity produced by both drugs was significantly enhanced by the epoxide hydrolase inhibitor trichloropropane oxide (TCPO). No significant cytotoxicity was observed in the presence of human liver microsomes. 3. Mianserin was metabolised by both human and mouse liver microsomes to a cytotoxin. Cytotoxicity was greater in the presence of human liver microsomes (13.7 +/- 2.2%; mean +/- s.d. for four livers, compared with 6.0 +/- 2.4%, mean +/- s.d., n = 4, with mouse liver microsomes), and was unaffected by pretreatment with TCPO. 4. Stable metabolites were quantified by radiometric high performance liquid chromatography. Phenytoin and sorbinil were metabolised to 5-(p-hydroxyphenyl)-5-phenyl-hydantoin (0.3-0.5% of incubated radioactivity) and 2-hydroxysorbinil (0.4-2.7% of incubated radioactivity), respectively, by both human and mouse liver microsomes. 5. Mianserin was metabolised to 8-hydroxymianserin and desmethylmianserin by both human and mouse liver microsomes. Desmethylmianserin was the major product in incubations with human liver microsomes (32.3 +/- 12%, mean +/- s.d. for four livers), whereas 8-hydroxymianserin was the predominant metabolite generated by mouse liver microsomes (25.9 +/- 1.5%, mean +/- s.d., n = 4). 6. Generation of electrophilic metabolites was assessed by determination of the amount of radiolabelled material which became irreversibly bound to protein. Only mouse liver microsomes activated phenytoin to a chemically reactive metabolite, whereas both mouse and human liver microsomes generated reactive metabolites from sorbinil and mianserin. 7. These studies show that drug cytotoxicity can be mediated by low concentrations (circa microM) of metabolites generated by NADPH-dependent hepatic microsomal enzymes; however demonstration of cytotoxicity in vitro has not been established as a means of predicting in vivo toxicity.

Adult↗
PubMed1988

Pharmacokinetics of bupivacaine after short and prolonged infusions in conscious dogs.

A conscious dog model was used to study pharmacokinetics of bupivacaine after a short infusion (SI) (15 min) and a prolonged infusion (PI) (24 hours). Bupivacaine was infused in six mongrel dogs at least 10 days after implantation of femoral arterial and venous catheters. Each dog received both the SI and the PI in a random crossover design at a one week interval. Bupivacaine concentration was measured in serum sampled during the SI, during the last hour of the PI, and at frequent intervals during eight hours after cessation of infusion. Indocyanine green (ICG) clearance also was measured during the last hour of the PI and 90 min after cessation of both the SI and the PI. The terminal half-life (T1/2Z) of bupivacaine increased after the PI compared with the SI, 167 +/- 86 vs 53 +/- 13 min, respectively (mean +/- SD; P less than 0.05), and total body clearance (Cl) decreased, 3.4 +/- 1.2 vs 9.5 +/- 4.5 ml.min-1.kg-1, (P less than 0.05), although the volumes of distribution (VZ and VSS) did not change. A decrease in hepatic blood flow did not cause the decrease in Cl because ICG clearance did not change during the three sets of measurements. Thus, the observed increase in T1/2Z and decrease in Cl after the PI as compared with the SI are due to a decrease in hepatic intrinsic clearance of bupivacaine. Differences in the kinetic profile of the two enantiomers of bupivacaine cannot be excluded as a cause. We conclude that the extrapolation of kinetic data of bupivacaine obtained after a short infusion (or a bolus injection) to prolonged dosage must be done with care.

Anesthetics, Local↗
PubMed1987

Efficacy and safety of intravenous and oral diltiazem for Wolff-Parkinson-White syndrome.

The electrophysiologic effects and safety of diltiazem administered either intravenously or orally were studied in 14 patients with Wolff-Parkinson-White syndrome during orthodromic reentrant tachycardia and atrial fibrillation (AF). Anterograde and retrograde effective refractory periods of the accessory pathway did not change significantly from baseline during either i.v. or oral administration. Administration by either route prevented induction of sustained reentrant tachycardia in 8 patients. In 6 patients, the reentrant tachycardia was either nonsustained (2 patients) or sustained at much slower rates than the baseline rates (mean +/- standard deviation, baseline, 290 +/- 41 ms; i.v., 355 +/- 40 ms [p less than 0.001]; and oral, 377 +/- 33 ms [p less than 0.001]). In these patients anterograde atrioventricular conduction was prolonged significantly from the mean baseline value of 163 +/- 36 ms to 212 +/- 35 ms with i.v. administration (p less than 0.005) and 225 +/- 33 ms with oral administration (p less than 0.005). Retrograde conduction via the accessory pathway did not change significantly after administration of diltiazem. The shortest preexcited RR intervals during AF were significantly reduced during i.v. but not during oral administration: control, 327 +/- 47 ms; i.v., 270 +/- 28 ms (p less than 0.001); and oral, 323 +/- 44 ms (difference not significant). In 5 patients AF was sustained for a mean of 20 minutes after i.v. and for 12 minutes after oral administration (p less than 0.20), compared with a baseline mean value of 0.83 minute.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Effect of high-dose ibuprofen on 24-hour blood pressure in healthy women.

The nonsteroidal antiinflammatory drug (NSAID) indomethacin has been shown to increase blood pressure in normotensive individuals. The effect of other NSAID on blood pressure has not been as well studied. We evaluated the effects of ibuprofen, an NSAID currently available without a prescription, on 24-hour ambulatory blood pressure in ten young, healthy, normotensive women. Using a randomized, crossover, double-blind design, subjects received ibuprofen 800 mg and a placebo identical in appearance to ibuprofen three times a day for eight days with a washout period between regimens. Subjects were instructed to follow a no-added salt diet during the study. Twenty-four-hour blood pressure monitoring and 24-hour urine collection for prostaglandin E2, creatinine, and sodium were performed on days 1 and 8 of each study week. Tablet counts and a 40 percent reduction in urinary prostaglandin E2 documented compliance with ibuprofen. Ibuprofen had no significant effect on systolic or diastolic blood pressure at any hour during the 24-hour period. Mean blood pressure for the 24-hour period was 112/73 and 111/73 mm Hg on day 1 and 111/73 and 112/73 mm Hg on day 8 for placebo and ibuprofen, respectively. We conclude that ibuprofen at doses as high as 2400 mg/d for up to seven days has no effect on blood pressure in normotensive women. Further studies are needed in hypertensive subjects.

Adult↗
PubMed1987

Lack of relation between the ventricular refractory period prolongation by amiodarone and the thyroid state in rats.

We investigated the possibility that the prolongation of the ventricular effective refractory period (VERP) by amiodarone might be mediated, at least in part, by inhibition of thyroid influence on the heart. VERP values were measured in vitro in isolated septal preparations obtained from control, thyroidectomized and thyroxine (tetraiodothyronine; T4)- or triiodothyronine (T3)-treated rats. Differences in thyroid influence on the heart between these groups were assessed by changes in the myosin isozyme (V1, V2, V3) pattern. VERP measurements were also done in similar groups treated with amiodarone for 7 days (50 mg/kg/day i.p.). VERP tended to be increased by thyroidectomy and was significantly reduced by T4 or T3 treatment when compared with the control group. Amiodarone treatment significantly prolonged VERP in control (33.4 +/- 1.9 to 45.0 +/- 4.5 msec), thyroidectomized (39.9 +/- 1.7 to 48.3 +/- 2.8 msec), T4-treated (26.2 +/- 1.0 to 37.4 +/- 1.3 msec) and T3-treated rats (25.6 +/- 1.1 to 34.3 +/- 1.3 msec). However, the magnitudes of the VERP prolongation by amiodarone were not significantly different among the four groups. The action of amiodarone on action potential duration was similar to its action on VERP. The myocardial concentrations of amiodarone and desethylamiodarone were not significantly different among the four groups. Amiodarone treatment produced a significant reduction of serum T3 levels in the control and in the T4-treated groups and an increase in reverse T3 levels. Thus, the class III action of amiodarone was not affected, in the present model, by experimental modification of thyroid influence on the heart.

Action Potentials↗
PubMed1987

Relation of transient silent ischemic episodes to daily activities.

In patients with coronary disease, asymptomatic ST segment depression during daily life is a reliable indicator of silent myocardial ischemia and is the most frequent form of ischemia in both symptomatic and asymptomatic patients. Silent ischemic episodes usually occur during activities not ordinarily thought to be ischemia provoking, and not necessarily with the same frequency, duration, or magnitude as painful episodes and may be the only type of ischemia detected in some patients. Some features suggest an important reduction in myocardial oxygen supply, in addition to an increase in demand, as a mechanism for silent ischemic episodes occurring during daily life.

Activities of Daily Living↗
PubMed1986

Effect of the induction of amiodarone biotransformation on ventricular refractory periods in rats.

Amiodarone is a potent class III antiarrhythmic agent that has a slow onset of action in patients (ca. 20 days). To determine if myocardial accumulation of desethylamiodarone (DEA), its main metabolite, influences its antiarrhythmic activity, three groups of six Wistar rats were given amiodarone, 50 mg/kg/day i.p. (A groups), and three groups received the same dose of amiodarone in combination with 80 mg/kg/day of phenobarbital to induce hepatic biotransformation (AP groups). After 3, 7 or 21 days, the rats were sacrificed and the ventricular effective refractory period (VERP) was determined by the extrastimulus technique in endocardial preparations superfused in the tissue bath. Control measurements of VERP were done in untreated rats. Myocardial concentrations of DEA measured by high-performance liquid chromatography were significantly higher in the AP groups than in the A groups (7.5 +/- 0.83 vs. 2.27 +/- 0.11 micrograms/g at 3 days, 6.09 +/- 0.70 vs. 2.82 +/- 0.30 micrograms/g at 7 days and 11.93 +/- 1.22 vs. 4.79 +/- 1.84 micrograms/g at 21 days: mean +/- S.E.). Control VERP value was 33.4 +/- 1.2 msec and was increased by 9, 35 and 42% after 3, 7 and 21 days in the A groups, and by 9, 38 and 39% in the AP groups. After 7 days of DEA administration yielding myocardial concentrations similar to those obtained after amiodarone treatment, there was a slight but nonsignificant prolongation of the VERP (12%). Thus, the prolongation of VERP after amiodarone administration did not appear to depend on myocardial DEA accumulation, suggesting that the slow onset of amiodarone class III action may not be related to DEA disposition.

Action Potentials↗
PubMed1986

[Localization of transcription regulatory sequences. Application to the genes of the prolactin family].

We are studying nucleotide sequences responsible for the regulation of eukaryotic gene expression. Our test system comprises the human genes coding for prolactin (hPRL), growth hormone (hGH-N) and placental lactogen (hCS-B). We have cloned these genes and are searching within their sequences for in vitro binding sites of the human glucocorticoid receptor on the hGH-N and hCS-B genes; the in vivo activity of such DNA sequences by assaying hybrid gene expression in transfected cells; in vivo "enhancer" activity of different hPRL gene fragments linked to a marker gene and transfected in cultured cells.

Base Sequence↗
PubMed1985

Antagonistic effects of thyrotropin and epidermal growth factor on thyroglobulin mRNA level in cultured thyroid cells.

Both thyrotropin (TSH) and epidermal growth factor (EGF) are potent mitogenic agents when added to dog thyroid cells in primary culture [Roger, P. P. and Dumont, J. E. (1984) Mol. Cell. Endocrinol. 36, 79-93]. The concomitant effect of these agents on the differentiation state of the cells was appreciated using cell morphology, iodide trapping, thyroglobulin synthesis and cytoplasmic thyroglobulin mRNA content as markers. Together with previous results [Mol. Cell. Endocrinol. 36, 79-93 (1984)] it is shown that cells cultured in the continuous presence of TSH maintain all the parameters at a near normal level. In the absence of TSH, thyroglobulin mRNA decreased to very low, though still detectable levels. Addition of TSH restored subnormal mRNA levels. Culture of cells in the presence of EGF for 4-6 days affected profoundly their morphology, abolished iodide trapping and decreased thyroglobulin synthesis and cytoplasmic mRNA content to undetectable levels. Addition of TSH to cells previously exposed to EGF reversed the growth factor effect on all four indexes. The redifferentiating effect of TSH was well observed within 3-4 days and was mimicked by the adenylate cyclase activators, forskolin and cholera toxin. When administered simultaneously, TSH and EGF achieved an intermediate situation, EGF antagonizing partially the effect of TSH on the expression of thyroglobulin gene. Another growth factor, fibroblast growth factor, while promoting thyroid cell proliferation also, did not interfere at all with TSH effects on cytoplasmic thyroglobulin mRNA content. Our results make the dog thyroid cell in primary culture an appropriate model to study the mechanisms involved in gene regulation by cyclic AMP and growth factors.

Animals↗
PubMed1985

The Keyes technique and self-inflicted injuries. Three case reports.

Three cases of self-inflicted gingival injuries resulting from the improper use of the Keyes technique are presented. The profession must assume responsibility for studies to determine the safety of the methods of application of the hydrogen peroxide, salt and baking soda mixtures and disseminate this information for the public interest.

Bicarbonates↗
PubMed1985

Influence of heart failure and sodium content in the diet on the natriuretic response to furosemide in hamsters.

The aims of this study were to investigate the influence of heart failure and dietary sodium content on the natriuretic effect of furosemide. Ten healthy Golden Syrian hamsters (HH) and 10 hamsters with a cardiomyopathy (CMH) were maintained on a normal sodium diet (NSD) and an equal number of animals on sodium deficient diet (SDD) for a minimum of 40 days. Three experiments were conducted on days 1, 20 and 40. Each experiment started with a 24-hour urine collection (control), followed by the administration of 5 mg/kg of furosemide i.p. and a second 24-hour urine collection and finally, the administration of 2 mg/kg of indomethacin i.p. followed 30 minutes later by 5 mg/kg of furosemide and a 24-hour urine collection as well as blood sampling. Sodium, creatinine, furosemide and arginine vasopressin (AVP) were measured in the urine and sodium, creatinine and AVP in plasma. After 134 days on a SDD, four HH resumed a NSD and the response to furosemide was again assessed after 12 days. Our results indicate that the natriuretic response to furosemide is higher in CMH than in HH. The SDD tended to increase the response to furosemide in HH as well as in CMH. Indomethacin did not influence the response to furosemide under any experimental condition. In four HH the increment in the fractional excretion of sodium in response to furosemide was 0.88 +/- 0.21% after 134 days on SDD and decreased to 0.35 +/- 0.12 (p less than 0.05) after 12 days on NSD. In all cases urinary excretion of furosemide was similar. Plasma AVP was higher in CMH and was not influenced by the SDD. In conclusion, SDD as well as cardiomyopathy with congestive heart failure do not decrease the natriuretic effect of furosemide and may not be a cause in the variability of the natriuretic response to furosemide.

Animals↗
PubMed1983

Effects of phenobarbital and tobacco smoking on furosemide kinetics and dynamics in normal subjects.

This study was carried out to determine whether furosemide (F) kinetics and dynamics were influenced by phenobarbital and tobacco smoking. Our subjects were 10 normal men: five nonsmokers (NS) and five smokers (S). They received a single intravenous F injection of 40 mg. Regular serum and urine collections were made. In a second study, the NS group received 100 mg phenobarbital orally for 15 days and then a second dose of F. Cumulative 8-hr urinary excretion of sodium was identical for NS, NS with phenobarbital, and S at 345 +/- 30, 357 +/- 29, and 353 +/- 25 mmol. Diuresis was smaller by 800 ml (20%) in S than in NS. F increased endogenous creatinine clearance from 117 +/- 13 to 196 +/- 17 ml/min in NS and from 110 +/- 12 to 222 +/- 30 ml/min in NS with phenobarbital. In the S group, endogenous creatinine clearance showed a tendency to increase only slightly, from 136 +/- 23 to 180 +/- 34 ml/min. The increase in free water clearance caused by F was smaller in the S group than in the NS group (P less than 0.05). Protein binding and distribution of F were not affected by phenobarbital or tobacco smoking. F clearance was slightly higher in S than in NS, which was primarily the result of a slight increase in extrarenal F clearance. In the NS group, F clearance remained constant after phenobarbital. It is concluded that tobacco smoking in normal subjects affects the diuretic response to F without modifying kinetics.

Adolescent↗
PubMed1983

Spontaneous electrodermal activity during sleep in man: an intranight study.

This study was designed to examine the intranight evolution of spontaneous electrodermal activity (EDA). Eight paid volunteer male students were recorded for 3 complete nights (after a habituation night). The results show that: during the first sleep cycle, EDA is significantly lower than during the rest of the night; rapid eye movement sleep evolves in a particular manner, which emphasizes the specificity of this sleep stage; and there is no internight habituation effect.

Adult↗