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Biomedical subjects

C Lambert

Publications and source records attributed to C Lambert.

At least 37 records · Page 2Linked to original sources
PubMed1990

Response by women aged 65-79 to invitation for screening for breast cancer by mammography: a pilot study.

OBJECTIVE: To determine whether there is sufficient benefit to be gained by offering screening for breast cancer with mammography to women aged 65-79, who are not normally invited for screening. DESIGN: Pilot study of women eligible for screening but not for personal invitation. The results of this study were compared with the results of routinely screened younger women (aged 50-64) from the same general practice. SETTING: One group general practice in south Manchester. PATIENTS: The 631 women aged 65-79 on the practice list. A total of 42 (7%) were excluded by the general practitioner, and 22 (4%) invitation letters were returned by the post office. MAIN OUTCOME MEASURES: Response rates to invitation for screening assessed by three indices: crude population coverage ratio, crude invited population coverage ratio, and corrected invited population coverage ratio. RESULTS: 344 Patients aged 65-79 (61% of those invited, excluding those who could not be traced) were screened compared with 77% of women aged 50-64. The three response indices were higher for younger women than older: crude population coverage ratio = 66.5%, crude invited population coverage ratio = 69.3%, corrected invited population coverage ratio = 76.8% for women aged 50-64, compared with 54.5%, 58.4%, and 60.7% respectively for women aged 65-79. All four biopsies done in the older women gave positive results, giving a cancer detection rate of 11.6/1000 compared with 4.1/1000 among younger women. CONCLUSIONS: These results show that there is a potential for high attendance at routine screening by older women if they are invited in the same way as younger women. If these results are found elsewhere the costs and benefits of screening older women should be reassessed.

Aged↗
PubMed1990

A pulse radiolysis investigation of the oxidation of methoxylated metabolites of indolic melanin precursors.

The rate constants associated with the series of successive transient absorptions initiated by one-electron oxidation of 6-hydroxy-5-methoxyindole (6H5MI) and its isomer 5-hydroxy-6-methoxyindole (5H6MI) have been studied by pulse radiolysis. These close analogues of 5,6-dihydroxyindole (DHI) are metabolites of the oxidative melanogenic pathway. The species initially produced from N3. oxidation of both methoxyindoles at pH 7.2-7.4 are assigned as the corresponding semiquinones. That from 6H5MI shows peak at 500, 370 and 330 nm, very close to those of the semiquinone of DHI, whereas the semiquinone of 5H6MI shows no absorption at 500 nm but bands at 420 and 340 nm. These spectral differences are attributed to marked changes in the degrees of electron delocalisation for the two types of radical, both rings of the indole being involved for the 6H5MI radical but only the benzenoid moiety for the 5H6MI radical. In both cases, the radicals decayed, probably by disproportionation, into products which absorbed in the 400-420 nm region. For 6H5MI, the subsequent decay in this region was best fitted by two consecutive first-order processes which were both strongly base-catalysed. The first of these processes is assigned to partial decay via deprotonation of the corresponding quinonoid cation to form an equilibrium mixture of this cation and the corresponding quinone methide. The second process is assigned to reaction of the quinone methide with water yielding hydroxylated product(s) which may subsequently react with remaining quinonoid cation or quinone methide to give dimeric product(s) with broad absorption centreing in the 550 nm region detected 0.5 s after the pulse. For 5H6MI, the decay at 430 nm fitted a single first-order process, which was weakly base-catalysed. This process is attributed to deprotonation of the corresponding quinonoid cation to the corresponding quinone imine absorbing below 350 nm, which was stable for at least tens of seconds. The current experiments suggest that our previous analogues observations (Lambert et al. (1989) Biochim. Biophys. Acta 993, 12-20) on the oxidation of the melanogenic precursors DHI and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) may be interpreted, as with 6H5MI, in terms of the corresponding indolequinones decaying into equilibrium mixtures of quinone, quinone imine and quinone methide. These decay via reaction of the methide with water generating hydroxylated species which proceed to give the coloured product(s) absorbing in the 550 nm region.

Free Radicals↗
PubMed1990

Efficacy of propafenone in preventing ventricular tachycardia: inverse correlation with rate-related prolongation of conduction time.

The efficacy of propafenone in preventing induction of ventricular tachycardia was evaluated in 25 consecutive patients (mean age 62 +/- 8 years) with remote myocardial infarction who underwent programmed electrical stimulation for ventricular arrhythmia using up to three extra-stimuli after basic drive at the right ventricular apex. In nine patients (Group A), propafenone prevented induction of sustained ventricular tachycardia (noninducible in four, nonsustained [less than 30 s] in five). In the other 16 patients (Group B), sustained ventricular tachycardia was still inducible; in 11 of the 16, the tachycardia configuration was unchanged but the cycle length was significantly longer (431 +/- 99 versus 284 +/- 44 ms, p less than 0.001). Propafenone did not significantly affect either sinus cycle length or AH and HV intervals. However, it prolonged QRS duration during sinus rhythm equally in both groups of patients. With ventricular pacing, propafenone also prolonged right ventricular effective and functional refractory periods and surface QRS duration. There was greater lengthening of the paced surface QRS duration when drug therapy was ineffective (for example, +35 +/- 12 ms in Group A versus +69 +/- 23 ms in Group B at a basic drive of 400 ms, p less than 0.01). Drug-induced prolongation of a paced QRS complex greater than 40 ms had a 94% positive predictive value for drug failure to prevent induction of ventricular tachycardia. Drug-induced percent prolongation of ventricular tachycardia cycle length in Group B did not correlate well with percent QRS prolongation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Pacing, Artificial↗
PubMed1990

Antiarrhythmic effect of amiodarone on doxorubicin acute toxicity in working rat hearts.

STUDY OBJECTIVE: The clinical application of doxorubicin, a potent cytotoxic agent, is limited by a dose dependent cardiotoxicity and by the acquired resistance of the neoplastic cells. Recently, the sensitivity of resistant cancer cells to doxorubicin has been enhanced by the acute administration of amiodarone. The aim of this study was to investigate whether or not this potentiates the cardiotoxicity of doxorubicin. DESIGN: Hearts from rats pretreated or not with amiodarone 50 mg.kg-1.d-1 for 5 d were perfused via the left atrium with a Krebs-Henseleit solution containing, or not, doxorubicin 6 mg.litre-1. After 40 min of perfusion, the left main coronary artery was ligated and the ligature was maintained for 10 min. It was then cut and reperfusion continued for 10 min. The cardiac output, heart rate, and mean fibrillation duration induced by the reperfusion were measured by timed collections and ECG recordings. SUBJECTS: 32 adult male Sprague-Dawley rats (250-300 g) were used throughout the study. MEASUREMENTS AND RESULTS: After 40 min of perfusion, the cardiac output in the control and amiodarone groups was constant, but significant decreases of 25.5 and 30.4% were noted in both doxorubicin groups. The mean fibrillation durations observed during reperfusion were 331(73), 66(22), 444(86), and 22(9) s for the control, amiodarone, doxorubicin and amiodarone-doxorubicin groups respectively. CONCLUSION: Amiodarone, while maintaining its antiarrhythmic effect, did not potentiate the negative inotropic effect of doxorubicin. These results suggest that the cardiotoxicity produced by the clinically acute administration of amiodarone with doxorubicin is not greater than that caused by doxorubicin given alone.

Amiodarone↗
PubMed1990

In-vitro activity of SCH39304 in comparison with amphotericin B and fluconazole.

The in-vitro activity of SCH39304, a new imidazole, was compared with that of amphotericin B using two media (Sabouraud dextrose and tissue culture (TC) medium) with or without 25% human serum. At an inoculum of 1.5 X 10(4) cfu/ml, the IC95% for amphotericin B ranged from 0.08 to 0.3 mg/l irrespective of the medium. At the same inoculum, the IC95% of the two imidazoles ranged from 0.3 to greater than 80 mg/l. The inoculum effect (from 1.5 X 10(4) to 1.5 X 10(5) cfu/ml) was less than 1 dilution for the three antifungal agents. Serum increased the inhibitory activity (IC80%) of SCH39304 and fluconazole but not of amphotericin B. The IC80%, IC95% and minimal fungicidal concentration (MFC) for amphotericin B usually ranged within two dilutions. Using kill curve methodology, the initial killing rate (0-4 h) of amphotericin B correlated with concentration (P less than 0.001), and was faster in TC medium than in Sabouraud dextrose (P less than 0.0006). SCH39304 and fluconazole did not produce any significant killing over the range of concentrations tested (0.5-20 mg/l). SCH39304 was similar to fluconazole.

Amphotericin B↗
PubMed1990

An inhibitor of the toxicity of tumour necrosis factor in the serum of patients with sarcoidosis, tuberculosis and Crohn's disease.

The activated macrophages present in the T cell-dependent granulomata of sarcoidosis and tuberculosis are primed for enhanced release of cytokines including tumour necrosis factor (TNF or cachectin). Release of this cytokine can induce an acute-phase response, fever, and necrosis in suitably prepared sites of inflammation; if chronic, its presence may contribute to weight loss. These clinical features are characteristic of tuberculosis, but not of sarcoidosis, though alveolar macrophages from both diseases release large quantities of TNF in vitro. We therefore postulated the presence in sarcoidosis patients of an inhibitor of TNF. We have studied levels of TNF inhibitory activity by determining the quantity of TNF required to give 50% kill of L929 cells in the presence of 20% heat-inactivated serum derived from various disease states (37 sarcoidosis, 13 tuberculosis, 13 Crohn's disease, 17 healthy donors). Normal sera used in this way do not inhibit significantly, but inhibition of TNF toxicity is caused by most sera from both sarcoidosis and tuberculosis. Used at 20%, five out of 37 sarcoidosis sera and one out of 13 tuberculosis sera caused complete inhibition of TNF, even when the latter was added at 100 times the concentration required to give 50% kill in control wells. This inhibitor may have an important physiological role.

Acute-Phase Proteins↗
PubMed1990

Anthralin-derived transients--II. Formation of the radical by spontaneous fragmentation of both singlet and triplet states of the 10,10'-dehydrodimer: radical pair multiplicity effects.

The singlet and triplet states of the anthralin (1,8-dihydroxy-9-anthrone) dehydrodimer have been produced selectively in benzene via pulsed laser excitation and pulse radiolysis respectively. The lifetime of S1 is less than or equal to 30 ps, that of T1 short but unspecified. Both states fragment spontaneously to yield a pair of anthralin radicals. The singlet radical pair predominantly undergoes geminate recombination within the solvent cage. In contrast, the corresponding triplet radical pair undergoes essentially exclusive cage escape to give the anthralin free radical (lambda max 370, 490 and 720 nm) which recombines under normal diffusive conditions. Both recombination processes lead, at least in part, to one or more species which have been assigned as tautomeric forms of the original dimer. The anthralin free radical in benzene is insensitive to the vitamin E model 6-hydroxy-2,2,5,7,8-pentamethylchroman and reacts only slowly with oxygen.

Anthralin↗
PubMed1990

Absence of prejunctional sympathetic effect of amiodarone in hearts of open-chest anesthetized dogs.

The effect of amiodarone (30 mg/kg p.o. each day for 3 weeks) on noradrenaline (NA) overflow into coronary sinus (CS) blood during left stellate stimulation (15 V, 2-ms square waves, 30 s duration at 1, 2, 4, and 8 Hz in random order) was investigated in an open-chest dog preparation. CS blood samples were taken before and during the stimulation period for plasma NA and hematocrit determinations. CS blood flow was monitored (extracorporal circulation with an electromagnetic flow meter) and used for NA output computation. The right atrium was paced throughout the experimental period. However, because AV block occurred at a high pacing rate in some amiodarone-treated dogs, pacing rate was lower in that group than in control dogs (132 +/- 13 vs. 161 +/- 10 min-1, ns). Mean arterial pressure was also lower in the treated group (95 +/- 9 vs. 110 +/- 13 mmHg, but increased in every dog upon stimulation (p less than 0.05). Basal left ventricular dP/dtmax was comparable in the two groups of dogs and increased in a similar fashion upon stimulation (p less than 0.05). The increase in plasma NA concentration upon stimulation was comparable between the control and the amiodarone-treated group (0.38 +/- 0.08 vs 0.40 +/- 0.12 ng/mL at 1 Hz and 12.7 +/- 3.1 vs 11.3 +/- 2.3 ng/mL at 8 Hz, ns). The increase in NA output was also comparable (7.0 +/- 1.6 vs. 10.7 +/- 5.4 ng/min at 1 Hz and 356 +/- 124 vs. 334 +/- 102 ng/min at 8 Hz, ns). Amiodarone did not alter the myocardial NA content. We conclude that amiodarone, administered orally for 3 weeks, does not interfere with neural NA release, or with the positive inotropic response, following sympathetic nerve stimulation in dogs.

Amiodarone↗
PubMed1989

A pulse radiolysis investigation of the oxidation of indolic melanin precursors: evidence for indolequinones and subsequent intermediates.

The rate constants associated with the series of successive transient absorptions initiated by one-electron oxidation of 5,6-dihydroxyindole (DHI), 5,6-dihydroxyindole-2-carboxylic acid (DHICA), precursors of melanin, and N-methyl-5,6-dihydroxyindole (NMDHI), a model compound, have been studied by pulse radiolysis. The initial transient species resulting from N3. oxidation reaction at pH 7.3-7.4 are assigned as the corresponding semiquinones. In each case, these radicals decayed, probably by disproportionation, into products most readily monitored in the 400-430 nm region. For DHI, the decay in this region could be fitted by two parent concentration independent first-order processes. These may correspond to transformations between 5,6-indolequinone, and its quinone-imine and quinone-methide tautomers. With NMDHI, on the other hand, a single longer-lived product with a peak around 430 nm predominated after decay of the corresponding radical, due almost certainly to N-methyl-5,6-indolequinone. The data appear to exclude significant melanin polymerisation by condensation of semiquinones, reaction of semiquinones with dihydroxyindoles, self-addition of indolequinones or tautomers, or reaction of indolequinones or tautomers with the parent dihydroxyindoles. It is suggested that polymerisation of melanin may rather occur by stepwise addition of indolequinone methide/imine to reduced oligomeric species.

Indoles↗
PubMed1989

Activation of mianserin and its metabolites by human liver microsomes.

Human liver microsomes metabolise mianserin to the stable 8-hydroxymianserin, desmethylmianserin and mianserin-2-oxide and in addition to one or more chemically reactive metabolites which bind, irreversibly, to microsomal protein. The stable metabolites were isolated by HPLC and characterized by mass spectrometry. The generation of each of these metabolites showed substantial inter-individual variation between eight sets of human liver microsomes studied. Inhibition of irreversible binding was observed with SKF-525A together with concomitant decrease in the formation of 8-hydroxymianserin and desmethylmianserin but not mianserin-2-oxide. Methimazole inhibited binding and the formation of each of the metabolites at a low concentration. Quinidine did not significantly inhibit irreversible binding but did inhibit the formation of 8-hydroxymianserin. Sulphaphenazole had no effect on irreversible binding or metabolism. The irreversible binding of mianserin was inhibited by ascorbic acid, glutathione and N-acetyl cysteine, whereas N-acetyl lysine and trichloropropane oxide had no effect. The irreversible binding of mianserin, 8-hydroxymianserin and desmethylmianserin was of the same order of magnitude however significantly greater binding was observed with the desmethyl metabolite. Incubations with [10-3H/14C]mianserin showed no change in the 3H/14C ratio when irreversible binding occurred. Inhibition of irreversible binding was demonstrated with sodium cyanide at concentrations which did not inhibit total metabolism, which suggest that metabolic activation by the cytochrome P-450 enzyme system may lead to the formation of a reactive iminium intermediate that can bind to nucleophilic groups on proteins.

Biotransformation↗
PubMed1989

How to digitalize and to maintain optimal digoxin levels in congestive heart failure.

Due to the narrow therapeutic-to-toxic ratio of digoxin, numerous studies have been done to assess the optimal digoxin level in patients with congestive heart failure. A digoxin level of 0.7-1.5 ng/mL (or 0.9-2.0 nMol/L) is generally considered optimal, but even at these levels toxicity may occur in certain clinical situations such as severe pulmonary disease or when electrolyte or metabolic disturbances are present. The optimal daily maintenance dose of digoxin depends on the preparation given and can be calculated by the equation of Jelliffe, which is largely based on the creatinine clearance of the patient. The daily digoxin dose must also be adjusted to take into consideration disease processes or concomitant drug therapy that can alter the volume of distribution, the biotransformation, or the excretion of the drug.

Digoxin↗
PubMed1989

Electrophysiologic effects of intravenous propafenone in Wolff-Parkinson-White syndrome.

The electrophysiologic effects of intravenous propafenone were studied in 15 consecutive patients with accessory pathways. Thirteen patients had sustained orthodromic supraventricular tachycardia induced during baseline study, and two patients needed isoproterenol to render it sustained. In all except one patient, propafenone, 2 mg/kg given intravenously over a 10-minute period, was successful in converting the arrhythmia to sinus rhythm. Atrial fibrillation was inducible in 10 patients before propafenone, but was no longer inducible in seven of these patients after the drug. The HV interval (23 +/- 20 to 41 +/- 25 msec) and the anterograde (310 +/- 96 to 509 +/- 145 msec) and retrograde (256 +/- 30 to 334 +/- 105 msec) effective refractory periods of the bypass tract were all significantly prolonged after the drug. The pacing cycle length that produced conduction block over the bypass tract anterogradely (319 +/- 126 to 446 +/- 150 msec) and retrogradely (272 +/- 25 to 360 +/- 97 msec) was also increased. During orthodromic tachycardia, propafenone increased conduction time in both the anterograde and retrograde limbs of the tachycardia. Tachycardia terminated in the retrograde limb in 64% of the patients. We conclude that propafenone is very effective in terminating orthodromic tachycardia when given intravenously and that it should be considered in patients initially seen with atrial fibrillation and short refractory periods.

Adult↗
PubMed1989

In-vitro activity of cilofungin (LY121019) in comparison with amphotericin B.

The in-vitro activity of cilofungin, a derivative of echinocandin B, was compared with that of amphotericin B in Sabouraud dextrose and Antibiotic Medium No. 3 against 100 clinical isolates of yeasts. Cilofungin appeared to be as effective, as amphotericin B against Candida albicans and yet more effective against Can. tropicalis as far as growth inhibition was concerned. Cilofungin was less active than amphotericin B against Can. (Torulopsis) glabrata and other species of Candida. It was not active against Cryptococcus neoformans. Minimum fungicidal concentrations (MFCs) of cilofungin were highly dependent on the medium, especially with Can. albicans. Low MFCs were observed in Antibiotic Medium 3 and very high MFCs were measured in Sabouraud's medium. Using a killing curve method, the initial rate of killing of amphotericin B was proportional to concentration with Can. albicans, Can. tropicalis, and Can. glabrata. With cilofungin the rate of killing was proportional to concentration only for Can. tropicalis.

Amphotericin B↗
PubMed1989

A stereochemical investigation of the cytotoxicity of mianserin metabolites in vitro.

1. The metabolism of the enantiomers of mianserin to stable, chemically reactive and cytotoxic metabolites by human liver microsomes has been investigated in vitro. 2. Both enantiomers were metabolised to three major oxidation products: 8-hydroxymianserin, desmethylmianserin and mianserin 2-oxide. Hydroxylation occurred more readily with the S-enantiomer, whereas desmethylmianserin was always the major metabolite of the R-enantiomer. 3. The generation of chemically reactive metabolites exhibited a marginal degree of stereoselectivity, as assessed by irreversible binding of drug to microsomal protein (S greater than or equal to R; P less than or equal to 0.05). 4. The formation of metabolites which were cytotoxic towards human mononuclear leucocytes was greater (P less than or equal to 0.001] for R(-)-mianserin than for S(+)-mianserin and showed a significant correlation with N-demethylation (r = 0.84, P less than or equal to 0.01).

Adult↗