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Biomedical subjects

H R Angelo

Publications and source records attributed to H R Angelo.

At least 37 records · Page 2Linked to original sources

Determination of isradipine and its pyridine metabolite in serum by capillary column gas chromatography with nitrogen-selective detection.

A relatively simple, sensitive and precise gas chromatographic method for the determination of isradipine, a calcium antagonist of the dihydropyridine type, and its main metabolite in serum is described. Using a one-step extraction procedure, a wide-bore column and a nitrogen-phosphorus detector, a limit of quantitation of 0.5 and 2.0 nM for isradipine and the metabolite was found. No interferences from several drugs were observed. The method was successfully used in a pharmacokinetic study in hypertensive women during pregnancy.

Calcium Channel Blockers↗

Stereospecific gas chromatographic method for determination of methadone in serum.

rac-Methadone is used clinically for the chronic maintenance treatment of heroin addiction and for the relief of pain. As the pharmacological activity of methadone is due primarily to the (-)-(R)-enantiomer, stereospecific measurements of methadone serum concentrations in methadone-treated patients are expected to be more relevant for clinical studies than earlier described total drug measurements. This study describes a stereospecific gas chromatographic (GC) method for the determination of methadone in serum. The extracted methadone was derivatizised with (-)-menthyl chloroformate. The diastereometric derivatives were analysed by GC on a capillary column and detected with a nitrogen-phosphorus detector. The resolution factor obtained for the methadone enantiomers was 1.1 with a relatively short time of analysis (30 min). By analysing the pure (-)-(R)-enantiomer, no racemization was seen during the analysis. The lower limit of quantitation was 75 nmol/l for each enantiomer. Measurements of the ratio between (-)-(R)- and (+)-(S)-methadone concentrations in serum from five methadone-treated patients showed interindividual differences (range 0.5-1.1). The patient results correlated well with those from another GC method measuring total methadone.

Chromatography, Gas↗

The effect of quinidine on the analgesic effect of codeine.

We have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pinprick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo. After codeine and placebo, the peak plasma concentration of morphine was 6-62 (median 18) nmol.l-1. When quinidine pre-treatment was given, no morphine could be detected (less than 4 nmol.l-1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds. These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results.

Adult↗

The influence of food on 8-methoxypsoralen serum concentration and minimal phototoxic dose.

Ten adult volunteers were given three oral doses of 0.46-0.56 mg/kg body weight of 8-methoxypsoralen (8-MOP) in a liquid formulation under fasting conditions, and after ingestion of a low-fat or fat-rich breakfast. 8-MOP serum levels and photosensitivity were measured 0.5-4 h after drug ingestion. The 1-h 8-MOP serum levels and photosensitivity were significantly higher in fasting conditions than after ingestion of a low-fat or fat-rich meal (intra-individual median difference in photosensitivity 7.5 J/cm2). On 12 of 20 occasions when the drug was taken after food ingestion, the 1-h 8-MOP serum concentration was below 30 ng/ml. A survey of 43 out-patients undergoing regular PUVA treatment showed that the frequency of erythemal reactions was significantly higher when 8-MOP was ingested with a > 50% smaller quantity of food than usual (P < 0.005). This study demonstrated food-induced variations in 8-MOP photosensitivity both in an experimental situation and in an out-patient survey. In order to optimize the therapeutic effect of PUVA, the quantity of food taken before 8-MOP should remain constant, and the timing of UVA irradiation should be adjusted according to the preceding food intake.

Adult↗

[Serum concentration of lidocaine and its active metabolite monoethylglycinexylidine during fiberoptic bronchoscopy under local anesthesia].

Fiberoptic bronchoscopy was performed in local anaesthesia with lidocaine in 16 patients. Serum concentrations of lidocaine and its active metabolite monoethylglycinexylidide (MEGX) were measured at regular intervals up to 120 min. after administration. Lidocaine was administered as aerosol in the upper respiratory tract and as solution in the bronchial tree. The total lidocaine dose was 243-608 mg (2.4-8.0 mg/kg); 163-508 mg (1.6-6.6 mg/kg) was given as aerosol, and 60-180 mg (0.8-2.5 mg/kg) as solution. The highest median S-lidocaine concentration, 10.5 mumol/l, was measured 20 min. after administration. None of the patients had toxic S-lidocaine levels (greater than 26 mumol/l) and no adverse effects were observed. The highest median S-MEGX concentration, 1.7 mumol/l, was measured 120 min. after administration. The highest individual S-MEGX was 3.5 mumol/l. The highest, although insignificant, correlation coefficients were found between lidocaine dose expressed in mg/kg body weight and S-lidocaine and S-MEGX.

Aerosols↗

Stereoselective pharmacokinetics of disopyramide and interaction with cimetidine.

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross-over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R-(-) enantiomer than the S-(+) enantiomer (7.9 vs 4.6 l h-1 and 89 vs 50 l, respectively), whereas no significant difference in half-life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S-(+) enantiomer than that of the R-(-) enantiomer (34.6 +/- 5.4 l h-1 vs 27.2 +/- 5.6 l h-1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/- 38 l vs 226 +/- 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration- or time-related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.

Adult↗

Dose-effect relationship of disulfiram in human volunteers. I: Clinical studies.

The aim of this study was to investigate the relation between Antabus dosage and the disulfiram-alcohol reaction (DAR) after ethanol challenge. Fifty-two healthy volunteers, 29 men and 23 women, aged 20-61 years, were treated with increasing doses of Antabuse (1, 100, 200, 300 mg) for 14 days each. At the end of each 14 days the volunteers were challenged with 0.15 g ethanol/kg body weight. Blood pressure, pulse rate, respiration rate, and symptoms such as flushing, heat sensation, nausea, vomiting, palpitations, breathlessness, and headache were monitored for the next 50 min. The volunteers left the study when they had experienced a valid DAR. A valid DAR, which was principally defined on the basis of the patients' feeling of discomfort, but for safety reasons also on the basis of unacceptable circulatory changes, was reached in 21 out of 52 volunteers after 100 mg Antabuse, in 27 after 200 mg, and in 4 after 300 mg. Most of them left the study after flushing and circulatory changes, but did not feel ill enough to be convinced that they should abstain from drinking. Ten volunteers with weak subjective symptoms, but with a valid DAR, were therefore rechallenged after the next increased dose and experienced a somewhat stronger reaction. We conclude that a daily dose of 200 mg Antabuse brings about a substantial reaction in volunteers in the presence of alcohol. The possible need for a 300 mg dose of Antabuse to prevent a patient from drinking was discussed.

Adult↗

Dose-effect relationship of disulfiram in human volunteers. II: A study of the relation between the disulfiram-alcohol reaction and plasma concentrations of acetaldehyde, diethyldithiocarbamic acid methyl ester, and erythrocyte aldehyde dehydrogenase activity.

The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus) provoking disulfiram-alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me-DDC) in the range of 8-472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7-197 mumol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14-47 mmHg) and an increase in pulse rate (9-40 beats/min.), accompanied by a two- to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Km values were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.

Acetaldehyde↗

Dopamine and dobutamine reduce myocardial d-propoxyphene content in experimentally intoxicated rats.

The effect of sympathomimetic intervention with dopamine or dobutamine on the myocardial uptake of d-propoxyphene was investigated experimentally in rats. The d-propoxyphene (19 mg kg-1 h-1) was continuously infused, intravenously, over 45 min. After 20 min of infusion the rats were given either dopamine (12.5 micrograms kg-1 min-1 or 25 micrograms kg-1 min-1), dobutamine (25 micrograms kg-1 min-1 or 45 micrograms kg-1 min-1) or normal saline (control). Each group consisted of eight rats. The myocardial d-propoxyphene content was significantly lower in the two groups given dopamine and in the group given dobutamine 45 micrograms kg-1 min-1 than in the control group (P less than 0.05). This finding indicates the benefit of early sympathomimetic intervention with either dopamine or dobutamine in d-propoxyphene intoxication.

Animals↗

Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine.

The analgesic efficacy and kinetics of a single oral dose of 75 mg codeine was investigated in 12 extensive metabolizers and 12 poor metabolizers of sparteine in a double-blind, placebo-controlled crossover study. The cosegregation of the O-demethylation of codeine to morphine with the sparteine oxidation polymorphism was confirmed. Hence morphine could not be detected in the plasma of any of the poor metabolizers, whereas detectable morphine plasma levels were found in 10 of 12 extensive metabolizers. Pain thresholds to laser stimuli were determined before drug intake and 90, 150, and 210 minutes after drug intake. Codeine significantly increased the pricking pain thresholds in the extensive metabolizers (p less than 0.05), whereas there were no significant changes in the poor metabolizers. No change in pain thresholds occurred with placebo in any of the two phenotypes. In the extensive metabolizers there was a significant positive correlation between the increase in pain threshold and plasma concentration of codeine. The study supports the hypothesis that morphine formation is essential for achievement of analgesia during codeine treatment.

Administration, Oral↗

The effect of food on serum concentrations of metopimazine.

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra-individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3. There was no evidence of dose-dependent kinetics at the dose levels studied. 4. Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml-1 h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially.

Adult↗

Relative bioavailability of methadone hydrochloride administered in chewing gum and tablets.

Methadone administered in chewing gum in doses of 16.7-22.6 mg to seven patients in a study using an open balanced cross-over design, was compared with 20 mg of methadone given perorally as tablets. There was no significant difference in the AUC/D obtained after administration of chewing gum and tablets (p greater than 0.05). It is concluded that the chewing gum formulation should be considered for further testing with respect to suppression of abstinence syndrome in narcotic addicts.

Adult↗

Cardiovascular function measured by ultrasound Doppler in healthy young men after ingestion of dextropropoxyphene napsylat.

In a double blind cross-over study 10 healthy male volunteers were given either 300 mg dextropropoxyphene napsylat (DP) or placebo daily for 16 days. The serum levels of DP and the metabolite nordextropropoxyphene were measured on day 3, 6 and 16. Haemodynamic measurements were made on day 1 and day 16, both at rest and during exercise. The measurements were made non-invasively, with a pulsed ultrasound Doppler. Blood pressure, heart rate, velocity, cardiac output, left cardiac work, increased during work, but showing no significant differences between the groups. The systolic time intervals were also measured by the ultrasound Doppler. The preejection period increased significantly in the DP-group, whereas the ratio preejection period/left ventricular ejection time which reflects the contractility of the heart did not differ significantly. It is concluded that DP taken daily in a normal dose for 16 days did not affect the heart function in healthy young men.

Adult↗

Disposition kinetics of disopyramide in human healthy volunteers described by an open three compartment model.

Disposition kinetics of disopyramide was examined in an open randomised cross-over study in 8 healthy volunteers. Disopyramide was randomly administered as a single bolus injection (150 mg) over a period of 5 min. and as an infusion (28.2) mg/h to steady state. Disposition kinetics of disopyramide were most precisely described by an open three compartment model according to Akaike's information criteria. Significant positive correlations (0.909 +/- 0.04, P less than 0.05 (injection study); 0.787 +/- 0.11, P less than 0.05 (infusion study] were observed between total serum concentrations of disopyramide and renal clearance while no significant correlation could be demonstrated between free serum concentrations and renal clearance. This implies a constant value of unbound renal clearance. The results are consistent with non linear kinetics (mainly caused by the variable free fraction of the drug), when based on total serum concentrations. The disposition of unbound disopyramide, however seems to be linear (i.e. the kinetic parameters are independent of dose) in the bolus injection study. Total elimination clearance (free and total), volume of distribution and elimination half-life were significantly higher in the steady state experiment than in the bolus injection study.

Adult↗

Anticonvulsive properties of pregnanolone emulsion compared with althesin and thiopentone in mice.

The anticonvulsive properties of pregnanolone (as an emulsion) were evaluated in mice and compared with similar properties of Althesin and thiopentone. Pregnanolone emulsion was found to antagonize convulsions induced by the GABA antagonists pentetrazole, bicuculline and picrotoxin and by the specific glycine receptor antagonist, strychnine. The drug was effective in all four convulsive tests at subanaesthetic doses with maximal activity appearing within less than 1 min. The anticonvulsive therapeutic indices of pregnanolone emulsion were superior when compared with the therapeutic indices of Althesin and thiopentone in all four tests. Pregnanolone emulsion might be a useful alternative drug in the management of convulsive states resistant to conventional therapy.

Alfaxalone Alfadolone Mixture↗

Elimination kinetics and urinary excretion of disopyramide in human healthy volunteers.

Elimination kinetics and the renal handling of disopyramide was examined in 8 healthy volunteers. Approximately 50% of the administered disopyramide undergoes hepatic metabolism (metabolic clearance = 116.1 +/- 42.2 ml/min.), while the rest is excreted by the kidneys (renal clearance = 101.9 +/- 21.6 ml/min.). Total renal excretion rate of disopyramide was 0.676 +/- 0.188 mumol/min. and 0.258 +/- 0.029 mumol/min. was excreted by glomerular filtration leaving a net tubular secretion of 60% of the total renal elimination. A significant positive correlation was observed between total serum concentrations and renal clearance values of disopyramide while no significant correlation could be obtained between serum concentrations of the unbound drug and renal clearance values of disopyramide, implying a constant value of unbound renal clearance. Hepatic blood flow was significantly (P less than 0.005) decreased following disopyramide infusion.

Adult↗