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Biomedical subjects

P J Neuvonen

Publications and source records attributed to P J Neuvonen.

At least 163 records · Page 9Linked to original sources
PubMed1994

Lack of interaction of erythromycin with temazepam.

Erythromycin is a strong inhibitor of cytochrome P450 [CYP3A4] and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between erythromycin and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers received 500 mg erythromycin or placebo orally three times a day for 6 days followed by a challenge dose of 20 mg temazepam. Plasma samples were collected for the determination of temazepam, oxazepam, and erythromycin, and psychomotor effects were measured during the 24 h after intake of temazepam. Erythromycin did not change the pharmacokinetics or pharmacodynamics of temazepam to a statistically significant degree. The metabolic fate of temazepam and its almost complete bioavailability explain the lack of interaction. Temazepam, unlike midazolam or triazolam, can thus be prescribed in the usual doses for patients receiving erythromycin.

Administration, Oral↗
PubMed1994

The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin.

The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin was studied in three separate, two-period crossover trials, each involving eight healthy volunteers. After an overnight fast, a single dose of norfloxacin (400 mg), ciprofloxacin (500 mg) or ofloxacin (400 mg) was administered with and without ferrous sulphate (corresponding to 100 mg elemental iron). The absorption of all the fluoroquinolones studied was significantly reduced when they were co-administered with ferrous sulphate. The reduction in the area under the plasma drug concentration-time curve from 0 to 24 h was most marked in the case of norfloxacin, while ofloxacin was least affected by ferrous sulphate. The AUC of norfloxacin was reduced by 73% (P < 0.001) and its peak plasma concentration by 75% (P < 0.01) by concomitant ingestion of ferrous sulphate. The AUC and peak plasma concentration of ciprofloxacin were reduced by 57% (P < 0.001) and 54% (P < 0.01), respectively, by ferrous sulphate. Concomitant ingestion of ferrous sulphate reduced the AUC and peak plasma concentration of ofloxacin by 25% (P < 0.01) and 36% (P < 0.01), respectively. Similar results were obtained with respect to the urinary recoveries of each fluoroquinolone. We recommend that norfloxacin and ciprofloxacin should not be taken together with ferrous sulphate. It would also be advisable not to take ofloxacin with ferrous sulphate, especially if the organism causing infection is only moderately susceptible.

Absorption↗
PubMed1994

Dose of midazolam should be reduced during diltiazem and verapamil treatments.

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration-time curve was increased from 12 +/- 1 microgram ml-1 min to 45 +/- 5 micrograms ml-1 min by diltiazem (P < 0.001) and to 35 +/- 5 micrograms ml-1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half-life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.

Administration, Oral↗
PubMed1994

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.

Administration, Oral↗
PubMed1994

The effect of activated charcoal on the absorption and elimination of astemizole.

1. The effect of activated charcoal on the absorption and elimination of astemizole and its metabolites was studied in healthy volunteers. 2. Subjects were divided into three groups containing seven subjects each. One group received 30 mg of astemizole with water only (control) and another group with 25 g of activated charcoal. The third group received multiple doses (12 g) of charcoal from 6 h onwards twice daily for 8 days. The concentrations of astemizole and its metabolites in plasma were measured by radioimmunoassay for 192 h. 3. Activated charcoal, administered immediately after astemizole ingestion, reduced the absorption of astemizole by 85% (P < 0.001). Multiple doses of activated charcoal, administered throughout the period of astemizole elimination, had no significant effect on the rate of elimination or the area under the curve from 0 to 192 h. 4. The absorption of astemizole from the gastrointestinal tract can be effectively prevented with activated charcoal. Because astemizole is rapidly absorbed, charcoal should be administered as soon as possible in acute astemizole poisoning. Multiple doses of charcoal do not seem to shorten the elimination half-life of astemizole.

Adult↗
PubMed1994

Enhancement of drug absorption by antacids. An unrecognised drug interaction.

Antacids are widely used for many disorders. The potential of antacids to interact with other concomitantly ingested drugs is well recognised. These interactions usually result in reduced or delayed absorption of the affected drug. However, this is not always the case. In contrast to aluminium hydroxide, magnesium hydroxide and sodium bicarbonate can enhance the absorption of some drugs. For example, magnesium hydroxide can increase the rate and sometimes even the extent of absorption of certain nonsteroidal anti-inflammatory drugs (e.g. tolfenamic acid, mefenamic acid and ibuprofen), sulphonylurea antidiabetic agents [e.g. glipizide, glibenclamide (glyburide) and tolbutamide] and the oral anticoagulant dicoumarol (bishydroxycoumarin). These weakly acidic drugs are nonionised at gastric pH, but are sparingly water soluble. Elevation of the gastric pH by administration of magnesium hydroxide or sodium bicarbonate increases the solubility and absorption of such sparingly water soluble agents. Chelate formation may be involved in the increased absorption of dicoumarol by magnesium hydroxide. In combination antacids containing both aluminium hydroxide and magnesium hydroxide, the absorption enhancing effect of magnesium hydroxide seems to be counterbalanced by the opposing effects of aluminium hydroxide. The clinical significance of increased drug absorption is not clear. However, accelerated and enhanced absorption of analgesic drugs may be beneficial when rapid pain relief is desired. In contrast, an unexpectedly increased hypoglycaemic or anticoagulant effect may be potentially dangerous. Therefore, a knowledge of the potential effect of antacids on the absorption of other drugs is clinically important.

Absorption↗
PubMed1994

The bioavailability of two beta-blockers preadsorbed onto charcoal.

The relative bioavailability of metoprolol and pindolol from capsules containing the drug preadsorbed onto activated charcoal (100 mg metoprolol tartrate/120 mg charcoal and 10 mg pindolol/20 mg charcoal) was studied in two separate studies, in healthy volunteers, using randomized, crossover designs. The metoprolol control was a capsule containing the drug only and the pindolol control was a conventional tablet. In an in vitro dissolution study, both control formulations showed a rapid, total release of the drug, whereas from each of the drug-charcoal complexes, around 30% of the drug was released rapidly after which the release continued more slowly, reaching 45-60% in 24 h. The absorption of metoprolol and pindolol was slower from the charcoal formulations than from the control formulations. Charcoal, however, also essentially decreased the bioavailability, reducing the mean AUC0-24h and the mean 24 h urinary excretion of both metoprolol and pindolol to one-half and the mean plasma Cmax to one-third compared to the control. The increase in the mean tmax was not statistically significant. These results indicate that desorption of metoprolol and pindolol from charcoal occurs in the human gastrointestinal tract, but the bioavailability remains low. In spite of the sustained in vitro release of both drugs, the absorption was only slightly retarded at these charcoal:drug ratios.

Administration, Oral↗
PubMed1994

Drug adsorption onto activated charcoal as a means of formulation.

The in vitro adsorption of metoprolol, pindolol, salbutamol, furosemide and clonidine onto activated charcoal was determined. The affinity of the drugs for charcoal decreased with increasing hydrophilicity. Also the rate of adsorption of clonidine onto four charcoal preparations having different particle sizes was studied. The equilibrium was reached rapidly with the charcoal having the smallest particle size, and the adsorption rate decreased as the particle size of the charcoal increased. The desorption of drugs from charcoal was investigated in the Sartorius dissolution apparatus at constant initial drug:charcoal ratio. The desorption had a two-step kinetics. The quantity of the initial rapid release, indicating the development of equilibrium, agreed with the adsorption data determined under the same conditions, except for salbutamol and furosemide at pH 7. The same was true for the Langmuir isotherms determined for adsorption and desorption. The following release step was slow and there were only minor differences between the release rates of the different drugs. The desorption rate (time to reach equilibrium) from the different charcoals was studied using a batch technique. An increase in the particle size of charcoal had, however, only limited sustaining effect on desorption. Although the affinity of the drugs for charcoal was in good agreement with their hydrophobicity, their desorption behavior was not necessarily proportional to their hydrophilicity. The in vitro release of the drugs from charcoal was retarded and was not significantly affected by the charcoal particle size.

Adsorption↗
PubMed1994

Desorption of furosemide from charcoal in vitro and in man.

The gastrointestinal absorption of furosemide preadsorbed onto activated charcoal was studied in 8 healthy volunteers using a randomized cross-over design with 3 phases. The 3 experimental furosemide formulations were capsules containing 40 mg furosemide only (reference) or 100 mg furosemide preadsorbed onto 160 mg or 200 mg charcoal. Timed plasma samples were taken and urine was collected for 24 hours for determination of drug concentrations and diuretic response. The release of furosemide from the formulations was also studied in vitro. Furosemide was found to dissolve rapidly from the reference formulation, whereas it was slowly desorbed from charcoal with the cumulative release reaching 50-60% in 24 hours (pH 5.3). The absorption rate of furosemide was smaller after intake of the charcoal formulations that after intake of the reference formulation. However, also the amounts of furosemide found in plasma and urine were clearly decreased due to preadsorption onto charcoal. The dose-adjusted relative bioavailabilities of the furosemide-charcoal formulations (compared to the reference formulation) remained less than 10%. The release mechanism of furosemide from charcoal is sensitive to physiological factors of the gastrointestinal tract. The large variability known to be typical for furosemide absorption was further increased when the drug was preadsorbed onto charcoal.

Administration, Oral↗
PubMed1993

A potentially hazardous interaction between erythromycin and midazolam.

Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Administration, Oral↗
PubMed1993

Anaesthesia affects plasma concentrations of vasopressin, von Willebrand factor and coagulation factor VIII in cardiac surgical patients.

Operative stress may affect haemostatic mechanisms through hormonal systems. As the endocrine stress response to surgery may be modulated by anaesthesia, we have altered stress hormone concentrations by using either opioid or inhalation based anaesthesia to study haemostatic mechanisms in cardiac surgical patients. Thirty patients undergoing coronary artery surgery were allocated randomly to receive fentanyl (non-stress group) or enflurane (stress group) as the main anaesthetic agent. After cardiopulmonary bypass (CPB), plasma arginine vasopressin (AVP) concentrations were significantly (P < 0.001) greater in the stress group (81.8 (46.9-142.9) pg ml-1, mean with 95% confidence limits) than in the non-stress group (5.8 (3.3-10.2) pg ml-1). Plasma noradrenaline and adrenaline concentrations increased similarly in both groups after CPB. Plasma concentrations of both von Willebrand factor (stress: 1.56 (1.33-1.79) IU ml-1; non-stress: 1.00 (0.76-1.25) IU ml-1) and coagulation factor VIII: C (stress 1.15 (0.87-1.44) IU ml-1; non-stress: 0.69 (0.55-0.80) IU ml-1) were significantly (P < 0.01) greater in the stress group than in the non-stress group after CPB. The results indicate that there is a temporal relationship between the increased plasma concentrations of AVP and von Willebrand factor and factor VIII: C. It is not clear if this indicates a causal relationship. However, variable stress control by anaesthesia may modify haemostasis in cardiac surgical patients.

Adult↗
PubMed1993

Haemodynamic and catecholamine responses to induction of anaesthesia and tracheal intubation: comparison between propofol and thiopentone.

We have studied the haemodynamic changes, QT intervals and catecholamine responses to induction of anaesthesia and tracheal intubation in 24 ASA I patients allocated randomly to receive either propofol 2.5 mg kg-1 or thiopentone 5 mg kg-1 over 60 s. After disappearance of the eyelash reflex, the lungs were ventilated with 100% oxygen for 3 min. The trachea was intubated after administration of vecuronium. With thiopentone, heart rate (HR) was greater than with propofol before intubation (P < 0.05). During induction, systolic (SAP) and diastolic arterial pressure (DAP) decreased more with propofol than with thiopentone. The QT interval was prolonged only during induction with thiopentone. In both groups, HR, SAP, DAP and the QT were increased in response to intubation (P < 0.001). The SAP and QT interval responses to intubation were significantly greater with thiopentone than with propofol (P < 0.05). One patient in the thiopentone group with a significantly prolonged QT interval had episodes of bigeminy and ventricular tachycardia. In both groups, concentrations of noradrenaline in mixed venous plasma increased after intubation (P < 0.001). Concentrations of adrenaline increased after intubation only in the thiopentone group (P < 0.001).

Adolescent↗
PubMed1993

The effects of different doses of sodium bicarbonate on the absorption and activity of non-micronized glibenclamide.

The effects of different doses of sodium bicarbonate on the absorption and activity of non-micronized glibenclamide were studied in six healthy volunteers, using a randomized crossover design with four phases. The subjects ingested a single dose of non-micronized glibenclamide (2.5 mg) with 150 ml of water or with 150 ml of water containing 0.3, 1.0 or 3.0 g of sodium bicarbonate. Plasma concentrations of glibenclamide, insulin and glucose were measured. Coadministration of 1.0 or 3.0 g of sodium bicarbonate with non-micronized glibenclamide increased the area under the plasma glibenclamide concentration-time curve (AUC) from 0 to 1 h 30-fold (p < 0.05) and 38-fold (p < 0.05), respectively. The 1.0- and 3.0-g doses of sodium bicarbonate also increased the AUC of plasma glibenclamide from 0 to 2 h, about 3-fold (p = 0.05 and 0.07, respectively). The peak plasma concentration, peak time and total extent of absorption of glibenclamide and the insulin and glucose responses were not significantly altered by any of the doses of sodium bicarbonate studied. Concomitant ingestion of 1.0 or 3.0 g of sodium bicarbonate and non-micronized glibenclamide greatly increased the early bioavailability of glibenclamide. However, this interaction did not alter the activity of glibenclamide.

Adult↗
PubMed1992

Reversible adsorption of nicotinic acid onto charcoal in vitro.

The effects of various factors on the adsorption of nicotinic acid onto and desorption from activated charcoal were investigated in vitro. The affinity of nicotinic acid for charcoal was poor both in acidic and neutral media. Adsorption increased with increasing charcoal:drug ratios and decreasing incubation volume:charcoal ratios. Desorption of nicotinic acid from dried drug-charcoal complexes was investigated in a Sartorius dissolution apparatus. The rate of the rapid, initial desorption depended on the pH and the amounts of charcoal and drug. As equilibrium was reached in the dissolution chamber, the release rate of nicotinic acid decreased slowly, depending mainly on the flow of the medium. Thus, nicotinic acid preadsorbed onto charcoal was released in a sustained manner under "continuous flow" conditions. However, because of the poor affinity for nicotinic acid, charcoal may not be a suitable matrix for sustained release of nicotinic acid.

Adsorption↗
PubMed1992

Effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide.

The effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide was examined in a total of 32 healthy volunteers in two separate, randomized parallel-group studies, with 16 subjects in each study. After an overnight fast, the first group of 8 volunteers ingested 500 mg tolbutamide or 250 mg chlorpropamide with 150 ml water, and the second group the same doses of the active drugs with 150 ml water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the area under the plasma tolbutamide concentration-time curve (AUC) from 0 to 1 h and from 0 to 2 h by 5-fold and 2.5-fold, respectively. The peak plasma concentration, peak time and total AUC were not significantly altered. The incremental insulin area and the decremental glucose area from 0 to 1.5 h were significantly larger in the magnesium hydroxide group than in the controls. The maximum insulin response to tolbutamide was increased fourfold by coadministration of magnesium hydroxide, and it occurred about 1 h earlier than in the control group. In addition, the maximum fall in plasma glucose concentration was attained about 1 h earlier in the antacid group. A tendency to an increased rate of chlorpropamide absorption was observed after magnesium hydroxide, but it did not appear to affect the insulin and glucose responses to chlorpropamide. It is concluded that magnesium hydroxide increased the early bioavailability of tolbutamide, resulting in enhanced insulin and glucose responses. A tendency toward accelerated chlorpropamide absorption by magnesium hydroxide was also observed, but the efficacy of chlorpropamide was unaffected.

Adult↗