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[Pharmacokinetics of dextromoramide in the surgical patient].

The pharmacokinetics of dextromoramide were studied in nine patients undergoing peripheral vascular surgery. All the patients were anaesthetised with thiopentone and vecuronium. After tracheal intubation, anaesthesia was maintained with 0.5 to 1.5 vol % halothane and a 60%-40% vol nitrous oxide-oxygen mixture. Once the patient's status was stable, a 0.8 mg.kg-1 bolus of dextromoramide was given intravenously. Blood samples were obtained 2, 5, 10, 30, 60, 90, 120, 180, 240, 300, 360, and 420 min afterwards by an arterial catheter. Dextromoramide serum concentrations were measured with high performance liquid chromatography after extraction with an original technique. The pharmacokinetic parameters were calculated by computer using TRIOMPHE. In five patients, a bi-exponential equation best fitted the results, whereas a tri-exponential equation was necessary for the other four. Mean elimination half-life was 215.3 +/- 78.4 min, and the apparent final volume of distribution was 0.58 +/- 0.20 l.kg-1. Hepatic extraction was low, as shown by a mean systemic clearance of 2.0 +/- 0.9 ml.kg-1.min-1. Liposolubility of this drug is the highest of all opiates, with a heptane/water partition coefficient of 12.3. These parameters demonstrate that, in the opiate drug group, dextromoramide has a place apart from the others.

Aged

Determination of dextromoramide by capillary gas chromatography and electron impact mass spectrometry.

A sensitive and specific quantitative assay for the determination of dextromoramide in human fluids and tissues is described. Dextromoramide and an internal standard, SKF 525 A, are isolated by a basic extraction and back-extraction process. The final extract is separated on a 25-m capillary column B.P. 1 and drugs are detected by selected ion monitoring at m/z 100 and m/z 86 for dextromoramide and the internal standard, respectively. The minimum detectable quantities are 0.5 and 0.3 ng/mL, for dextromoramide in plasma and urine, respectively. Coefficients of variation for within-run data were less than 6%.

Dextromoramide

[Chromatographic identification and analysis of dextromoramide in the plasma by the method of high performance liquid chromatography].

Dextromoramide and pethidine were separated and identified by thin-layer chromatography on silica gel, using ammonia and methanol (1.5:100) as the mobile phase, after previous extraction with dicthyl ether or with a mixture of n-hexane and isoamyl alcohol (98.5:1.5) from blood alkalized to pH 10.3 Dextromoramide can be revealed on the chromatograms in the amount of 0.5 micrograms and pethidine in the amount of 1 micrograms using the Dragendorff reagent. Reversed-phase TLC proved less sensitive. High-performance liquid chromatography on the column of LiChrosorb RP-18 was applied to the determination of dextromoramide in blood after extraction with diethyl ether, using methanol--phosphate buffer pH 4.5 (95:5) as the mobile phase. The determination range was of 0.5-5.0 micrograms per 2 cm3 of blood plasma (1.26.10(-8)-1.26.10(-7) mole/dm3).

Chromatography, High Pressure Liquid

Teratogenic potential of two neurotropic drugs, haloperidol and dextromoramide, tested on mouse embryos.

Potential teratogenic activity of two neurotropic drugs, haloperidol and dextromoramide tartrate, was tested by using the mouse embryo experimental model. Like numerous other drugs of this class these two are also embryotoxic. After treatment 1 hour into the 9th gestation day they induce the neurotropic syndrome of malformations comprising exencephaly, craniorachischisis, kinking of the spinal cord, brachyury, and dilation of the fourth brain ventricle. In addition, dextromoramide tartrate was found to induce one more, so far unknown, neural tube defect, namely the ectopia of the neural tube. Delay of treatment by 1 or 2 hours tends to displace the location of the neural tube defects along the length of the neural axis towards the anterior and posterior directions. Even after accumulating these results at relatively high doses, it is difficult to estimate human reproductive risks from this animal data for human therapeutic doses.

Animals

Characterization of dextromoramide (Palfium) abuse by hair analysis in a denied case.

By providing information on exposure to drugs over time, hair analysis is useful in verifying the history of drug use. In a clinical case, where drug abuse was denied, it was possible to identify dextromoramide in the hair of the subject. After acid hydrolysis of the hair with 0.1 M HCl, in the presence of SKF 525A as an internal standard, the drug was extracted at pH 8.4 with chloroform-isopropanol-n-heptane (50:17:33 v/v) and quantified by gas chromatography/mass spectrometry. The hair strands were cut into 3 sections of 2.5 cm, corresponding to a growth period of 2 months. Concentrations were 1.09, 1.93 and 1.48 ng/mg from the root to the end, respectively. This is the first report on dextromoramide testing in human hair.

Dextromoramide

Determination of dextromoramide in plasma and whole blood using high-performance liquid chromatography with ultraviolet absorbance detection.

Dextromoramide was determined in plasma and whole blood after solid-phase isolation by high-performance liquid chromatography using dextropropoxyphene as internal standard and ultraviolet detection at 215 nm. Owing to its good selectivity, sensitivity and reproducibility, the technique is available for forensic toxicology purposes as well as for clinical pharmacology. The concentrations of dextromoramide were determined in three cancer patients receiving intravenous treatment with one to three 5-mg daily doses. On the fourth day the plasma level was 13.85 +/- 3.27 ng ml-1 just before the first daily dose and 84.28 +/- 12.60 ng ml-1 30 min after dosing. The whole blood concentration, determined in one of the patients, was undetectable just before the dose and was 76 ng ml-1 30 min after dosing.

Chromatography, High Pressure Liquid

Simultaneous determination of dextromoramide, propoxyphene and norpropoxyphene in necropsic whole blood by liquid chromatography.

Dextromoramide, propoxyphene and its main metabolite, norpropoxyphene, were determined in blood after solid-liquid extraction by means of an HPLC method using photodiode-array detection. Two cases of fatal overdose resulting from abuse of the two drugs are presented. In case 1 the necropsic whole blood contained dextromoramide at toxic level (194 ng ml-1) and propoxyphene (614 ng ml-1) and norpropoxyphene (1100 ng ml-1) within the therapeutic range; the death could be due to the combined effect of the two analgesics and, perhaps, other associated drugs. In case 2, the necropsic whole blood concentrations of propoxyphene and norpropoxyphene were 4330 and 3800 ng ml-1, respectively, and could be considered as lethal.

Adult

Gas chromatographic mass-specific investigation of dextromoramide (Palfium) metabolism in the horse.

Dextromoramide (Palfium) was given by intravenous injection to a Thoroughbred horse at a dosage of 20 mg and urine was collected 2, 4, 6 and 8 h after drug administration. Enzymatic hydrolysis of the urine followed by solvent extraction gave a residue which was back-extracted into 0.1 M sulphuric acid. After basification to pH 9 and solvent extraction, the resulting residue was submitted to gas chromatographic-mass spectrometric analysis. Both electron-impact and ammonia chemical-ionization mass spectra were recorded and, based on the observed fragmentation patterns, the principal metabolites in horse urine were shown to be 2,2-diphenyl-3-methyl-4-morpholinobutyramide (compound 2) and the product of hydroxylation of one phenyl ring in dextromoramide (compound 3), respectively. The electron-impact mass spectra of compounds 2 and 3, and of their derivatisation products from oncolumn methylation in the gas chromatograph, are reported.

Animals

Fatal intoxication by dextromoramide: a report on two cases.

Two cases involving an overdose resulting from the abuse of dextromoramide are presented. The drug was quantified with a gas chromatograph equipped with a nitrogen phosphorous detector (NPD). The whole blood dextromoramide concentrations were 984.3 ng/mL for case 1 and 871.1 ng/mL for case 2. No correlations could be established with the postmortem levels in blood and in bile.

Adult

Pharmacokinetics of dextromoramide in surgical patients.

The pharmacokinetics of the narcotic analgesic dextromoramide was investigated by means of a specific GC-MS method in 9 patients who were given a single oral dose of the drug (7.5 mg) together with an anticholinergic before undergoing minor orthopedic surgery. Dextromoramide was rapidly absorbed from the gastrointestinal tract, with peak plasma levels between 68 and 177 micrograms/L usually achieved within 0.5-4.0 h after dosing. In 5 patients, the decline of plasma concentrations after the peak followed a biphasic pattern, with half-lives of 0.4-1.6 h for the first phase and 6.3-21.8 h for the terminal phase. In the remaining patients, no clear-cut biphasic pattern was seen and half-lives calculated over the period between 4 h and 10 h after administration ranged from 1.5 to 4.7 h. Apparent clearance and volume of distribution values ranged from 0.06 to 0.36 1.h-1.kg-1 and from 0.6 to 2.4 l.kg-1, respectively. Less than 0.06% of the dose was excreted unchanged in urine within 8 h of administration. The concentration of the drug in a CSF sample collected 1 h after dosing was below the limit of detection (2 micrograms/L) in all subjects.

Adolescent

Tissue distribution of dextromoramide in the rat.

The tissue distribution of dextromoramide was studied in rats after the intraperitoneal injection of 0.2 mg/kg of the drug. The pattern of distribution was similar at 15, 30, 60 and 90 min, with the highest concentrations being found in the liver and the myocardium, while other organs were not able to concentrate dextromoramide.

Animals

A dextromoramide-related fatality.

A 38-year-old man was found in his car suffering from a heart attack. Serum analysis by capillary gas chromatography and mass spectrometry confirmed the presence of dextromoramide (Palfium), methadone, and lidocaine. The serum concentrations at admission to the hospital were: 1.9 micrograms/mL of dextromoramide, 0.4 micrograms/mL of methadone, and 0.4 micrograms/mL of lidocaine. A serum alcohol analysis performed using headspace gas chromatography was negative.

Adult

Toxicological findings after fatal dextromoramide injection.

A death involving dextromoramide injection is presented. The drug was analyzed in whole blood, bile, stomach contents, kidney, brain and liver. The whole blood concentration was 1526 ng/ml. The results are compared with the existing literature.

Adult

Crystal structures of synthetic analgetics. V. Dextromoramide.

The molecular and crystal structure of dextromoramide has been determined by X-ray methods. The crystals are orthorhombic, space group P212121 with unit cell dimensions a = 9.720(4) A; b = 12.226(3) A; c = 18.381(3) A. The structure was determined by direct methods and the model refined to an R-value of 0.036 for 1788 observed reflections. The mean e.s.d.'s in bond lengths and angles are 0.004 A and 0.3, respectively. The morpholine moiety is nearly in antiposition relative to the quaternary carbon atom C6, the pertinent angle C6 - C7 - C9 - N2 being - 159.4. This conformation is similar to that previously reported for the bitartrate of the title compound. The pyrrolidine ring has the envelope conformation and the amide group is strictly planar. The conformation of some acyclic analgetics are discussed.

Dextromoramide

[Neuroplegia and extracorporeal circulation. Comparison between combinations of droperidol-phenoperidine and chlorprothixene-dextromoramide in cardiac surgery].

After a quick review of the physiopathology of extra-corporeal circulation, the value of the use of neuroplegic drugs in cardiac surgery is recalled by means of pharmacological arguments. The experimental differences existing between the combinations droperidol - phenoperidine and chlorportixene - dextromoramide, on the rate of flow and on the pressure of the perfusion, and on the esophago-rectal thermic gradients during E.C.C. is then demonstrated. Statistic calculation confirmed the superiority of chlorprotixene in the realm of tissue perfusion during E.C.C. under hypothermia.

Adult

Identification and determination of dextromoramide, a nonopiate narcotic.

A method for the identification and quantification of dextromoramide in plasma by GC/NPD is presented. The procedure employs alfentanil as the internal standard and requires no derivatization. After a single-step extraction, analysis is performed on a 3% OV-17 Chromosorb Q glass column. The lower limit of detectability was found to be 2 ng/ml in plasma.

Chromatography, Gas

[Comparison of the endocrine response under 2 kinds of anesthesia: neuroleptanalgesia of the chlorprothixene-dextromoramide type and venous anesthesia of the type alfadione-fentanyl].

In 14 patients anaesthetized before undergoing an orthopedic surgical intervention, the variations induced by anaesthesia in the 17 hydroxycorticosterone rate, catecholamine, somatotropic hormone (STH), insulin, glycemia, free fatty acids and thyrotropin (TSH), all these variations were studied before the surgery. The patients were divided into 2 groups of 7, the first one being anaesthestized by chlorprothixene dextromoramide Neurolept-Analgesia and the second one by Alfadione Fentanyl venous anaesthesia.

Alfaxalone Alfadolone Mixture

Influence of the restoration of vagal tone by intracisternal injection of dextromoramide on the cardiac effects of the antiarrhythmic drugs.

The effects of four antiarrhythmic drugs, quinidine, procainamide, amiodarone and verapamil were studied on sinus rate, conduction time and, when possible, effective refractory period (ERP) in atrioventricular node (AV node), and finally atrial muscle ERP. This study was made under two types of conditions, vagal tone being absent or present after restoration in the anesthetized dog by a new technique, the intracisternal injection of dextromoramide. Quinidine and procainamide which tend to slow down sinus rate and conduction in the former case accelerate them considerably in the latter by opposing the effects of acetylcholine released by vagal endings. The prolongation of atrial ERP also induced by these drugs results from both this process and their own capacity. Amiodarone and verapamil, usually responsible for bradycardia, notable delay in AV node conduction and lengthening of AV node ERP are, however, liable to elicit opposite effects, especially amiodarone when vagal tone is very high. The reduction of vagal influence is, in the case of these drugs, the only factor in the prolongation of atrial ERP. In any case, the response of both specialized and common tissue of the heart to antiarrhythmic drugs should not be interpreted unless the degree of vagal tone is known.

Amiodarone