Biomedical subjects

R Aderjan

Publications and source records attributed to R Aderjan.

At least 19 recordsLinked to original sources

PubMed2003

The role of active metabolites in dihydrocodeine effects.

OBJECTIVE: The metabolism of dihydrocodeine to dihydromorphine, a high affinity mu-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. METHODS: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. RESULTS: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. CONCLUSION: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.

Analgesics, Opioid↗

PubMed2001

Saliva testing after single and chronic administration of dihydrocodeine.

In the present study, concentrations of dihydrocodeine and its metabolites in saliva and serum were compared after single low-dose and chronic high-dosage administration of the drug. In the first investigation, blood and saliva were collected periodically from six subjects after oral administration of 60 mg dihydrocodeine. In the second study, 20 subjects on oral dihydrocodeine maintenance provided single samples of blood and saliva simultaneously. Serum protein binding of salivary analytes and their recovery from the adsorbing material of the collection device as well as pH values of saliva samples were determined. The fluids were analyzed for dihydrocodeine and the major metabolites by high-performance liquid chromatography. In the single dose study dihydrocodeine was the only analyte found in saliva for up to 12-24 h post-dose. The half-life of dihydrocodeine in saliva was about twice that found in blood. The ratios of saliva/serum concentrations ranged from 1.2 to 17.0. After chronic high-dosage use, dihydrocodeine was the main salivary analyte and N-nordihydrocodeine was present in a few samples. Saliva/serum concentration ratios of dihydrocodeine were strongly dependent on the pH value of saliva and, to a lesser extent, on serum-protein binding. The saliva/serum ratios were more similar after chronic administration. The data suggest a passive diffusion process as the underlying mechanism for the transport of dihydrocodeine into saliva. After both single and chronic use, the presence of the drug in saliva can be used as evidence of recent substance administration.

Biotransformation↗

PubMed2001

Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.

BACKGROUND: The antidiarrheal drug loperamide is frequently used to treat ritonavir-associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its low bioavailability and its poor penetration of the blood-brain barrier, both of which might be altered by ritonavir, a potent P-glycoprotein and cytochrome P4503A inhibitor. METHODS: A 16-mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo. Detailed pharmacokinetics of loperamide and its metabolites were determined over 72 hours. Central opioid effects were measured by evaluation of pupil diameter, cold pressor test, and transcutaneous PCO2 and PO2. RESULTS: Ritonavir caused a major pharmacokinetic interaction, increasing the area under the concentration-time curve of loperamide from 104 +/- 60 h x pmol/ml after placebo to 276 +/- 68 h. pmol/ml and delayed formation of the major metabolite desmethylloperamide (time to reach maximum concentration after drug administration [t(max)], 7.1 +/- 2.6 hours versus 19.6 +/- 9.1 hours). The urinary metabolic ratio of loperamide increased 3 times whereas the total molar amount of loperamide and metabolites excreted in urine remained unchanged. No central pharmacodynamic effects were observed after coadministration of loperamide with either ritonavir or placebo. CONCLUSION: This study demonstrates a major metabolic interaction probably by cytochrome P4503A4 with no evidence of P-glycoprotein involvement. This might explain the lack of central effects after ritonavir.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Analysis of cocaine, benzoylecgonine, ecogonine methyl ester, and ecgonine by high-pressure liquid chromatography-API mass spectrometry and application to a short-term degradation study of cocaine in plasma.

A method for the determination of cocaine (COC), benzoylecgonine (BE), ecgonine methyl ester (EME), and ecgonine (ECG) in plasma by liquid chromatography-mass spectrometry (LC-MS-MS) was developed. The analytes were isolated from human plasma by subsequent solid-phase extraction and were separated on a Zorbax Eclipse XDB-C8 narrow-bore column using an ammonium acetate buffer/acetonitrile/methanol gradient. A Turbolonspray source was used for ionization. The analytes were characterized by their particular molecular ion and several fragments. Multiple reaction monitoring (MRM) was used for isolation and quantitation. The assay was rapid, highly sensitive, and reliable. The method was applied to monitor the in vitro degradation of cocaine in plasma. Fresh unpreserved and preserved (0.25% KF) plasma samples were spiked with 1,000 ng cocaine/mL. Aliquots of both series were stored at 4 degrees C and 20 degrees C and were analyzed at selected storage times of up to 15 days. In all samples, degradation of cocaine that was dependent on storage time and temperature and on sample preservation could be observed. The formation of BE did not occur to a significant extent (< 12%, referred to the initial concentration of COC), and its concentration was slightly higher in preserved compared with unpreserved plasma at both storage temperatures chosen. EME was formed in considerably higher amounts compared to BE. As already observed for COC, its formation and degradation were dependent on storage time, temperature, and preservation. EME is suggested to be the major source of ECG, which was detectable in all samples after 1-2 days of storage. Although the degradation of COC was shown to be highly dynamic in nature, the sum of all hydrolysis products of COC accounted for the initial COC concentration at any particular time of storage. Therefore, production of hitherto unknown degradation products of COC seems unlikely. Moreover, the common transformation product of BE and EME appeared to be stable, and ECG is suggested as a promising postcollection artifact.

Artifacts↗

PubMed1999

Determination of ethyl glucuronide, a minor metabolite of ethanol, in human serum by liquid chromatography-electrospray ionization mass spectrometry.

A rapid and sensitive determination procedure using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) has been developed for the determination of ethyl glucuronide (EtG) in human serum. Samples were precipitated with methanol, centrifuged and the supernatant was evaporated to dryness followed by reconstitution with distilled water. As mobile phase 30 mM ammonium acetate-acetonitrile (30:70, v/v) was utilized. The base peak observed at m/z 221 was the [M-H]- ion of EtG, which was detectable in satisfactory sense. The detection limit was 0.03 microg/ml in the selected ion monitoring mode. A calibration graph constructed for EtG in serum gave good linearity over the range from 0.1 to 25 microg/ml. This paper also presents the application of this LC-ESI-MS procedure to the analysis of authentic serum samples.

Alcohol Drinking↗

PubMed1999

The detection of dihydrocodeine and its main metabolites in cases of fatal overdose.

The levels of dihydrocodeine found in impaired individuals and in fatalities show a wide overlap in the ranges. Among other factors, the genetically controlled metabolism of dihydrocodeine should play an important role in dihydrocodeine toxicity. For the first time, the most important metabolites of dihydrocodeine were investigated in femoral blood from three fatal cases by simultaneous determination using HPLC and native fluorescence for detection. The amount of parent drug always exceeded dihydrocodeine-glucuronide formation and dihydromorphine concentrations ranged from 0.16-0.21 mg/L. The similar binding affinities of dihydromorphine and morphine to mu-opioid receptors suggest similar pharmacological effects and adverse reactions. The determination of the pharmacologically active metabolites should help to clarify the cause of death in fatal cases especially if a relatively low concentration of the parent drug is found.

Adult↗

PubMed1999

The influence of the route of administration: a comparative study at steady state of oral sustained release morphine and morphine sulfate suppositories.

Steady state pharmacokinetics of morphine (M), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were investigated in 6 patients with intractable cancer pain administered orally with MST (Mundipharma, Limburg, Germany) and, subsequently, rectally with MSR to make a judgment whether orally administered morphine can be replaced by rectally administered morphine. The parent drug and glucuronide metabolites were measured simultaneously using high-performance liquid chromatography (HPLC) and native fluorescence detection. The mean morphine area under the curve (AUC) value (0-8 h) was smaller (434.3 +/- 170.2 nmolL(-1)h) in the oral administration than in the rectal administration (574.8 +/- 285.0 nmolL(-1)h) (p < 0.05). The rectal administration resulted in less production of M3G and M6G. There were no significant differences in the mean steady state concentrations (C(ss)) of morphine, M3G, and M6G between the oral and rectal administrations (p > 0.05). The median AUC ratio--M3G/M and M6G/M, 12.58 and 1.85--following MSR rectal administration was smaller than following MST oral administration in 6 patients (19.97 and 2.59; p < 0.05), whereas the median AUC ratio M3G/M6G in the rectal dosing was 6.24 (range 5.2-7.6) was almost the same as the median ratio M3G/M6G in the oral dosing was 6.49 (range 5.8-8.5; p > 0.1). Four of the 6 patients had a greater Cmax of M3G and M6G after oral administration than after rectal administration. The same 4 had lower fluctuation rates for morphine, M3G (p < 0.05), and M6G (p < 0.05) after rectal administration. Therefore, during chronic morphine treatment, it still seems difficult to decide whether oral administration can be replaced by rectal administration.

Administration, Oral↗

PubMed1998

Fatal chloroquine intoxication.

A suicidal ingestion of an unknown quantity of Resochin (chloroquine) tablets is described. Although chloroquine is known since 1934, intoxications due to chloroquine overdose are rather rare in European countries. The authors report on a new and fast method of analysing and determining the chloroquine concentration in body fluids and postmortem specimens. The analytes were extracted from alkalinized samples into ethyl acetate before GC/MS analysis. The analyses of chloroquine were performed without any complex sample clean-up steps and, in addition, with little sample material. The proposed method resulted in a rapid procedure most useful in cases of deliberate poisoning with the anti-inflammatory and antimalarial drug chloroquine.

Adult↗

PubMed1998

Postmortem distribution of dihydrocodeine and metabolites in a fatal case of dihydrocodeine intoxication.

A report of a fatal dihydrocodeine ingestion under substitution therapy is given. Quantitation of dihydrocodeine, dihydromorphine, N-nordihydrocodeine, dihydrocodeine-6-, dihydromorphine-6- and dihydromorphine-3-glucuronide was performed simultaneously after solid-phase extraction prior to HPLC analysis, and the analytes were detected using their native fluorescence. Postmortem concentrations of blood samples from different sampling sites as well as from liver, kidney and cerebrum are reported. A hair sample was investigated to prove long-term use of the substitute drug. Site-to-site differences of the analytes from blood samples were very small. The partition behavior of the opioid glucuronides depended on the hematocrit value of the particular blood sample. Most important findings seemed that dihydromorphine and dihydromorphine-6-glucuronide concentrations decisively contributed to the toxicity of dihydrocodeine. This case report outlines that in dihydrocodeine related deaths the concentrations of the pharmacologically active metabolites should additionally be determined for reliable interpretation.

Adult↗

PubMed1997

An in vitro experiment for postmortem vascular permeation. The passage of morphine and morphine glucuronides across a vascular wall.

A venous blood sample taken at autopsy cannot be considered to represent the antemortem blood concentration of a particular substance. Autolytic processes cause disintegration and increasing permeability of the physiological and anatomical barriers such as vascular walls and lead to changes in substance concentrations. In the present study, the experimental design represents an in vitro postmortem simulation of a drug substance crossing a venous wall. The postmortem behavior of morphine, morphine-3- and morphine-6-glucuronide was investigated. A Chien-Valia-diffusion chamber with a patch of inferior vena cava as diffusion barrier was used. For optimal simulation of postmortem events, vein sampling was restricted to selected autopsy cases. Parameters for the analysis of diffusion across the vascular tissue were dependence on time, temperature, and initial substance concentrations. The penetration behavior simulating venous efflux and influx of the substances was studied by different orientation of the venous wall in the experiments. Rhodamine B was used as a model substance to visualize the binding to the tissue and the passage across the venous wall. The permeation of morphine, morphine-3- and morphine-6-glucuronide across a vein tissue was found to be mainly dependent on the disintegration of the vascular wall and on the postmortem time period as well as on concentration gradients. From the data of this preliminary in vitro study, it can be concluded that a lag time for transvascular diffusion exists postmortem. However, it could be demonstrated, that adsorption to and penetration into the vascular tissue may alter intraluminal blood concentrations even at an early stage of the postmortem time period.

Biological Transport↗

PubMed1997

Ethyl glucuronide concentration in serum of human volunteers, teetotalers, and suspected drinking drivers.

The kinetic profile of ethanol and ethyl glucuronide (EtG) in serum was investigated in three subject groups: 1) Healthy, moderately drinking volunteers (daily intake less than 30 g ethanol) who ingested a single dose of ethanol. In this group the maximum of serum ethyl glucuronide concentration (SEtGC) and of serum ethanol concentration (SEC) did not exceed 3.7 mg/L and 1.5 g/L respectively. EtG peaked 2 to 3.5 h later than ethanol. EtG was eliminated with a terminal half-life of 2 to 3 h. EtG decreased slower than ethanol--the metabolite could still be determined in serum up to 8 h after complete ethanol elimination. 2) In serum samples of teetotalers neither ethanol nor EtG could be found. 3) In 37 of 50 serum samples of drivers suspected of driving under the influence of ethanol, SEtGC was found between the limit of detection (0.1 mg/L) and 20 mg/L. If the SEC is less than 1 g/L and the SEtGC is significantly higher than 5 mg/L, we assume alcohol misuse.

Adult↗

PubMed1996

Fatal poisoning with the antidepressive agent opipramol.

An ingestion of an unknown quantity ( < or = 3000 mg) of opipramol dihydrochloride in a suicide case is described. Quantitation of opipramol and its deshydroxyethyl metabolite was performed simultaneously after liquid-liquid extraction from alkalinized samples prior to HPLC analysis. Postmortem concentrations of opipramol and of the metabolite in body fluids and organs are given. The distribution pattern of opipramol in tissue was comparable to findings from animal studies. The results showed the high uptake of opipramol in parenchymal tissues resulting in a low blood concentration. A possibly low contribution of deshydroxyethyl opipramol to the antidepressive effect may be concluded as the concentration was considerably lower in brain compared to other organs.

Adult↗

PubMed1996

Postmortem distribution pattern of morphine and morphine glucuronides in heroin overdose.

The postmortem distribution of morphine and its metabolites was investigated in four cases of heroin overdose to evaluate some of the factors that influence intravasal blood concentrations. Variables included were the chemical stability of morphine conjugates, hemoconcentration, incomplete distribution of the drug and diffusion processes. Blood samples from different sampling sites including the aorta, the infra- and suprarenal portion of the inferior vena cava, the superior vena cava, the femoral and subclavian veins, and the right and left ventricles were examined for morphine, morphine-3-glucuronide and morphine-6-glucuronide, hematocrit and water content. Drug concentrations were determined by HPLC based on the native fluorescence of the analytes. Morphine glucuronides proved to be stable for a time period of 72 h. The water content ranged from 65 to 83% and hematocrit values from 25 to 75%, and were seen as contributory factors to the dramatic differences observed for drug concentrations from different sampling sites. The differences could neither be attributed to incomplete distribution during life-time nor to a diffusion process following the different distribution volumes of morphine and its conjugates. A definite relationship between the ratio of the molar concentrations of morphine and its glucuronides, as assessed in pharmacokinetical studies after morphine dosing, could not be established. For a better understanding more cases and changes over time and tissue concentrations should be analysed.

Adult↗

PubMed1996

Experimental investigations on hair fibers as diffusion bridges and opiates as solutes in solution.

Diffusion experiments were performed using clipped hair fibers as diffusion bridges and aqueous solutions of morphine, codeine and dihydrocodeine. Natural as well as predamaged hair fibers were investigated. The test series were conducted at ambient temperature and at high humidity. After 312 or 372 hours the middle segments of the strands were clipped, washed and analyzed by GC/MS. Only when virgin hair samples were used the solutes passed along the fiber at full length resulting in a positive immunological finding at the end of the diffusion bridge. Most of the washing fluids were positive for opiates. All centerpieces had a high opiate content. The opiate concentration in damaged hair was significantly higher. Radial swelling of the hair fiber with radial diffusion was the first and main process to appear when hair was exposed to water. The diffusion process in hair could not be placed in a simple mathematical treatment.

Asian People↗

PubMed1995

[Hair analysis in the diagnosis of toxic hepatitis after Ecstasy abuse].

HISTORY AND CLINICAL FINDINGS: A young man, aged 18 years, was admitted to hospital for suspected hepatitis, having developed increasing jaundice without any pain. His urine was light brown in colour and the stools often liquid and pale. Every 14 days for the last 4 months he had been taking 2 tablets of "ecstasy" (methylenedioxyamphetamine; MDMA). Physical examination was unremarkable and the patient was in good general condition. TESTS: The activities of GOT, GPT and alkaline phosphatase were raised (to 903, 744 and 270 U/l, respectively) as was the bilirubin concentration (16.8 mg/dl). Tests were negative for: leptospira and the viruses of mumps, HI, varicella zoster, picornavirus, cytomegaly, Coxsackie and hepatitis, A, B and C. Ultrasound revealed hepatomegaly, with a normal echo pattern. Hair analysis demonstrated, in two different hair segments (0-2 cm and 2-4 cm, respectively) both MDMA (6.4 and 4.3 micrograms/g hair) and its metabolite MDA (0.7 and 5.0 micrograms/g hair). TREATMENT AND COURSE: No specific treatment was required. After intake of the drug had been stopped the transferase activities and bilirubin concentration became essentially normal. CONCLUSION: Hair analysis can be valuable in confirming "ecstasy" abuse, especially when it is denied, and thus contribute to clarifying the cause of toxic hepatitis.

Adolescent↗

PubMed1995

[Congener analysis in a drinking trial with unusually high alcohol content].

The aforementioned case proves very convincingly that a very high dose of alcohol consumed within a short time span can be absorbed completely within 2 hours. Numerical models based on low to moderate alcohol consumption were lower than expected in cases of severe alcohol intake. The claim of alcohol consumption after an event can best be verified by means of a drinking experiment under intensive medical supervision.

Accidents, Traffic↗

PubMed1994

Fatal overdose of 2,4-dichlorophenoxyacetic acid (2,4-D).

An ingestion of an unknown quantity of U 46 D-Fluid (500 g dichlorophenoxyacetic acid/l) in a suicide is described. Although 2,4-dichlorophenoxyacetic acid (2,4 D) is widely used as a herbicide, intoxications are relatively rare. Quantitation of 2,4-D was performed by diethyl ether extraction from acidified samples (viscera) or by deproteinization (blood, plasma) with methanol before HPLC analysis. Postmortem concentrations of 2,4-D in body fluids and tissues are given. The proposed method resulted in a rapid procedure most useful in cases of deliberate poisoning with phenoxyacetic herbicides.

2,4-Dichlorophenoxyacetic Acid↗

PubMed1992

[Glue solvent as the cause of a "breath alcohol value" of "1.96 promille"].

After sniffing of glue solvents (mixture of aliphatic hydrocarbons: boiling fraction 60-90 degrees C, ethylacetate and toluene) a blood alcohol concentration of 1.96 permille was indicated with an instrument using the infrared wavelength of 3.4 micrometer for the spectrophotometrical determination of breath alcohol. Testing of the individual solvents with a simple manual procedure showed linear relationships between concentrations in breathing air and the false positive breath alcohol values. Aliphatic hydrocarbons predominantly are responsible for the false positive breath alcohol determination. With 500 micrograms/liter a value of nearly 1.5 permille can be produced (using the factor of 2100 for the calculation of the blood alcohol concentration from breath alcohol). With ethylacetate or toluene up to 1 milligram/liter 0.5 permille ethanol in the blood will erroneously be found. The problem of recognition of crossreactive other gases by the measurement at two wavelengths (3.4 and 9.2 micrometer) is discussed.

Adult↗