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Biomedical subjects

H D Dell

Publications and source records attributed to H D Dell.

At least 19 recordsLinked to original sources
PubMed1992

[Plasma- and tissue concentrations following intramuscular administration of etofenamat. Pharmacokinetics of etofenamat and flufenamic acid in plasma, synovium, and tissues of patients with chronic polyarthritis after administration of an oily solution of etofenamat].

Studies on Plasma and Tissue Concentrations of Etofenamate following Intramuscular Application/Pharmacokinetics of etofenamate and flutenamic acid in plasma, synovia and tissues of patients with chronic polyarthritis after application of oily etofenamat solution Pharmacokinetics of etofenamate (ETO, CAS 30544-47-9; Rheumon i.m.) and flufenamic acid (FLU, CAS 530-78-9) were investigated in plasma, synovial fluid, and tissues after single intramuscular application of etofenamate to patients with rheumatoid arthritis. 62 patients with indicated operative procedure in the knee-joint received a single dose of etofenamate dissolved in oil before operation. At definite times between 1.5 and 48 h post injectionem samples from 6 patients of each time group were collected. Samples of plasma, synovial fluid, synovial membrane, muscle, bone, hyaline cartilage, and fat tissue and in some cases meniscus cartilage were taken. Concentrations of ETO and its active metabolite, FLU, were determined by HPTLC. In all tissues investigated, concentration/time courses of ETO and FLU were observed. ETO and FLU were measured first in all matrices 1.5 h at the latest 3 h post injectionem. Pharmacokinetics in tissues follows that in plasma. Rate-limiting step is the liberation of drug from the oil depot. For a long period pharmacokinetics of ETO and FLU is mainly determined by the constant liberation from the oil depot (zero order kinetics of liberation). Zero order kinetics is deduced from the linear ascent of the cumulated AUC (in percent) vs. time plot. It is directly related to the liberation of drug from the galenical formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

[Anti-inflammatory and analgesic activity of etofenamate after intramuscular injection in laboratory animals].

Antiphlogistic and Analgetic Activity of Etofenamate in Laboratory Animals after Intramuscular Administration by injection of an oily solution of 10.5; 15; 19.5 mg etofenamate/kg body weight it was possible to inhibit the development of the carrageenan edema in the rat paw. Even four days after the single i.m. injection of etofenamate (active substance of Rheumon i.m.) the swelling of the rat paw is effectively prevented. By the Randall-Selitto-analgesia test it was possible to demonstrate the fast onset. Already 1 h after the injection of 15 mg/kg the pain threshold is increased to about 60%. Even in this testsystem the prolonged efficacy of oil diluted etofenamate can be found.

Animals↗
PubMed1990

[Animal experimental evidence of the long-lasting efficacy of etofenamate by prolongation of the half-life after intramuscular application].

Animal Experimental Evidence of Long-lasting Liberation of Etofenamate by Half-life Prolongation after Intramuscular Application. The purpose of this investigation was to show in animal experiments that by i.m. injection of etofenamate (active substance of Rheumon i.m.) in oily solution the following effects could be obtained: a fast onset of action (gain of therapeutically relevant drug levels shortly after injection) a long-lasting efficacy (prolonged liberation from the oil depot) and better tolerability as compared to other intramuscularly applicable antiinflammatory drugs (avoidance of high plasma spikes). Etofenamate in rats is liberated with a half-life of 1.29 days from the place of application (cutaneous half-life 8.5 h). Flufenamic acid in muscles is found only in traces. After i.m. administration of etofenamate to dogs maximum plasma levels of etofenamate and flufenamic acid were reached within 2 and 4 h, resp. The mean half-lives of plasma elimination are 14 h for etofenamate and 23.2 h for flufenamic acid formed esterolytically from etofenamate (flufenamic acid oral half-life 2-4 h). Maximum plasma levels after etofenamate are only 6.5-11.8% of the maximum levels after equivalent amounts of flufenamic acid administered orally. According to these data etofenamate i.m. is a drug formulation with fast increasing plasma levels, prolonged half-life and lower maximum plasma levels as compared to orally administered preparations. The results are confirmed in animals (pharmacodynamics, toxicology and tolerability) and man (kinetics, clinical studies).

Administration, Oral↗
PubMed1990

[Plasma level studies in volunteers after intramuscular injection of various doses of etofenamate in an oily solution].

Plasma level Studies on Volunteers after Intramuscular Application of Different Doses of Etofenamate in Oily Solution. After i.m. injections of etofenamate (active substance of Rheumon i.m.) in oily solution to 12 volunteers, courses of plasma levels of etofenamate, flufenamic acid and fenamate (sum of etofenamate and flufenamic acid) were measured by HPTLC. Maximum levels of etofenamate, flufenamic acid and fenamate, as well as areas under the plasma level time curve (AUC) after 250, 500 and 1000 mg etofenamate respectively are proportional to dose. Maxima of fenamate plasma levels are reached after 6.3, 6.2 and 5.4 h respectively, half maximal levels are present already after 2 h. The mean residence time is 21.8, 18.8 and 15.7 h. These values obtained from different doses are not statistically different from each other. Pharmacokinetics are therefore linear and dose independent. The courses of fenamate levels can be described by a two compartment model. The elimination half lives after 250, 500 and 1000 mg are 2.1, 2.3 and 1.9 h, the invasion half-lives (dominant half-life) 8.8, 7.8 and 6.8 h. Terminal half-lives are 50.3, 63.7 and 35.4 h. Since plasma levels have decreased to 2% of the maximum level after one terminal half-life, they have no practical importance for the duration of activity or for accumulation. No sex related differences are found for dose dependent and independent parameters. From the data it can be derived that after i.m. injection of etofenamate in oily solution a prolongation of the dominant half-life occurs by a factor of 4-5 (as compared to oral data) which is caused by prolonged liberation from the oily depot. This long lasting liberation of etofenamate leads to a prolonged residence time after a fast increase, at the same time avoiding unnecessary high peak levels. Therefore it is guaranteed that even after i.m. administration of 1000 mg etofenamate in oily solution plasma levels of fenamate do not exceed those after 300 mg given orally. According to pharmacokinetic data a fast onset of action, good tolerability and a therapeutic action over a period of 24 h can be expected.

Adult↗
PubMed1990

[Renal elimination and metabolism of etofenamate in volunteers after administration of various doses].

Renal Elimination and Metabolism of Etofenamate after Intramuscular Administration of Different Doses to volunteers. Renal elimination of etofenamate (active substance of Rheumon i.m.) after i.m. injection of oily solution of etofenamate to volunteers was investigated by HPTLC and GC. After injection of 250, 500 and 1000 mg etofenamate, free and conjugated flufenamic acid (flu), 5-hydroxy- and 4'-hydroxy flufenamic acid (5-OH-flu, 4'-OH-flu) were found as main metabolites in urine. Besides that several minor metabolites were identified. The ratio of free to conjugated metabolites was 1:10 to 1:25. From the doses administered 30% were eliminated as main metabolites. Overall amounts (in mg) of the eliminated metabolites and the doses correlated with each other (r = 0.9334), whereas the percent ratio of 5-OH-flu and of 4'-OH-flu increased with dose. Half lives of renal elimination for flu, 5-OH-flu and 4'-OH-flu are largely independent of dose. The half life of flufenamic acid corresponds roughly to data from plasma levels (7-9 h), the two hydroxy derivatives are eliminated into urine with half lives from 15 to 24 h. The results show, that i.m. injection of an oily etofenamate solution follows a linear dose independent kinetic, while the amounts absorbed and renally eliminated are proportional to dose. The results correspond to plasma level studies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

[Acemetacin in patients with rheumatic disease with concomitant liver diseases. Pharmacokinetics, effectiveness and tolerance].

10 male patients suffering from rheumatic diseases and from a liver disease (fat liver, cirrhosis) received acemetacin (Rantudil forte capsules) t.i.d. for 10 days. Blood levels were measured on days 2, 4, 7 and 9, 2 and 4 hours after the administration at noon, as well as after the last dose (day 10) during a 48 hours elimination period. The following kinetic parameters were determined: maximal blood level (cmax), elimination half life (during the 48 hours elimination period), area under the blood level time curve (AUC). Values are compared to corresponding data of rheumatic patients and healthy volunteers. Daily doses were 180 mg acemetacin each. Mean maximal blood levels (cmax) were 1.51 +/- 0.19 (rheumatic patients with liver diseases), 1.85 +/- 0.33 (rheumatic patients without liver diseases) and 1.24 +/- 0.05 mumol/l (healthy volunteers). Elimination half lives are 4.63 +/- 2.25, 4.52 +/- 2.81 and 4.03 hours. AUC-values were in the same range for rheumatic patients with liver diseases (11.62 +/- 5.56) and volunteers after Rantudil forte (14.30 +/- 8.79) or Rantudil retard (12.52 +/- 5.90 mumol.l-1.h). Toxic or infective liver damage therefore does not substantially change kinetics of acemetacin. The drug was efficient and well tolerated in all patients. There were no hints as for a special risk for patients with liver damage taking this drug.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1986

Quantitative determination of acemetacin and its metabolite indometacin in blood and plasma by column liquid chromatography.

A column liquid chromatographic (LC) method using UV detection for the determination of acemetacin and its metabolite indometacin in blood is described. The lower detection limit for both compounds is ca. 25 micrograms/l, the precision (coefficient of variation) is 6% for acemetacin and 10% for indometacin. The method is also suited for determination of both compounds in plasma, precisions in this case are even better than for blood, i.e. around 3% for both acemetacin and indometacin. Blood samples of three volunteers who had received 90 mg of acemetacin orally were analysed using the new method and very good agreement with results from a thin-layer chromatographic/fluorescence method was found.

Biological Availability↗
PubMed1986

[Retard effect of acemetacin from a commercial preparation--kinetics in humans following single and multiple administration].

Acemetacin was given to 14 volunteers in a randomized cross-over arrangement as one single administration of 90 mg (1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxyacetic acid) (as Rantudil, Rantudil forte and Rantudil retard) and the courses of blood levels curves compared. Half-life of absorption was considerably higher with the retard formulation (2.01 instead of 0.58 h). The blood level maximum (tmax) was significantly (p less than 0.05) delayed by the retardation, blood levels were lower after 2 h (p less than 0.01), not significantly different 3-4 h after administration and higher (p less than 0.05) than the immediate release form after 6-10 h. AUC's are 5.82 +/- 4.04 (normal) and 6.75 +/- 3.24 (mumol X l-1 X h retarded). The mean residence time was prolonged from 4.1 to 6.3 h, yielding a sustained release quotient of 1.54. After multiple administration (2 retard capsules/d for 8 d) cmax corresponded to the results obtained after single application, maximum levels at 1.24 mumol X l-1 (mean) being somewhat higher than after single application (1.11 mumol X l-1), which is the usual steady-state behavior. Minimum levels in the steady-state (cmin) were 0.24-0.53 mumol X l-1. Bioavailability (AUC's between applications) was not significantly different. No accumulation was found. Levels measured during 8 days of administration of the Rantudil retard formulation corresponded to blood levels from computer simulations. Biological half-life was 4.03 h, which was similar to data obtained with Rantudil (3 X 60 mg/d) in rheumatic patients.

Delayed-Action Preparations↗
PubMed1984

[Biochemical studies on tienocarbine and related compounds].

Tienocarbine (1,9-dimethyl-7,8,9,10-tetrahydrothieno[3,2-e] pyrido[4,3-b] indole lactate) in oral doses of 10 mg X kg-1 lowers dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striata of rats without influencing contents of biogenic amines; this points to a reduced dopamine (DA) turnover. This effect is still present after 28 days of daily application. At the same time the serotonin (5-HT) turnover is not influenced. Tienocarbine displaces 3H-DA and 3H-spiperone from their specific binding sites in the nucleus caudatus of calf brain. Structural variation results in preponderance of either dopamineagonistic (turnover lowered) or antagonistic (turnover increased) properties of the molecules. The whole class of compounds therefore can be considered as mixed dopamine agonists-antagonists.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

[Pharmacokinetics of tienocarbine in rats].

1,9-Dimethyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b] indole lactate (tienocarbine) 1, is absorbed and distributed very fast after a single oral or i.v. dose in rats. Half-lives (beta-phase) (i.v./p.o.) 1.9 and 2.2 h, respectively, VD 6.1/6.4 l/kg, oral bioavailability approx. 50%. After dosage for 28 days (2.5 mg/kg/d) all organs investigated contained tienocarbine, the N-desmethyl derivate was also found in lung and kidneys. 3 days after the last dose no 1 could be found in any organ. The quotient brain/blood is approx. 31 after single or repeated doses. With these low values of VD, the high brain/blood ratio and the constancy of these values tienocarbine differs from many other CNS active substances. 1 is intensively metabolised in rats; unchanged substance was found neither in urine nor in feces. Besides the N-desmethyl derivative, several as yet not identified metabolites occur.

Animals↗
PubMed1982

[Pharmacokinetics of Morocromen in animals and man (author's transl)].

Investigations in animals (rat, rabbit, dog) and man show, that N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl]-4-morpholinocarboxamide (morocromen) is absorbed fast and is found as unchanged substance in organs (highest concentration in liver and kidneys, low concentration in brain), blood, bile, urine, saliva, sweat and feces. Extent of absorption, metabolisation and half-life are species-dependent. Five metabolites were found in rat, three in dogs and two in traces in man. After oral application unchanged morocromen is excreted renally by rat, dog and man (14, 18 and 54--64%, respectively). Renal elimination is pH-dependent, but not dependent on sex, dosis and urine volume. Oral bioavailability is approx. 60% in dogs, 67--79% in man. Elimination half-life (blood) is approx. 2 h in dogs, 3--4 hr in man. Organ distribution studies in animals and elimination studies in man (1 to 30 applications) give no hint for accumulation or enzyme induction. Morocromen is distinctly different from carbocromen by a longer biological half-life, by distribution and elimination as mostly unchanged drug and by a better bioavailability.

Animals↗
PubMed1981

[Gas-liquid chromatographic determination of etofenamate/ Determination, method and use in biological material (author's transl)].

Etofenamate in biological specimen can be determined by gas-liquid chromatography with etofenamate benzyl ether as internal standard. Determination in urine is done directly after extraction and concentration, whereas plasma and homogenates from organs have to be prepurified by thin-layer chromatography. Unchanged etofenamate is found in small amounts in human urine (0--4, 6--6, 6--8 h p. appl.). Inflamed rat paws after local application contain up to 75 microgram etofenamate/g in comparison to only 2 microgram flufenamic acid/g tissue. Both compounds are also found in non-inflamed paws, contents being only 3--4% as compared to the inflamed tissue. Elimination of etofenamate from the inflamed area occurs with a half-life of approx. 8.5 h. These results from gas-liquid chromatography correspond to results from t.l.c./fluorescence measurements.

Animals↗
PubMed1981

[Studies on metabolism and elimination of etofenamate by dogs (author's transl)].

Renal elimination of etofenamate was studied after oral (200--1200 mg/kg) and intravenous (75 mg/kg) application to dogs. Free flufenamic acid and total fenamates (except phenolic metabolites) were determined. In accordance with other N-arylanthranilic acid derivatives after etofenamate only small amounts are renally eliminated; these results are specific for dog and differ to other animal species. Renally eliminated amounts (up to 8%) are not dependent on dose, the i.v. results also being in the same range. Proportions of free flufenamic acid is small in comparison to total fenamates. Renal elimination occurs preferentially on the first day after application. Biliary elimination of etofenamate and its metabolites was investigated after intravenous as well as intragastric application. Intact etofenamate was found after i.v. and i.g. application, part of it being conjugated. Hydroxyderivatives of Etofenamate (eto) were identified: 5-OH-eto (i.v. and i.g.), 4'-OH-eto (i.v.) and the 5.4'-dihydroxy-eto (i.g.). A further eto-derivative found after i.v. application could not be characterized. Amounts of flufenamic acid (flu) and its hydroxyderivatives (esp. 5-OH-flu) were increased after hydrolytic degradation. These results show that metabolic degradation does not occur primarily be conversion to flufenamic acid; etofenamate itself is degraded by hydroxylation and/or conjugation and subsequent formation of the corresponding flufenamic derivatives.

Animals↗
PubMed1981

[Metabolism of etofenamate / Identification and analytic of metabolites, their pharmacological properties and species dependence of metabolism (author's transl)].

After oral application of etofenamate to animals (rat, rabbit, dog, monkey) unchanged etofenamate and numerous metabolites are found in urine. Analytical properties (thin-layer chromatographic behavior, UV- and fluorescence data) of etofenamate, 5-hydroxy-, 4'-hydroxy, 5,4'-dihydroxy-etofenamate, flufenamic acid, 5-hydroxy-, 4'-hydroxy-, 5,4'-dihydroxy-flufenamic acid are described. Derivatives of etofenamate and flufenamic acid are excreted by rabbit, dog, monkey and man, whereas flufenamic acid derivatives are excreted preferentially by rats; profound degradation takes place in dogs. Metabolism in man is more similar to monkey than to dog and rodents. Metabolic pattern after oral and cutaneous application is quite similar. The six hydroxy derivatives have no pharmacological activity--they do not contribute to the pharmacological action of the substance.

Animals↗
PubMed1981

Pharmacokinetic investigation on the dehydrodipeptide N-[2-acetylamino-3-(2-thienyl)-2-propenoyl]-tyrosine in the rat.

The dehydrodipeptide N-[2-Acetylamino-3-(2-thienyl)-2-propenoyl]-tyrosine (1) is eliminated from the plasma of the rat after i.v. application with a half-life of 12.3 min, 58.1% via the kidneys (2/3 as the free 1, 1/3 as the glucuronide), 2.8% in the faeces. After oral application, the plasma concentration of 1 is very low and 2% and 53.6% are excreted in the urine and faeces, respectively. In both cases, elimination occurs during the first day after application. Three unidentified metabolites are found in the urine. Degradation of the molecule to tyrosine does not occur as the plasma and urine levels of tyrosine are not increased. The renal elimination following either a single or repeated (90X) oral application is the proportion of the glucuronide derivative. A 50% absorption was calculated on the basis of measurements of residual amounts in the gastrointestinal tract. Fluorimetric determinations were done after TLC separation of the extracts, the analysis of the faeces was done fluorimetrically by derivatisation to the methyl ester of 1.

Animals↗