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H D Dell

Publications and source records attributed to H D Dell.

At least 37 records · Page 2Linked to original sources
PubMed1980

[Analytical methods and in vitro studies with acemetacin].

1. Analytical methods (isolation, TLC, UV-spectroscopic and preferably fluorimetric determination) of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy] acetic acid (acemetacin, TV 1322, Rantudil), its analogues, hydrolysis-products and metabolites from biological material are described. 2. Stability is also dealt with. Hydrolysis of the p-chlorobenzoyl group results in strongly fluorescing compounds and can be used in determination of acemetacin, indometacin and derivatives 3. Proof is given that in in vitro studies, such as e.g. Mizushima's protein turbidity test or the test for inhibition of prostaglandin-synthetase, only intact acemetacin (and none of its potential break-down products) is present and is active. 4. In in vitro studies, such as the inhibition of total complement and of the increase in activity of serum sulfhydryl groups, acemetacin and a series of its salts proved to be at least as effective as indometacin. 5. In comparing protein binding, acemetacin, like indometacin, is found to bind strongly to albumin. The portion of free, non-protein bound acemetacin, which thus remains available for the pharmacological action, is found to be approx. 60% higher than the corresponding portion of free indometacin.

Animals↗
PubMed1980

[On the pharmacodynamics of acemetacin (author's transl)].

Pharmacodynamic studies were carried out on (1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy]acetic acid (acemetacin, TV 1322, Rantudil), a new strongly acting non-steroidal anti-inflammatory agent for elucidation of its mechanism of action. Despite its strong anti-inflammatory activity, acemetacin is only a weak inhibitor of prostaglandin release. Release of histamine from mast cells induced by N-methylhomoanisylamine-formaldehyde condensate (compound 48/80) was strongly inhibited by acemetacin in a dose dependent manner. It was also highly effective in in vitro tests, for example, in the protein turbidity test of Mizushima. In accordance to the weak inhibition of prostaglandin release very little damage was done to the mucous membrane of the gastrointestinal tract by this anti-inflammatory agent. From these data and from the strong anti-inflammatory activity a broad therapeutic margin can be derived. Analgetic properties were shown in the benzoquinone test after oral and in the Randall-Selitto test after i.m. application. Hyperthermia caused by Pyrifer and by yeast is inhibited by acemetacin in a dose dependent manner. Corresponding to the weak influence on prostaglandin release the reduction of diuresis by acemetacin was only small. No tocolytic effect could be detected on the gravid uterus in vitro. Function of the heart (isolated heart of guinea-pig) was unaffected, but we registered an increase in sytolic and diastolic blood pressures in the anesthetized dog. Correspondingly, left ventricular pressure also increased, these changes were accompanied by bradycardia. Coronary flow, peripheral flow and dp/dt did not change, only the pressure in the right atrium rose slightly. In cats, acemetacin caused a short-lasting decrease in the arterial blood pressure. Effects on CNS were not found. Smooth muscles (bronchial/intestinal) were not influenced by acemetacin. Like many non-steroidal anti-inflammatory compounds acemetacin inhibits also platelet aggregation. Motility of animals was lowered. In a granuloma pouch test a strong anti-inflammatory action was shown in vivo even without metabolic degradation of acemetacin. For the explanation of the anti-inflammatory action several mechanisms have to be taken into account.

Animals↗
PubMed1980

[Anti-inflammatory action of acemetacin (author's transl)].

The anti-inflammatory efficacy of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy]acetic acid (acemetacin, TV 1322, Rantudil) a new non-steroidal anti-inflammatory agent, is described. The stronger inhibition of inflammation in kaolin-induced edema of the rat paw could experimentally be proved with the new compound in comparison with a series of marketed anti-inflammatory agents. Acemetacin is highly effective following both oral and parenteral administration. Following provocation of inflammation in the rat paw by a series of other different agents acemetacin was more strongly effective than indometacin following oral administration. Clear advantage of acemetacin as against indometacin were shown after influencing Freund's adjuvant induced arthritis. In local inflammation too, for example in the wool pellet test, the development of granulation tissue and exudate was inhibited to the same extent as following application of corticosteroid. Both skin erythema and dye-stuff spreading by inhibition of hyaluronidase were antagonised. From the results obtained with acemetacin in numerous inflammatory models conclusion can be drawn as to the multiple sites of action in the reaction chain of inflammation.

Animals↗
PubMed1980

[Metabolism and pharmacokinetics of acemetacin in man (author's transl)].

Metabolism and pharmacokinetics of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy]-acetic acid (acemetacin, TV 1322, Rantudil) in comparison to equimolar doses of indometacin was investigated in human volunteers after a single oral application and in rheumatic patients after multiple application. After multiple application (t.i.d. for 10 days) of equimolar doses of acemetacin and indometacin, mean blood level curves. The bioavailability of acemetacin derived from these data, corresponds to that of indometacin, i.e., approx. 100%, whereas after a single dose bioavailability of acemetcin is found to be smaller (66% from blood level, 64% from urine). This difference between single and multiple application is explained by slow filling-up of compartments. Degradation of acemetacin occurs by esterolytic cleavage to indometacin, by O-demethylation and N-desacylation and by partial conjugation of all these compounds to glucuronic acid. Blood level ratios of acemetacin and indometacin are equal after single and after multiple application of acemetacin. Therefore, degradation of acemetacin is not induced after multiple application. After a steady-state has been reached half-life of elimination is 4.5 +/- 2.8 h, which is longer than for indometacin (2.2 +/- 0.5 h). Interindividual differences are in the same range as described for indometacin.

Anti-Inflammatory Agents↗
PubMed1980

[Toxicology of acemetacin].

Acute toxicity (DL50) of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy]-acetic acid (acemetacin, TV 1322, Rantudil) was determined following different forms of application and in various animal species. Acemetacin was tolerated better than indometacin in all cases. Taking into consideration the anti-inflammatory effect (DE50 kaolin edema) a better therapeutic spectrum of acemetacin could be proved compared to a number of other anti-inflammatory agents on the market. The toxicity was typical for the symptoms of non-steroidal anti-inflammatory agents. During 6 months of chronic feeding studies in rats and monkeys better tolerance of acemetacin was observed. teratogenic effects in rats and rabbits were not traceable.

Aging↗
PubMed1977

[Analysis of etofenamate. Particular determination in biological material (author's transl)].

The determination of 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate, active principle of Rheumon gel) following its isolation from biological material is reported. Depending on the method of extraction etofenamate, free and alkali-labile conjugated flufenamic acid, total conjugates or the sum of CF3-containing compounds (sum of metabolites) are isolated. Separation is achieved by TLC, quantitative determination is made by degradation to flufenamic acid and fluorimetric measurement in CCl4/trichloracetic acid at 372/445 nm. Etofenamate can be identified by TLC, derivatisation, UV- and fluorescence spectroscopy and differentiated from its metabolites. It is demonstrated that etofenamate is the main component of fenamates in inflamed tissue.

Animals↗
PubMed1977

[Pharmacology and toxicology of etofenamate. 1st Communication (author's transl)].

1. The reliable antiphlogistic action of 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate active principle of Rheumon Gel) in various experimental inflammatory models in animals is demonstrated following oral and cutaneous administration. 2. The proven inhibition of inflammatory edema by chronic administration of Rheumon gel evidences the percutaneous absorption of the active principle through the intact skin. 3. The effect of Rheumon gel sets in independently of whether the gel is applied to normal or to pathologically inflamed tissue areas. 4. Gastrointestinal mucous tolerance is better for etofenamate than for flufenamic acid, phenylbutazone and other anti-inflammatory drugs.

Animals↗
PubMed1977

[Pharmacology and toxicology of etofenamate. 2].

1. Since the anti-inflammatory effect of 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)anthranilate (etofenamate, TVX 485, Rheumon Gel) is occasionally stronger than that of flufenamic acid and as its toxicity is in the same range as that of the latter, a wider therapeutic margin may be expected for etofenamate in therapeutic use of Rheumon gel. 2. In subchronic oral administration, rats tolerated 22 mg/kg and dogs 100 mg/kg without any signs of toxicity. Sub-chronic cutaneous administration of Rheumon gel in pigs (2 g/kg) likewise showed no signs of toxicity. Thus, an adequate safety factor would seem to exist, bearing in mind the comparative daily dose in man of approx. 0.3 g gel/kg body weight. In histological tests oedema of kidney papillas or degeneration of papillas, respectively, could not be seen. 3. In the dose range tested, etofenamate shows no signs of teratogenic or fetotoxic effects in either rats or rabbits. 4. The evidence of the cutaneous absorption of etofenamate from Rheumon gel could be demonstrated by the biological effect in animal experiments.

Animals↗
PubMed1976

[Proceedings: Age and sex specificity of organ distribution and metabolism of chlorprothixene and nortriptyline in the rat (author's transl)].

Chlorprothixene and its N-desmethyl derivative are found to be present in the brain, liver, kidneys and lungs of young animals in larger quantities and for a longer period of time than in older animals. The N-demethylation rate is significantly higher in the brain, liver, kidney and lungs of older animals than of young animals. In general, female animals show higher levels in the organs. The "youth dependent" hyper-content exceeds that of the older animals by the factor of appr. 2. For nortriptyline there is an inverse ratio, with more nortriptyline and desmethylnortriptyline in the older animals than in the young ones. The organ content is also higher in the females than in the males. The "age-dependent" hyper-content exceeds that of the younger animals by the factor of appr. 2. These results correspond roughly with the differences in toxicity.

Aging↗
PubMed1975

[Placental transfer of psychotherapeutics of the thioxanthene type (author's transl)].

The hitherto existing investigations on the placental transfer of psycholeptic drugs mostly do not answer the question whether the active compounds themselves or their metabolites or both get into the fetus. As published informations on this problem partly are contradictory the placental transfer of psycholeptic drugs was investigated with the thioxanthenes flupentixol and chlorprothixen for examples. After oral application to rats on the 15th and 20th days of gestation the intact thioxenthenes themselves as well as their sulfoxides and desalkylated metabolites were detectable in placenta, uterus and fetus. The last mentioned substances and the intact thioxanthenes were determined quantitatively. The concentration (mug/g tissue) in the fetus is lower than in uterus and placenta. The results are discussed.

Animals↗