[Effect of additives on the amination of 2-oxoglutaric acid by gamma-radiation].

The effect of added substances was studied on the yield of glutamic acid produced by gamma-ray irradiation of 2-oxoglutaric acid and ammonia in aqueous solution. The contents of amino acids in the irradiated solutions were determined with amino acids analyzer. Sodium nitrate, allyl alcohol or sodium formate was used as an added substance. The yield of glutamic acid significantly decreased by the addition of nitrate, and it was little affected by the addition of allyl alcohol. In the presence of formate the yield increased from G = 0.4 (2-oxoglutaric acid 0.05M and ammonium hydroxide 2M) to G = 1.1. As a result, it was found that hydrated electron contributes on the formation of glutamic acid, but hydroxyl radical does not. The yield showed a maximum at ca. 0.1 M ammonium hydroxide concentration. These facts indicate that NH2 radical does not contribute to the formation of glutamic acid. As a reaction mechanism, it can be explained that 2-oxoglutaric acid which had been reduced by hydrated electron reacts with ammonia.


[Radiolysis of benzyl alcohol in aqueous solution].

Radiolysis of 0.05% aqueous solution of benzyl alcohol with 50Co gamma-rays ranging from 1 X 10(4) to 7 X 10(5) rad was investigated, in order to presume the change of it contained in radiopharmaceuticals. For both O2 free and oxygenated solutions, an approximately linear relationship holds between the retaining benzyl alcohol and dose in the range from 1 X 10(5) to 7 X 10(5) rads. The G(-M) values of benzyl alcohol calculated from the relation were 2.34 in the absence and 1.92 in presence of oxygen. In the presence of oxygen, a main product was benzaldehyde and its G value was 0.87. In the absence of oxygen, the main products of the radiolysis were dibenzyl, benzyl phenylcalbinol and hydrobenzoin, which were regarded as the radicao-reaction products of PhCH2 and PhCHOH, and the yield of benzaldehyde was negligible. Irrespective of the presence of oxygen, o- and p-hhdroxylated products of benzyl alcohol were found only in small quantity.


[Whole body autoradiography with 201Tl and clinical results].

Thallium-201 has been suggested as a useful diagnostic agent for myocardial scanning. We report herewith the clinical usefulness of Tl-201 as a result of our animal studies with rats as well as clinical trial for human being. After intravenous injection, we killed rats at regular intervals, then measured the activity in each anatomized organ by gamma-well counter and observed the internal distribution and examined autoradiograms with the naked eye. As a result, the accumulation of Tl=201 in the myocardium observed in 5 min after injection, reaching the maximum level in 30 min and gradually decreased hereafter. We performed 22 myocardial clinical scans. In adults we could clearly detect the lesion of myocardial infarction, but in children found it difficult to obtain full sufficient information due to small heart size and high pulse rate. Judging from the foregoing we think it possible to obtain much clearer images by using a data analyzer.


[Computer processing of radioisotope images. Hybrid processing system].

A hydrid type image file and processing system are devised by the author to file and the radioisotope image processing with analog display. This system has some functions as follows: 1) Ten thousand images can be stored in 60 feets length video-tape-recorder (VTR) tape. 2) Maximum of an image on the VTR tape is within 15 sec. 3) An image display enabled by the analog memory, which has brightness more than 15 gray levels. 4) By using the analog memories, effective image processing can be done by the small computer. 5) Many signal sources can be inputted into the hybrid system. This system can be applied many fields to both routine works and multi-purpose radioisotope image processing.


[Diagnosis of cold thyroid nodules by 201T1 scientigraphy].

Fifty two patients with cold thyroid nodule demonstrated on the thyroid scan were imaged with 201Tl which were given intravenously as thallium chloride in dose of 2 mCi. Thirty nine of 52 patients were confirmed and investigated whether 201Tl concentrated or not. Fourteen of 15 (93 percent) thyroid carcinomas, 5 of 17 (29 percent) thyroid adenomas, 1 of 2 adenomatous goiters and all of 5 of chronic thyroiditis were visualized as positive with 201 Tl. One thyroid carcinoma did not concentrate 201Tl which was confirmed to have cystic degeneration. Of the 19 benign cold thyroid nodules except chronic thyroiditis 6 were positively visualized with 201Tl. However, 201Tl did not accumulate in the other 13 benign nodules, 11 out of which were confirmed to have cystic degeneration. The data suggests that if the thyroid nodule is found to have negative accumulation of 201Tl, malignancy can be ruled out except a small microscopical lesion.


The thyroid reserve in patients with breast cancer.

Patients with breast cancer were studied with regard to changes in the levels of serum thyroxine (T4) and serum triidothyronine (T3) after intramuscular administration of TSH for three days to investigate the thyroid reserve in these patients. The changes were examined also in normal subjects, in patients with Hashimoto's thyroiditis and primary hypothyroidism. In primary hypothyroidism no increase was seen in serum T4 and T3 levels after TSH administration, and the thyroid reserve was considered to be absent. In Hashimoto's thyroiditis the serum T3 levels after TSH administration were the same as in normal subjects, but the serum T4 levels were significantly lower than normal. This suggests that in patients with Hashimoto's thyroiditis the thyroid reserve is decreased and is in a state of so-called low thyroid reserve. In patients with breast cancer, however, the levels of serum T4 and T3 showed no difference as compared with those in normal subjects after TSH administration, and this implies that the thyroid reserve is well maintained.


Diagnosis and treatment of "verminous aneurysm" formation in the horse.

The clinical manifestations, diagnosis and differential diagnosis of "verminous aneurysm" formation at the root of the cranial mesenteric artery and coeliac artery resulting from Strongylus vulgaris larvae migration are described. Forty-nine of 57 cases were successfully treated with low molecular weight dextran (dextran 70).


[Homologous and heterologous antibody induction in influenzal infection and immunization].

Serological examinations were carried out in 72 patients with influenza and 384 volunteers immunized with a vaccine from different strains of influenza A virus. A high level of antibody (greater than 1:64) was found to protect against influenza infection by a homologous strain as well as strains with certain immunologic affinity in the main virus structures, hemagglutinin and neuraminidase.


[Meniscus lesions (author's transl)].

Pathogenesis, pathological anatomy, diagnosis and therapy of meniscus lesions especially by soccer players and other sportsmen are represented. However, soccer has by far the highest percentage of incidence of meniscus lesions. Because the efficiency of the knee after meniscectomy is decreased, maintenance and restitution of adequate quadriceps strength are important for an uneventful postoperative course. As far as possible an individual after-care and excerise programme have to be made. Some aspects of pathogenesis of arthrosis deformans after meniscectomy are shortly discussed. The author points to the functional union of the femoro-tibial and femoro-patellar part of the knee joint.


[Registration of cytostatic effects on cultured cells in vitro and their current significance for individualized chemotherapy of tumors in advanced ovarian carcinoma].

In vitro tests of cell cultures have revealed individual responses of ovarian carcinomas to various cytostatic agents, the most effective ones being cyclophosphamide and trenimon. The role of pretherapeutical sensibilization tests for the chemotherapy of advanced ovarian carcinomas was investigated in a controlled clinical trial as part of a cooperative study. The survival curves of patients treated individually according to the given test result were at any time more favourable than those of a group nonindividually treated with trenimon. No significance between the two curves could be demonstrated on the basis of our preliminary results.


The prediction of fetal maturity: a comparison between the bubble stability test and cytological evaluation of maturity.

Amniotic fluid from fifty women soon to be delivered, or already in labour, was analysed in the Obstetric unit of University Teaching Hospital, Lusaka. A Bubble Stability Test (Clements et al, 1972) and cytological screening for maturity (Sharma & Trussell, 1970) was carried out on each specimen. The latter test has been routinely used in the Obstetric unit for three years. The intent was to discover which test was the most useful indicator of fetal maturity.


The influence of hypophysectomy on NSILA concentrations in the dog: evidence for partially pituitary-independent regulation.

Non-suppressible insulin-like activity (NSILA) was determined in 5 dogs before and after hypophysectomy. All NSILA determinations were carried out on serum samples after acidic Sephadex G-50 chromatography by two different assay systems, i.e. a bioassay and a protein binding assay. The levels of NSILA decreased significantly after hypophysectomy and returned to near normal levels after 2 weeks. T3-, T4- and cortisol levels were drastically reduced during the entire period of the experiment. Several GH determinations after hypophysectomy revealed very low levels. Insulin-induced hypoglycaemia failed to provoke a rise of GH levels as late as 4 months after hypophysectomy. These findings indicate that: 1) The pituitary gland cannot be the site of synthesis of NSILA. 2) NSILA concentrations in the dog are maintained at a near normal level in the presence of very low growth hormone and thyroid hormone concentrations, so that these latter hormones do not appear to be the only regulatory factors concerned in NSILA synthesis.


The effect of 1,25-dihydroxycholecalciferol on the parathyroid hormone secretion of porcine parathyroid glands and human parathyroid adenomas in vitro.

The effect of 1,25-dihydroxycholecalciferol (1,25-(OH)2-D3) on parathyroid hormone secretion by porcine parathyroid glands and human parathyroid adenoma tissue was investigated by in vitro incubation. The addition of 100 nmoles 1,25-(OH)2-D3 to the medium inhibited significantly the release of immunoreactive parathyroid hormone by 63--65%. This suppression was reversible when 1,25-(OH)2-D3 was removed again. The inhibition of parathyroid hormone release observed in human parathyroid adenoma tissue was similar to that in normal porcine parathyroid glands. This indicates that adenoma tissue is sensitive to regulatory influences. As well as calcium, 1,25-(OH)2-D3 may act as another feedback inhibitor of parathyroid hormone secretion.


The effect of a placental mammotrophin and cortisol on the ultrastructure of rat mammary gland in organ culture.

Mammary gland explants obtained from 13 days pregnant rats were cultured for 3, 6 and 9 days in the presence of serum of either virgin rats or 13 days pregnant rats. Insulin was added alone or in combination with cortisol. The way these different forms of treatment affected the ultrastructure was studied. With virgin rat serum plus insulin alone the mammary gland regressed to a lower state of development comparable to that of the virgin rat in vivo. When virgin rat serum was replaced by 13 days pregnant rat serum--which contains rat chorionic mammotrophin--the initial development was maintained, but synthesis of secretory products ceased. When cortisol was added to the virgin rat serum plus insulin, cortisol maintained the differentiated state originally present. Even some secretory activity was induced, but at a minimal level. With cortisol added to the pregnant rat serum plus insulin, the explants were stimulated to synthetize the extrude secretion products.


Metabolic and hormonal effects of post-menopausal oestrogen replacement treatment. I. Glucose, insulin and human growth hormone levels during oral glucose tolerance tests.

Glucose, insulin and growth hormone (GH) levels were measured during 3h oral glucose tolerance tests, performed in two groups of post-menopausal women. Nineteen subjects were given ethinyloestradiol (EOe) 0.05 mg daily and 20 received oestradiol valerinate (OeV) 2 mg daily. The tests were performed twice before treatment and after 1, 3 and 6 cycles of medication. EOe induced a slight but statistically significant deterioration of the glucose tolerance concomitant with a tendency to elevated insulin levels. The women taking OeV showed no significant alteration of the glucose or insulin levels. The GH concentrations were increased in both groups although the elevation was more pronounced in those taking EOe. The reduced carbohydrate tolerance was not believed to have been responsible for the raised GH levels.


Plasma 20 alpha-dihydroprogesterone, progesterone and 17-hydroxyprogesterone in normal human pregnancy.

The peripheral plasma levels of 20alpha-dihydroprogesterone (20alpha-DHP), progesterone (P) and 17-hydroxyprogesterone (17-OHP) were measured by radioimmunoassay techniques in 440 samples during normal human pregnancy between weeks 4 and 41. The levels of 20alpha--DHP in plasma from the 4th to the 6th week were between 6.0 and 6.6 ng/ml. From then until the 21st week the average plasma 20alpha-DHP concentrations remained at the same level between 4.0 and 6.3 ng/ml; they then rose significantly to and beyond term, levels reaching over 40 ng/ml. The range of mean plasma concentration of P during the first trimester of pregnancy fell to a nadir in the 9th week (170 ng/ml) then rose with increased gestation until the 39th week (190.4 ng/ml) followed by a slight and not significant drop. Single measurements of plasma 17--OHP from the 4th to the 6th week of pregnancy gave value between 2.8 and 3.6 ng/ml, but from the 7th week the mean plasma 17--OHP levels gradually declined, then from week 30 the 17-OHP concentration increased to reach a mean level of 7.63 ng/ml in the 41st week. The ratio P/20alpha--DHP increased from the 4th (3.5:1) to the 24th week (15.6:1) and then decreased from 25th week (7.9:1) towards term (3.2:1).


Serum gonadotrophins, testosterone and spermatogenesis in subfertile men.

In 210 subfertile men there existed a significant positive correlation between serum FSH and LH (0.41). No correlation was observed between the gonadotrophin levels and testosterone. In contrast to this FSH as well as LH were negatively correlated with the natural logarithm (ln) of the sperm count/ml ejacate (-0.44 and -0.18, respectively). When the positive correlation which existed between FSH and LH was used to calculate partial correlation coefficients, the coefficient between FSH and ln sperm count did hardly change (-0.41) the coefficient between LH and ln sperm count on the other hand became insignificant (-0.05). This suggests that spermatogenesis influences FSH serum levels in subfertile men by a decreased suppression when sperm production is diminished. Testicular biopsies taken from 97 of these patients were used to determine biopsy scores. These scores showed a significant negative correlation with FSH (-0.34) and a positive one with ln sperm count/ml ejaculate (0.45). Interestingly the biopsy score of 16 patients who fertilized their wives, was found to be higher compared with the score of the other patients who did not fertilize. The number of sperm/ml ejaculate and the FSH values of these 2 groups of biopsied patients were, however, not significantly different. This leads to the conclusion that the biopsy score is a better parameter for the evaluation of oligospermic men than either sperm count or FSH serum values.


Influence of psoralen on melatonin formation in rat pineal gland in organ culture.

8-Methoxypsoralen (10(-4) M) added to the medium of rat pineal glands in organ culture induces a five-fold increase of 14C-labelled N-acetylserotonin and melatonin formation when serotonin is used as 14C-labelled precursor. Addition of d-amphetamine (10(-5) M) to pineal glands also results in an increase of N-acetylserotonin and melatonin formation. This increase is enhanced by the addition of 8-methoxypsoralen (10(-5) M). In pineal glands pre-incubated for 24 h 8-methoxypsoralen (10(-4) M) caused an increased production of N-acetylserotonin and melatonin. This indicates that the effect of 8-methoxypsoralen is mediated through a postsynaptic event and not by release of noradrenaline or blocked re-uptake of amines to nerve terminals in the pineal gland. Further studies of the clinical significance of the effect of psoralen on pineal gland metabolism seems warranted.


Changes in insulin receptor concentration in rat fat cells following treatment with the gestagens clomegestone acetate and cyproterone acetate.

Specific insulin receptors were measured in isolated fat cells of rats after treatment with clomegestone acetate. Under conditions when peripheral insulin insensitivity was observed, the number of insulin receptors was simultaneously reduced. A similar though smaller decrease in insulin receptor concentration was seen in rats after treatment with cyproterone acetate, a compound which did not cause insulin resistance. It is concluded that the gestagenic compounds tested decrease insulin receptor concentration. Only drastic reduction of the number of binding sites results in significant perturbations of carbohydrate metabolism.


Influence of oestrogen administration in vivo and in vitro on the release and synthesis of prolactin from incubated pituitaries.

The release and synthesis of prolactin were studied in incubated adenohypophyses from ovariectomized rats. After a 4 h incubation period the prolactin concentration in the medium markedly increased whereas that in the gland was reduced. However, the concentration of prolactin in the system, tissue plus medium, after 4 h was almost twice as much as that present at the beginning of incubation indicating spontaneous synthesis. This spontaneous release and synthesis of prolactin was greatly increased in incubated glands from ovariectomized oestrogen-treated rats. Oestradiol benzoate was injected in doses of 2.5, 5.0 or 10.0 microgram/rat 2 or 24 h before killing the animals. Lower effects were obtained in glands from 2 h-oestradiol-pre-treated rats than from 24 h-oestradiol-primed rats. Oestradiol-17beta (55, 166, 500 and 1500 ng/ml) added to the incubation medium also enhanced the release and synthesis of prolactin and the effect was more marked in glands from oestrogen injected rats than in those of non-treated animals. The increase was dose-related although the higher doses were less effective. These results provide further evidence of the effect of oestrogen on the release and synthesis of prolactin by a direct action on the pituitary gland. They also show that oestradiol pre-treatment in vivo increase the response of the prolactin cells towards oestradiol in vitro.


HLA-BW35 and B5 in Japanese patients with Graves' disease.

Thirty-three Japanese patients with Graves' disease and 106 healthy controls living in the Kagoshima area, the southernmost part of the Japanese mainland, were HLA typed by the NIH method. None of them were related to each other. The only antigen showing an increased frequency in Japanese patients with Graves' disease was HLA-BW35 (corrected P less than 0.02). A decreased frequency of B5 in the patients was also statistically significant (corrected p less than 0.02).


Effects of blinding, pinealectomy and superior cervical ganglionectomy on free thyroxine index of male golden hamsters.

Blinding young male golden hamsters led to a depression of the plasma free thyroxine index after an 8 week period. Removal of either the pineal gland or the superior cervical ganglia of blind hamsters reversed the effects of blinding on free thyroxine index. No significant effects were observed 2 weeks after treatment. Previously reported effects of blinking, and removal of the pineal gland or the superior cervical ganglia on testicular weight were confirmed. A similar mechanism of pineal inhibition of thyroid function and gonadal function is suggested.


TSH and catecholamines: independent effects on active transport and iodine organification in isolated thyroid cells.

Catecholamines greatly stimulated iodine organification in thyroid cells isolated by trypsinization but failed to increase the cell-medium (C/M) ratio of 131I- or 99mTcO4- in the same cells preparation. Both TSH and catecholamines increased the concentration of organified iodine in thyroid cell despite the presence of active transport inhibitors, suggesting either the existence of a second thyroidal transport system or the possibility of an accelerated entry of anions into thyroid cells in the presence of stimulatory agents.


Comparison between the 5,6-cis and 5,6-trans isomers of 25-hydroxyvitamin D3 in chronic hypoparathyroidism.

Five patients with chronic post-operative hypoparathyroidism were treated with 450 microgram/day 5,6-trans-25-hydroxyvitamin D3 (5,6-trans-25OHD3) for 14 days, and the treatment was continued with 150 microgram/day for one year. At the end of this period the patients received 450 microgram/day 5,6-cis-25-hydroxyvitamin D3 (5,6-cis-25OHD3) for 14 days. Comparison of the effects of both isomers revealed a similar ability to enhance intestinal calcium absorption and to normalize serum calcium; serum phosphate and alkaline phosphatase, however, remained unaffected. Urinary phosphate and hydroxyproline excretion decreased on the cis-isomer and increased on the trans-isomer. During treatment with the lower dose of 5,6-trans-25OHD3 intestinal calcium absorption remained in the normal range for one year, whereas the serum calcium decreased to the levels observed before administration of 450 microgram/day within 6 weeks. The results suggest that in hypoparathyroidism 5,6-cis-25OHD3 and 5,6-trans-25OHD3 are equally effective on serum calcium and on intestinal calcium absorption, but that their mode of action on renal phosphate handling and on calcium release from bone is different.


Mammary growth and function and pituitary prolactin secretion in female nude mice.

Mammary structural growth in the wholemount preparation, content and synthesis of mammary DNA and RNA estimated by the incorporation of [3H]thymidine and [14C]uridine, pituitary and plasma levels of prolactin and weights and histological structures of some organs of female nude mice (nu/nu) were compared to those of the control (nu/+) with the same genetical background (BALB/c). Both at 3 months of age and on day 1 of lactation, the weights per 100 g body weight of adrenals, spleen and liver of nu/nu mice were significantly higher than those of nu/+ mice. Mammary growth stimulation by pituitary graft was much more marked in nu/nu mice than in nu/+ mice. Slight differences between groups were found in the pituitary and plasma levels of prolactin, in the histological structures of ovaries as well as of the adrenals and thyroids and in the pattern of oestrous cycles. On the other hand, the content and synthesis of mammary DNA at 3 months of age and content and synthesis of both DNA and RNA and RNA/DNA ratio on day 1 of lactation were significantly higher in nu/+mice than in nu/nu mice. All findings suggest that thymus deficient immunosuppression has deleterious effects on mammary growth and function without its alteration in the secretion of prolactin and oestrogen and probably through its decrease in mammary responsiveness to mammotrophins.


Variations in uterine cytosolic oestrogen and progesterone receptor levels during the rat oestrous cycle.

The levels of cytosol receptors for both oestradiol and progesterone were simultaneous monitored in the uterus at various stages of the rat oestrous cycle. The use of the synthetic gestagen R-5020, with its high specificity and affinity for the progesterone receptor, eliminated interference arising from corticosteroid binding globulin (CBG) contamination of uterine extracts. The results show that the patterns for both receptors are markedly different over the cycle. The variation can be correlated with changes in ovarian steroid output. The results also suggest that oestradiol and progesterone interact not only with their specific receptor, but also influence the other receptor system.


Cellular hypersensitivity to oral lichen planus lesions in vitro.

The purpose of the present investigation was to demonstrate in vitro cellular hypersensitivity to oral lichen planus lesions. Twenty oral lichen planus patients and 20 control persons matched by and sex were examined by the leukocyte migration agarose technique with tissue extracts from oral lichen planus lesions, normal oral mucosa and normal human kidney, the two latter extracts serving as control antigens. The female lichen planus patients showed statistically significant (P=0.004) migration inhibition with extracts from oral lichen planus lesions, which supports the hypothesis of cellular hypersensitivity to oral lichen planus lesions. However, the male lichen planus patients did not show any significant reaction. No significant reaction was found with the control antigens. The findings do not exclude the hypothesis of cellular hypersensitivity to oral lichen planus lesions. Furthermore, they do not support the hypothesis of oral lichen planus being an autoimmune disease.


Immunotherapy for grass pollenosis with allpyral allergen extracts. Improved results by objective control of treatment requirements.

Nasal provocation testing using a measured dose of dry grass pollen has been used as a method of controlling the amount of injection treatment required to achieve decreased sensitivity to grass pollen. This could seldom be shown at the usual top dose of 10,000 P.N.U., but by repeating the top dose until the reaction was negative, complete freedom from pollenosis was achieved in most cases. Strict criteria for assessment of results were used. Conventional dosage regimens produced only 27 percent excellent results, but 94 percent of those patients who became demonstrably nasal test-negative were completely or almost completely free from symptoms in the pollen season.


House dust mites in Switzerland. III. Allergenic properties of the mites.

The allergenic properties of the nine mite species prevalent in the house dust of northwestern Switzerland (Basel and surroundings) were studies. For the preparation of mite extracts, the average weight of each species was first determined and then the number per culture  glass counted. Thus the extracts were prepared according to the weight of the mites. They were tested on 115 patients with ashma and/or rhinitis. Tests with patients own house dust and with a human dander/yeast mixture, which served as culture medium for the mites, were carried out simultaneously. Test results were either positive or negative for all substances in 93 patients (80 per cent). Dermatophagoides pteronyssinus, D. farinae and Euroglyphus maynei caused the most frequent and most severe reactions. The species Glycyphagus destructor, G. privatus, Chortoglyphus arcuatus, Gohieria fusca, Tyrophagus putrescentiae and Acarus siro seem to play a less important role, if any, in house dust allergies.


Childrens' asthma register. Description of a data-system and patient material.

An asthma data register which collects annually certain data from all known local asthmatic children has been presented. The data register is utilized to make a two-page print-out for every patient, and statistics of the whole material. These data make the continuous surveillance and guidance of the patients possible. The easy-to-use and accurate data material has contributed to rationalization of routine work in an asthma clinic. Team work has also improved because the uniform data material enables various workers to quickly pick out a specific problem from the whole material. The cost, $ 2 to 3 per patient per year, is low compared with the immediate benefit. Indirect benefit is to be expected because the system helps to investigate the problems of asthmatic children.


Iron absorption from infant milk formula and the optimal level of iron supplementation.

Thirty healthy infants, aged 11-13 months, were studied with regard to the iron absorption from proprietary milk formula. The infants were divided into three groups (I-III) depending on the concentration of iron in the formula: 0.8 (I), 6.8 (II), and 12.8 (III) mg/l, respectively. The calculated amount of iron absorbed per test dose of 50 ml of milk averaged 5 microgram (I), 32 microgram (II), and 43 microgram (III). Group I differed significantly from groups II and III. No correlation was found between iron absorption and hemoglobin, MCV, serum transferrin saturation or serum ferritin within the range of normal values. Our findings suggest that at least 7 mg of iron as ferrous sulphate per litre of formula is required to prevent iron deficiency.


Pharmacokinetic studies on clopenthixol decanoate; a comparison with clopenthixol in dogs and rats.

The release from the depot, hydrolysis and distribution in the organsim as well as the metabolism and elimination of intramuscularly injected clopenthixol decanoate in Viscoleo have been studied in dogs and rats with radioactive as well as non-labelled drug after single as well as repeated administration. The studies clearly demonstrate the depot effect of clopenthixol decanoate given intramuscularly in oil compared to orally administered clopenthixol. The amounts of drug remaining at the site of injection in dogs suggest monoexponential release of drug from the depot and a half-life of 4-5 days. Rapid hydrolysis to clopenthixol in the organism was indicated by in vitro experiments and in vivo findings. Clopenthixol was found to be the main compound in the organism after single as well as repeated doses. The clopenthixol formed by hydrolysis appeared to be metabolized in the same way as clopenthixol given orally i.e. by dealkylation of the side chain and by S-oxide and N-oxide formation. The elimination pattern with predominant fecal excretion also appeared to be the same after clopenthixol and its esterified derivative apart from the reflection in the latter case of the slow release from depot. A rapid exchange in the organism between tritium from the drugs and hydrogen from the body water was demonstrated. This has to be considered in studies with tritium labelled drugs, where estimation of total radioactivity gives the sum of tritium in drug, metabolites and water.


Selenium content of tissues in Finnish infants and adults with various diseases, and studies on the effects of selenium supplementation in neuronal ceroid lipofuscinosis patients.

A low blood selenium level has previously been observed in healthy inhabitants of Finland (WESTERMARCK et al. 1977). In this study even lower blood selenium values were observed in patients with acrodermatitis enteropathica, dystrophia musculorum progressiva (Duchenne), infantile and juvenile type of neuronal ceroid lipofuscinosis (NCL), severe mental retardation caused by various factors, and myocardial infarction. The selenium content of the brain, heart, kidney and liver in patients of different ages was also determined. The highest selenium level was found in the kidney. The mean liver selenium concentrations in stillborn, premature and full-term neonates were 1.11 +/- 0.23 (8), 1.21 +/- 0.17 (12) and 0.93 +/- 0.16 microgram/g dry weight (12) respectively (the number of subjects in parentheses). The selenium values are considerably higher than those in infants of from one to nine months of age and adults, whose liver selenium values were 0.58 +/- 0.21 (8) and 0.67 +/- 0.08 microgram/g dry weight (8) respectively. The vitamin E levels of serum in patients with NCL, as well as in subjects with severe mental retardation (controls), were low compared with values in healthy normal subjects. Sodium selenite supplementation in patients with NCL produced at least a transitory improvement without causing any toxic effects during one year of administration.


Actions of neurotensin and (Gln4)-neurotensin on isolated tissues.

The actions of neurotensin and (Gln4)-neurotensin have been investigated on a number of isolated tissues. They were ineffective in contracting the guinea pig vas deferens, the rabbit aortic strip or the frog rectus abdominis muscle in concentrations up to 0.24 micron. Neurotensin and (Gln4)-neurotensin relaxed the rat duodenum at fairly high concentrations (24 nM). The guinea pig ileum contracted in response to increasing doses, although the maximum response were only one half that caused by histamine. Tachyphylaxis was observed at dose intervals of less than 12 minutes, but this tachyphylaxis did not inhibit responses to acetylcholine, histamine, 5-HT or to DMPP, suggesting that the neurotensins may act at specific receptor sites. They contracted the rat fundus strip at concentrations of 0.24 nM and higher. The neurotensins and 5-HT were approximately equipotent on this tissue, although the maximum responses was about 80% of that to 5-HT. The contractions of the rat fundus strip could not be blocked by atropine, hexamethonium, methysergide, morphine or by 7-OH-THC. These data indicate that neurotensin and (Gln4)-neurotensin are equipotent as far as smooth muscle stimulating activity is concerned. Of those organs tested, the rat fundus strip seems to be the most suitable one for studies concerning structure-activity relationships.


Increased plasma binding and decreased blood cell binding of quinidine in blood from anuric rats.

The blood cell/plasma concentration ratio of quinidine, as influenced by the plasma protein binding, was studied in normal and anuric rats by applying incubation and equilibrium dialysis techniques on blood and plasma, respectively, from normal and anuric rats. The plasma protein binding of quinidine in anuria was increased at concentrations of unbound drug of less than 1.75 X 10(-4) M and decreased above this concentration. At an assumed "therapeutic" quinidine concentration (1 X 10(-5) M), the mean concentration ratio (total quinidine in blood cells)/(total quinidine in plasma) was 1.84 in normals and 0.46 in anuria, and the mean ratio (total quinidine in blood cells)/(unbound in plasma) was 4.45 and 1.81, respectively. As the latter ratios were concentration dependent and greater than could be accounted for by pH-dependent distribution, quinidine is presumably bound in/on the blood cells. Reduced distribution ratio in anuria, even when related to unbound quinidine in plasma, also indicates changed binding in blood cells, a finding confirmed by applying the data to modified Scatchard plot. this may have implication for the use of blood cell/plasma concentration ratio as screening procedure for the altered plasma binding of quinidine in patients.


Influence of serum protein binding on the pharmacokinetics of quinidine in normal and anuric rats.

The pharmacokinetics of quinidine were investigated in normal and anuric rats after intravenous injection (25 mg per kg b.wt.). In normal rats only 2.6% of the injected dose was excreted as unchanged quinidine in the urine. Quinidine concentrations were determined in the blood and in different tissues after injection, and the serum protein binding was measured. Results were applied to a one compartment model. In normal rats a total body clearance of 18.5 ml/min. and a renal clearance of 0.5 ml/min. was found. The residual non-renal clearance (18.0 ml/min.), presumably taking place in the liver, exceeds the estimated liver blood flow (16.8 ml/min.), indicating efficient extraction of quinidine from plasma and blood cells (non-restrictive elimination). The apparent volume of distribution was greatly reduced, biological half-life slightly longer and the body clearance greatly reduced in anuric as compared to normal rats. The fraction of unbound quinidine in serum was 30.6 +/- 0.6 (n = 23) and 16.7 +/- 0.5) (n = 23) percent in normal and anuric rats. The reduction in the apparent volume of distribution is mainly explained by increased serum binding. The decline of body clearance of quinidine is most likely caused by a decreased liver blood flow in this complex state of renal insufficiency.


Effect of fluoride on glycerol production in rat adipocytes in vitro.

The effect of 10 mM fluoride on glycerol production in vitro from rat epididymal adipocytes was investigated. Fluoride had no effect on the basal glycerol production, irrespective of the presence or absence of Ca++ and Mg++ ions. When stimulating the glycerol production with 10 mM theophylline, fluoride reduced the stimulation in the absence of either Ca++ or Mg++ or both. In the presence of both ions, fluoride had no effect on the theophylline stimulation. Fluoride also reduced the stimulative effect of adrenaline on glycerol production, but not that of glucagon. Increased adrenaline concentration could not overcome the inhibitory effect of fluoride.


Morphological lesions in guinea pigs during skin exposure to 1,1,2-trichloroethane.

Guinea pigs were exposed to 1,1,2-trichloroethane applied directly on the skin of the back for periods between 15 minutes and twelve hours under anaesthesia. Morphological changes could be observed in the epidermis after 15 minutes and continued to progress during continuing exposure. The changes consisted of pyknotic nuclei, perinuclear  oedema of basal and suprabasilar cells as well as a focal separation of the epidermis from the corium with vesicle formations. The liver tissue showed reduction of glycogen content as well as hydropic changes  in the centrilobular areas six hours after the start of exposure. The liver changes were less marked 12 hours after exposure and absent in nonanaesthetized animals. No morphological changes were observed in the kidney or the brain.


The pharmacology of a new potent, long  acting neuroleptic, piflutixol.

Piflutixol, 6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene, has been shown to have pronounced neuroleptic properties. It is a very potent inhibitor  of methylphenidate-induced stereotypies in mice, amphetamine and apomorphine-induced stereotypies in rats, apomorphine-induced stereotypies and vomiting in dogs. Furthermore piflutixol causes cataleptic reaction in small doses and inhibits conditioned avoidance reaction in rats. The compound is equally potent orally and parenterally and has a prolonged effect. Piflutixol has up to the present proved to be the most  potent inhibitor of dopamine-stimulated adenylate cyclase in rat striatum in vitro. Piflutixol has a stron sedative effect (inhibition of spontaneous motor activity, induction of ptosis and potentiation of barbiturate anaesthesia) and  in addition inhibits reticular arousal reaction in very low doses. Thus piflutixol constitutes a unique combination of potent anti-stereotyped activity with potent sedative effects. This means that piflutixol may prove to be a low-dose basic neuroleptic with long duration of action.


Selectivity of food colours for different organic acid  transport systems in rat renal cortex.

Seventeen food colours were tested as inhibitors of the simultaneous uptake of labelled o-iodohippurate and iodipamide into slices of rat renal cortex. The results have been interpreted in terms of inhibition of two different aniontransport systems: the hippurate of H-system and the liver-like L-system. No  clearcut relation was found between inhibition ability and system specificity on the one hand and moleculr weight or structure on the other. However, most disulphonic azo dyes and quinoline yellow show an L-system affinity while tri-and tetra-sulphonic azo dyes, triarylmethanes and erytrosine show very little predilection for either of the two systems.


Electrical activity of the rat uterus during early pregnancy and abortion.

Electrical activity of the rat uterus was recorded for 1 h daily on days 2--9 of pregnancy with 6 electrodes chronically implanted in the left uterine horn. In 10 untreated and 7 ergocornine treated rats, activity decreased in frequency and intensity during the first days of pregnancy. After day 3 activity was present in only about 30% of electrodes as compared to 85% on day 2. Abortion was induced by ergocornine injected on day 5. In these rats the frequency of bursts increased on days 8 and 9. During the peak of activity the majority of bursts spread in the cervical direction.


Peroxydisulfate anion-induced crosslinking of proteins.

Peroxydisulfate anion in aqueous solutions is a strong oxidizing agent decomposing to sulfate free radicals and subsequently to hydroxyl radicals. In the presence of proteins, aqueous solutions of peroxydisulfate undergo more rapid induced decomposition to these free radical species, which in turn leads to oxidative attack and crosslinking and/or degradation of the protein. Under mild conditions and at low peroxydisulfate concentrations, protein crosslinking predominates over degradation. Peroxydisulfate-induced crosslinking of gelatin, fibroin, and other proteins is reviewed. The mechanism of crosslinking is interpreted in light of physical and chemical data, amino acid analyses, peroxydisulfate's known mode of decomposition, the effect of protein modification on oxidative crosslinking, and related model compound studies.


Gas-liquid chromatography and mass spectrometry of lanthionine, lysinoalanine, and S-carboxyethylcysteine.

A programmed-temperature gas-liquid chromatographic method of analysis of amino acids as their n-butyl esters of N(O)-trifluoroacetyl derivatives with a dual column system using OV-17 and Dexsil 300 GC as stationary phase is discussed. The method is particularly suitable for analysis of chemically modified amino acids in the hydrolyzates of chemically modified wool and other protein fibers. Combined gas-liquid chromatography-mass spectrometry is used to identify unequivocally the molecular structure of modified amino acids. Lanthionine, lysinoalanine, and S-(2-carboxyethyl)-cysteine in the hydrolyzates of chemically modified wool fibers can be quantitatively analyzed by the gas-liquid chromatographic method of Dexsil 300 GC. N(epsilon)-(2-Carboxyethyl) lysine was detected by the combined gas-liquid chromatography-mass spectrometry in the hydrolyzate of reduced wool treated with acrylonitrile.


Genetic polymorphism of chicken 7S immunoglobulins.

A survey of 48 inbred lines derived from five sources in the United States and Europe revealed considerable genetic polymorphism of the CS-1 gene. A minimum of ten alleles were detected as unique combinations of CS-1 specificities. The relationship of some of the alleles would indicate that intracistronic recombination may have played a role in the production of some of the polymorphism.


Airborne micro-organisms and prevalence of byssinotic symptoms in cotton mills.

The concentration of airborne microbes, their endotoxins and the prevalence of byssinotic symptoms among workers were measured in the cardrooms of seven cotton spinning, a wool spinning and two cotton waste mills and in a dusty workroom of a group of five willowing mills, a tea-packing plant and a pipe tobacco factory. The concentration of microbes cultured on endoagar plates were found to correlate with byssinosis prevalence (r greater than 0.95, P less than 0.001). The concentration of nutrient agar microbes correlated with prevalence less well (r greater than 0.77, P less than 0.01) and that of fungi and endotoxins not at all.


Transformation of nodular lymphoma to an immunoblastic IgM-producing tumor.

Two cases of nodular lymphocytic lymphoma that transformed into leukemic processes with IgM-kappa-type monoclonal proteins are reported. The transformations occurred 21 and 34 months after the diagnosis of lymphoma and were associated with rapid deterioration of the patients' conditions. The leukemic phase was characterized by plasmacytic and immunoblastic appearing lymphoid cells in the peripheral blood and marrow. Such transformation, though rare, is not unexpected in view of the currently postulated origin of nodular lymphomas in germinal center cells and of immunoglobulin-producing tumors in cells derived from germinal center cells.


False aneurysm of the descending aorta: a complication of umbilical artery catheterization.

A patient had an aneurysm of the descending aorta secondary to aortitis arising from umbilical artery catheterization and in association with coarctation of the aorta. The aortitis probably was the direct result of bacterial contamination of the umbillicus and catheter with Staphylococcus aureus and the placement of the catheter tip just distal to a coarctation of the aorta. The patient required surgical resection of the coarctation and aneurysm of the descending aorta and placement of a tubular Dacron graft at 6 month of age. This is, to our knowledge, a hitherto unreported complication of umbilical artery catheterization.


Injection into the extra-arachnoid subdural space. Experience in the treatment of intractable cervical pain and in the conduct of extradural (epidural) analgesia.

The anatomy and radiological appearances of the subdural space in the cervical region are described. Recognition of this space facilitates neurolytic injections for severe cancer pain in the distribution of the cervical nerve roots. The subdural space may have significance also in explaining the extensive sensory block which follows a delayed or 'massive' lumbar extradural injection.


Protracted diarrhoea in infancy. Analysis of 82 cases with particular reference to diagnosis and management.

Eighty-two cases of protracted diarrhoea in infancy presenting over a 6-year period have been analysed, with particular reference to diagnosis and management. The patients fell into 1 of 2 categories according to whether a specific diagnosis was established or not. A diagnosis (category 1) was established in 59 (72%), the commonest diagnoses being coeliac disease (33-2%), secondary disaccharide intolerance (12-2%), and cows' milk protein intolerance (12-3%). Other diagnoses included primary sucrase-isomaltase deficiency, Shwachman's syndrome, ulcerative colitis, ganglioneuroma, defective opsonization, staphylococcal pneumonia, and Hirschsprung's disease. Despite intensive investigation in diagnosis could not be established in 23 (28%) infants (category 2). Age of onset of symptoms in this group tended to be earlier than in category 1 patients, and 6 (7%) presented with diarrhoea dating from birth. Of particular interest in these 6 patients was the high incidence of associated extraintestinal anomalies, and of sibs who had died after protracted diarrhoea dating from birth. 4 of these 6 infants died, accounting for a mortality of 5% for the whole series. The remaining 17 (21%) patients in category 2 presented at a mean age of 4-9 weeks with a range of 1-18 weeks. All these 17 patients made an excellent response after institution of a chicken-based dietary formula, the details of which are presented. The pathophysiological mechanisms which may be operating in infants with protracted diarrhoea are discussed.


[The special position of primary lymphosarcoma of the lung (author's transl)].

There has been made a comparison between a total of 121 primary lymphatic sarcomas of the lungs with 314 other histomorphological forms of primary sarcomas of the lungs found in the literature from 1957 to 1972. Histomorphology, clinic and prognosis are discussed. Beside a higher average age and a predominating right-hand localization, the favourable postoperative prognose is impressing.


[The importance of the "contingent negative variation" (CNV) for audiometry (author's transl)].

Previous proofs of "central processes" in hearing were based on the determination of the late "auditory evoked potentials" (AEP's: 50--300 ms) in EEG. The appearance of AEP's in different sleep stages raises the question, if the AEP actually conscious hearing. Since the discovery of the "Contingent Negative Variation" (CNV), as a potential depending on conscious and cognitive factors, an appropriate "instrument" is available to solve this problem. Using the CNV-technique three proofs of central auditory perception are described and discussed: a) "The objective proof of the perception of pure-tones", useful for threshold determination, test in the case of simulation and central hearing disorders. b) "The objective proof of the perception of stimulus-changes", useful for exact determination of differential thresholds for frequencies or intensities. c) "The objective speech audiometry", proof of speech comprehension, useful in case of aphasia and simulation.


[A proposition for mutual genesis of hearing loss, recruitment and ear murmurs in the case of acute inner ear alterations (author's transl)].

Pathological changes on the stereocilia of cochlear hair cells observed by Bredberg et al. (1972) after noise exposure and in the early stages of antibiotic intoxication are suggested to cause a mechanical decoupling between the tectorial membrane and the hair cells. During acute episodes of endolymphatic hydrops a similar decoupling is suggested to occur, although for different reasons. Harris (1968) calculated the noise generated at the input to the hair cells on account of the Brownian motion of air particles in front of the tympanic membrane. For tight coupling, he obtained a level of (--)22 dB re auditory threshold. For loose coupling this noise was found to increase to +33 dB, i.e., for 55 dB. These two independent findings are used to account for the combination of hearing loss, recruitment, and tinnitus observed with the inner-ear pathologies mentioned. The proposed hypothesis is in good agreement with clinical observations.


The effect of the removal of the endolymphatic duct and sac anlage upon organogenesis of the mammalian inner ear "in vitro": a preliminary report.

Preliminary observations of the effect of surgical excision of the endolymphatic duct and sac anlage in normal mouse embryo inner ear embryogenesis "in vitro" are reported. Otocysts of twelfth and thirteenth gestation day mouse embryos were grown in organ culture for 9 and 8 days respectively. The organ culture specimens of each gestational age group were further divided into otocysts with intact endolymphatic duct and sac anlages and otocysts that had their endolymphatic duct and sac anlages surgically excised prior to explantation. The resultant histological quantification of inner ear embryogenesis did not reveal any significant differences in morphogenesis, histodifferentiation of inner ear sensory structures or presence of endolymphatic hydrops in any of the organ culture specimens. It was concluded that in the system studied the absence of the endolymphatic duct and sac anlage did not have an effect on the organogenesis of the inner ear with the exception of the resultant lack of development of an endolymphatic duct and sac.


[Scentilleography of the pulmonary tensive active Iodine-131 in humans].

For the first time in the world we take surfactant scan in 3 normal volunteers and in one patient with pneumonia lobar, using 400 microCuries of surfactant Iodine-131. No intolerance, or radiotoxicity was found in 3 months of clinical follow up of the subjects. The results are very encorageous. A great variety of clinical situations could be now examinated with this new technic and radiocompound and given new perspectives in its study and diagnoses and a better knowledge of its physiophatology.


Histology of the cochlear vessels in the guinea pig.

Normal adult guinea pigs were studied in phase contrast microscopy. Perivascular spaces were clearly more common in vessels facing perilymph than in vessels facing endolymph. The so-called "avascular channels" which have been suggested to signify a degenerative phenomenon were found in some inner ear vessels in the normal animal. These sections of vessels, lacking blood cells, may constitute a normal vessel, subjected to plasma skimming. Small openings were found on some of these "avascular channels". Both perivascular spaces and "avascular channels" appear to be a part of the fluid transport system in the cochlea.


Scanning electron microscopy of the nerves within the organ of Corti.

A method of studying the innervation inside the organ of Corti is presented. Rabbits, guinea pigs and chinchillas were fixed with perfusion of the perilymphatic spaces. The cochleas were dissected according to the surface specimen technique and the specimens critical point dried, coated with gold and studied in the SEM. The final dissection into the planes of the fluid spaces of the organ of Corti was done in the dry state using especially sharpened watch makers forceps and razor blade knives. The course of the afferent and efferent innervation is described and differences between the species illustrated. Small high nerve endings on the outer hair cell degenerate after cutting the efferent nerve supply by dividing the vestibular nerve indicating their efferent nature.


Freeze-fracture aspects of the junctional complexes in the round window membrane.

Replicas of the freeze-fractured round window membrane were studied in chinchillas. Morphologically identifiable zonulae occludentes were found between the cells facing the tympanic cavity and between the cells bordering the perilymphatic space. Gap junctions were only found between the perilymphatic cells.


Sources of endolymph and EP. Does the perilymph or Reissner's membrane influence the ionic content of the endolymph and EP?

The source of EP and the production of the endolymph are often considered to be at the stria vascularis. However, the significance of Reissner's membrane in maintaining the ionic composition of the endolymph cannot be ruled out. We perfused the entire perilymphatic space of guinea pigs with paraffin oil to determine the effects on the endolymph and perilymph. After 1 and 2 h the endolymph was removed from the second turn and the ionic concentration of these samples was measured by flamephotometry. The results revealed no significant changes in Na+ and K+ concentration as compared to normal endolymph. EP was measured from the second turn under an equivalent experimental condition. During 1 h of oil perfusion, EP remained fairly constant. From these experiments we surmise that perilymph and Reissner's membrane do not influence the ionic composition of the endolymph and EP during 1 or 2 h of our experiments.


[The effects of intratympanally applied streptomycin-sulfate on the ipsi- and contralateral hearing potentials in the guinea pig (author's transl)].

11 Guinea pigs had a 50% streptomycin-sulfate solution injected into the middle ear. Complete loss of function of the peripheral vestibular organ occurred after two days, as was detectable by means of the caloric test. The high-degree decrease of the microphonic-potentials and the compound action potential was significant. Threshold and adaptation of the potentials of the opposite side were not affected. The results are discussed with regard to the treatment of Menière's disease by means of intratympanally applied streptomycin.


[Problems of localization of noise damage in the cochlea - 70 years after Wittmaacks first animal experiments (author's transl)].

Wittmaack was the first, who investigated noise damage of the inner ear by animal experiments 70 years ago. This paper deals with the problem of estimating the extend of the damaged area on the basilar membrane following noise exposure by evaluating the microphonic potentials (MP) detected from the round window. With the aid of a mathematic model it is possible to predict both the decrease of the MP after noise exposure and the localization of the damaged area on Corti's organ. These predictions are examined by morphological investigations using the method of Spoendlin and Brun.


Mathematical analysis of concentration-response relationships. Method for the evaluation of the ED50 and the number of binding sites per receptor molecule using the logit transformation.

The mathematical analysis of concentration-response relationships is performed by means of the mass law and the drug-receptor theory. It is demonstrated that the calculation of the median effective dose (ED50), which is decisive for the pharmacological characterisation of a certain drug, may only be effected by means of the logit transformation. In addition, it is shown that this transformation is most suitable to evaluate in a mathematically simple way the number of drug binding sites of the receptor molecule.


[On a possible mechanism of the gastrointestinal absorption of ionic drugs (author's transl)].

An attempt was made to explain the mechanism of penetration of ionic medicinal substances through the lipoid membranes of the gastrointestinal tract. The equations worked out helped in the determination of constants which support and clarify further the already known concepts about the mechanisms of penetration of ionic drugs through the gastrointestinal tract.


Fluorescence data and studies on the lipid solubility and chemical structure of N-propyl-ajmaline as compared to ajmaline.

The quaternary N-propyl-ajmaline was found to have a higher lipid solubility than ajmaline. Lipid solubility was pH dependent. From chemical, fluorescence and IR-spectroscopic studies it is concluded that the existence of N-propyl-ajmaline in a tautomeric state between a carbinol-ammonium and an aldehyde-amine structure is responsible for the high lipid solubility.


[A new model for demonstrating the hepatic first-pass effect (author's transl)].

A procedure is reported for inserting chronically implanted vascular catheters into the hepatic vein, aorta and portal vein. Dogs are used as experimental animals. By rinsing the catheters daily it is possible to maintain their patency for months, thus permitting numerous test series.


Experimental hypertension. Apparatus for reliable inderect determination of blood pressure in conscious rats.

A new apparatus for reliable indirect routine determination of blood pressure in rats is presented. The device provides a reproducible good correlation between indirect measuring and direct intraarterial blood pressure and allows an accurate determination of pulse rate of the unanesthetized animal.


[Pharmacologically active polymers. 9th communication: retard forms of morphine antagonists (author's transl)].

Acryloyl, methacryloyl, N-vinylcarbamoyl, and methacryloyl-glycyl derivatives of the morphine antagonist (--)-alpha-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane have been synthesized. The different unsaturated derivatives were copolymerized with appropriate comonomers to yield water-soluble polymers. Pharmacological tests in mice showed a 2--30 fold increase in duration of action in comparison to the free antagonist. The binding of the antagonist to the polymers resulted in a reduced acute toxicity.


Synthesis and biological activity of some 2-aminoimidazoles.

A review of the literature showed that 2-amino-imidazoles have not benn taken into consideration as antimicrobial agents. Our preliminary data indicating that 2-amino-4(5)-phenylimidazole possessed a moderate in vitro activity prompted us to prepare a limited series of 2-amino-4(5)-arylimidazoles and of some related derivatives. In vitro atimicrobial screening gave evidence of a broad spectrum activity for some of them. Several compounds have been tested also against S. mutans. In particular, 2-amino-4(5)-(4-biphenylyl)-imidazole hydrochloride showed substantial activity in this test, confirmed also against defferent representative strains of S. mutans. When submitted to a plaque inhibition test, it strongly inhibited the plaque forming ability of a S. mutans  strain.


[Studies on the effect of urapidil on the central nervous system and various organ functions in animal experiments (author's transl)].

Compared to the changes in spontaneous behaviour of mice and rats, 6-(3-[4-(o-methoxyphenyl)-1-piperazinyl]-propyl-amino)-1,3-dimethyluracil (urapidil, Ebrantil) in doses from 10 mg/kg p.o. has a central sedative action, for which it is typical that it can be interrupted by external stimuli after doses of up to approx. 100 mg/kg. By this action urapidil differs from other central-acting drugs, e.g. chlor-promazine, diazepam and clonidine. It can be assumed that urapidil has no central dopamine blocking qualities because it does neither influence the conditioned avoidance response nor the amphetamine-induced gnawing of the rat. Urapidil is also different from diazepam bacause it does not hinder spinal polysynaptic motor reflexes of the decerebrated cat. Up to 80 mg/kg p.o. of urapidil, there was no hypotensive effect in the rat to be seen and, therefore, it can be concluded that changes in spontaneous and reactive behaviour are not due to acute changes in cardiovascular functions. The antihistamine effect of urapidil in the isolated ileum of the guinea pig is approx. 15 times weaker than that of chlorpromazine, furthermore urapidil has no anticholinergic quality.


[Toxicologic study on the antihypertensive agent urapidil].

The acute toxicity of 6-(3-[4-(o-methoxyphenyl)-1-piperazinyl-propylamino)-1,3-dimethyluracil (urapidil, Ebrantil) was tested in rats and mice using oral and intravenous routes. The tolerance upon repeated oral administration was tested in subacute and chronic toxicity studies lasting 3 weeks, 3, 6 and 12 months in the rat, as well as studies lasting 4 weeks and 6 months in the dog. The effect of urapidil on the reproduction in mice, rats and rabbits was also investigated. Sedation is seen in mice and rats after a single administration of urapidil, at lethal doses, tremor and convulsions appear. The same symptoms were seen in experiments with repeated oral administration in the rat (stomach tube) or in the dog (tablets) as the criterium of tolerance. In feeding  studies in the rat, the decreased body weight gain was the criterium of toxicity. The no-effect dose in the rat is 42 times the therapeutic dose in man. The no-effect dose in the dog lies between 8 and 21 times the average therapeutic dose. An inhibition of the estrus cycle in the rat proved to be species-specific. In reproductin studies, significant toxic effects were seen besides functional disturbances specific to the rat. Urapidil was not teratogenic. The development and reproductive capacity of the F1-generation was not affected.


[Anticovulsant activity of N-(p-sulfamoyl-phenyl)-succinimide derivatives (author's transl)].

A series of newly synthesized N-phenyl-substituted derivatives of succinimide were screened for anticonvulsant activity. Addition of a sulfonamide group in the p-position was of great consequence for the anticonvulsant effect. Substitution of a halogen in the m- or o-position improved activity against electroshock induced seizures. Pentylenetetrazole convulsions could only be prevented by few of these substances in smaller than 200 mg/kg oral doses. Activity could be further enhanced by adding more aliphatic or aromatic groups to the succinimide ring. The lethal doses of most of the active succinimides were higher than 5000 mg/kg p.o. With sublethal doses mice sometimes become drowsy and had myoclonic seizures and/or diarrhoea. At therapeutic dose levels kinetic disturbances, potentiation of pentobarbitone hypnosis or analgesia were rarely observed.


Hair embolism in lungs of rats after intravenous injection into caudal veins.

In case of intravenous injection into caudal veins of rats, the occasional inoculation of hair particles into the lumen of the vein cannot be avoided. These hairs either cause a local thrombophlebitis or are floated with the blood stream until they are thoughout caught by the pulmonary filters, even if they measure less than 10 mu in length. In capillaries or alveoli of lungs phagocytosis by giant cells will start after about 3 days and will be fully terminated within four weeks.


Antithrombotic effects of some flavonoids alone and combined with acetylsalicylic acid.

In the rat, a selection of two experimental models of "prethrombotic states", one of venostatic thrombosis and one of arterial thrombosis was used to compare the antithrombotic of three flavonoid preparations: O,-(beta-hydroxyethyl)-rutosides (HR), an association of trihydroxyethylrutoside and coumarin (troxerutin) and 7-mono-hydroxyethylrutoside (7-Mono-HR), as well as acetylsalicylic acid (ASA). The flavonoids were very effective "protectors" on the prethrombotic models, but only ASA was active on the model of arterial thrombosis. No compound showed a clear protection on the venostatic model if direct activation by kaolin was used. However, if an indirect activation by vessel wall stimulation was used, 7-Mono-HR possessed a marked protective effect. The most favourable results were obtained with an association of 7-Mono-HR and ASA, which could be considered for investigation in clinical thrombosis prophylaxis.


The effect of fasting on galactosamine induced hepatitis in experimental animals.

Fasting prior to galactosamine treatment caused a significant modification in the liver damage in both rats and hamsters. Fasting after galactosamine treatment did not affect the course of the liver damage. Liver glycogen levels were significantly lower than normal after either fasting or galactosamine treatment in rats and after galactosamine treatment in hamsters. In rats fasted and treated with galactosamine the liver glycogen content was significantly higher than normal. A 24-h period of fasting did not cause any alteration in liver glycogen levels of hamsters.


Interaction of phenoxybenzamine with angiotensin II in the isolated perfused rabbit kidney. Short communication.

Interaction of phenoxybenzamine with angiotensin II was studied in the isolated perfused rabbit kidney. Angiotensin II induced a dose-dependent increase in perfusion pressure and urine flow when given through the renal artery. Phenoxybenzamine when added to the perfusion medium caused a decrease in perfusion pressure but an increase in urine flow. Further addition of acetyl salicylic acid to the perfusion medium significantly reversed both agonistic effects of angiotensin II. The possible mechanisms of these findings are discussed.


[Studies on the toxicity of thiaminedisulfide monoorotate. Short communication (author's transl)].

The water soluble thiaminedisulfide monoorotate (thiooratin) was studied in mice and rats for its acute and subchronic toxicity. After continuous administration over 8 weeks no organic damages, in particular no fatty livers, were found.


[Inhibition of anaphylactic reactions in atopic dogs by means of a new antiallergic drug (BM 06.001) (author's transl)].

The antiallergic action of an orally administered piperazinopropyl-adenine (BM 06.001) was demonstrated in atopic dogs. It was shown that the substance was able to inhibit both the skin reactions and the bronchial obstruction caused by ascaris antigen at approximately the same dosage.


[Clinical study on metabolic effects of estriol-succinate (author's transl)].

Allowing for the restrictions outlined in "Methods", treatment with estriol-succinate of 10 menopausal women for several weeks had no effect on some lipid and carbohydrate parameters, nor on serum enzymes nor plasma hormone levels. A slight increase in serum alkaline phosphatase, within normal limits, could not be related to a disturbance of liver function, when considering the other parameters.


[Kinetics of digitoxin during antirheumatic therapy with azapropazone (author's transl)].

The effect of chronic therapy with 5-dimethylamino-9-methylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a] [1,2,4] benzotriazine-1,3-(2H)-dione-dihydrate (azapropazone-dihydrate; Prolixan 300) on the elimination of a single i.v. dose of digitoxin was studied in 8 patients with rheumatoid arthritis and osteoarthritis using a crossover design. 0.5 mg digitoxin were injected i.v. alone and together with a chronic oral therapy of azapropazone starting 3 weeks before digitoxin was given. Digitoxin plasma levels were determined by radioimmunoassay over a period of 19 days. The half-life for plasma digitoxin was 6.4 +/- 0.5 days after digitoxin alone and 7.0 +/- 0.6 days during azapropazone treatment. In two patients the half-life of digitoxin was increased by about one-third during azapropazone therapy. The areas under the plasma digitoxin curve were 2592 +/- 262 ng/ml X h and 2615 +/- 273 ng/ml X h, respectively. None of the differences were statistically significant. It was concluded that there was no clinically significant interaction between azapropazone and a single dose of digitoxin.


[Effect of tibric acid (CP-18.254) on plasma lipids in patients with primary endogenous hyperlipoproteinemia].

Tibric acid [CP-18.524; 2-chloro-5-(3,5-dimethyl-piperidino-sulfonyl-benzoic acid], a new hypolipidemic drug was given to 20 patients with primary endogenous hyperlipoproteinemia of type II, III, IV and V Fredrickson in a daily dose of 1.5 g for 1 year. As compared to a 4-week placebo period, the treatment with tibric acid led to a significant decrease in plasma cholesterol in 6 type-II patients (p less than 0.02) and to a significant decrease in plasma cholesterol and triglycerides in 6 type-III patients (p less than 0.001 and p less than 0.001, resp.) and in 4 type-IV patients (p less than 0.001 and p less than 0.001, resp.). No significant effect of tibric acid on plasma lipids was noted in 4 type-V patients. Apart from a moderate nausea in two patients, no side effects occurred.


[Determination of gentamicin in the serum of patients with normal renal function with the purpose of avoiding subtherapeutic antibiotic levels (author's transl)].

In 24 patients with normal renal function the serum concentration of gentamicin was checked during a period of 3--5 days. The biological test is simple and rapid to perform. The patients were given doses of 80--240 mg gentamicin per day. Even at doses of 240 mg/day no accumulation of the drug occurred. Intramuscular application of an 80 mg maximum dose of gentamicin did not result in any toxic serum concentrations. The measurement of peak concentrations--1 h after application--is therefore jus aimed at correcting too low dosages. The median values of the serum peak concentrations are 4--6 microgram/ml in the case of single dose application of 80 mg and 3 microgram/ml in the case of single dose application of 40 mg. Consequently serum concentrations effective against moderately susceptible bacteria (MIC = 1--4 microgram/ml) do not act for a sufficiently long time, since the half-life for elimination is 2 h. Daily dosages of up to 240 mg (3X80 mg) gentamicin are only effective in infections caused by very susceptible bacteria with a MIC up to 1 microgram/ml.


[On the chemistry of etofenamate, a novel anti-inflammatory agent from the series of N-arylanthranilic acid derivatives (author's transl)].

Etofenamate is 2-(2-hydroxyethoxy)ethyl-N-(a,a,a,-trifluorom-tolyl)anthranilate and has been selected as an antiphlogistic agent for percutaneous therapy. Its characteristic alcohol-ether-ester structure brings about an increase in lipophilia and in its ability to penetrate through the intact skin. Furthermore, its oily consistency renders it ideal for pharmaceutical formulation in gels. The physico-chemical material constants, partition coefficients (RM values) as a measure for lipophilia, spectra and molecular models of etofenamate are described. Various methods of synthesis of etofenamate and of its intermediates are described. Structural identification is made of by-products simultaneously obtained in the reaction. Pure etofenamate is obtained through repeated molecular distillation. The synthesis is carried out uniformly with protected reaction components and, after splitting off the protective groups, extremely pure etofenamate is obtained.


[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.


[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.


[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.


[Experience with etofenamate in sport injuries (author's transl)].

Experience with 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate; active principle of Rheumon Gel) in the treatment of traumatic injury to the ankle joint is reported. In testing the effect of the product, volumetric measurements were carried out using an apparatus that permits highly accurate assessment by a simple and rapid method of measurement. The studies were carried out as a double blind trial. The result of the study shows that compared with placebo gel the increase in volume due to haematoma is reduced statistically significantly more rapidly under treatment with etofenamate. No localized or generalized side effects were observed.


[On a novel Fomocaine synthesis/10th communication: on syntheses of new compounds with local anaesthetic activity (author's transl)].

4-[3-(4-phenoxymethyl-phenyl)-propyl]-morpholine (fomocaine, Erbocain) is a very active topical local anaesthetic with low toxicity. A new synthesis starting from 4-phenoxy-methyl-benzonitrile, via a modified Willgerodt-Kindler reaction, is reported. The yield is of the same order as with the known technical process starting from 3-phenylpropanol. The distinct advantage of the new procedure is the avoidance of the C-chloromethylation of 3-phenylpropylchloride during which process the o-chloromethyl derivative is also formed, and this cannot be separated by fractional distillation.


Derivatives of 2-bromo-6beta-fluoropregna-1,4-diene-3,20-dione and their antiinflammatory activity.

As part of a systematic study of the effects of chemical modifications on the antiinflammatory activity of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate, Topicon), a new potent antiinflammatory, a series of derivatives of 2-bromo-6beta-fluoropregna-1,4-diene-3,20-dione was prepared for pharmacological screening. Different synthetic approaches are described. All the synthesized compounds had topical antiinflammatory activity, with no side effects, but were lower in activity than halopredone acetate. Most of them showed topical antiinflammatory activity comparable to that of fluocinolone acetonide. Only two of the synthesized compounds were found to have systemic anti-inflammatory activity comparable to that of betamethasone.


New esters of Halopredone for topical antiinflammatory use.

A series of new halopredone esters has been prepared and screened for local and systemic antiinflammatory activity. High local activity with no side effects, equivalent to that of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon), is obtained when either the 17- or 21-OH of halopredone are benzoylated.


Physico-chemical and analytical studies on Halopredone acetate.

Physico-chemical, spectroscopic (UV, CD, ORD, IR-1H-DMR, 19F-NMR, PFT13C-NMR, MS), and chromatographic (TLC, HPLC) properties of 17,21-bis(acetyloxy)-2-bromo-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione (halopredone acetate; Topicon) are reported. Densitometric and high-pressure liquid chromatographic quantitative analytical methods are described. The usual descriptive data, purity tests, potential impurities arising from the synthesis and stability tests are given.


Syntheses and primary pharmacological screening of tandamine and related tetrahydrothiopyranoindoles with potential antidepressant properties.

A series of novel 1,3,4,9-tetrahydro-1-methyl-thiopyrano-[3,4-b]indole-1-ethanamines has been synthesized and examined for effects on reserpine-induced ptosis and reserpine-induced hypothermia in mice. One member of the series, the 9-ethyl-N,N-dimethyl derivative V (tandamine), was selected for further studies in regard to its possible use as an antidepressant agent. Tandamine has been resolved, and the levorotatory enantiomer was found to be more active than the racemic compound. The N-desmethyl derivative XIII, a metabolite of tandamine, has been prepared. The 5-ethyl-1,3,4,5-tetrahydro-N,N,1-trimethylthiopyrano[4,3-b]indole-1-ethanamine XXI, an analog of tandamine with the isomeric ring system, has also been synthesized and evaluated. In the primary pharmacological screening and in the drug-interaction studies with reserpine, tetrabenazine, and tremorine, tandamine was compared to the clinically effective tricyclic antidepressants--desipramine, imipramine, and amitriptyline. Tandamine was more effective than these agents in several screening procedures indicative of potential antidepressant activity.


Synthesis and antitussive activity of 3-azabicyclo[3.2.2]nonane derivatives.

Mannich bases derived from a number of substituted acetophenones and propiophenones and 3-azabicyclo[3.2.2]nonane have been evaluated for antitussive activity. One of these compounds was as potent as codeine and dextromethorphan in its antitussive activity. The most potent compound of the series, 3-(3-azabicyclo[2.2.2]nonan-3-yl)-4'-benzyloxy-2-methyl propiophenone, also exhibited antimorphine activity. There was no direct correlation between the antitussive effect and antimorphine activity.


Synthesis and pharmacological properties of some 4-amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)pyrimidin-7(6H)-one-2(3H)-thiones.

4-Amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)-pyrimidin-7(6H)-one-2(3H)-thiones have been synthesized and screened for antimicrobial and pharmacological activities. Significant analgesic, antiinflammatory, anticonvulsant and antimicrobial properties have been found in some of the compounds synthesized. Analgesic and antiinflammatory activities are reported for the first time in thiazole-2(3H)-thiones.


[Modification by drugs of cellular and humoral resistance mechanisms in animal experiments. I. In-vitro studies of peritoneal leukocytes and serums in rats].

44 rats were fed p.o. with 3.1 ml/kg of Esberitox over a period of 5 days once daily, for increasing their non-specific resistance against injections. It could be shown that peritoneal leucocytes exhibited an increased phagocytosis of staphylococcus aureus. Besides the direct influence on the ingestion of this pathogenic microorganism, the leucocytes of the Esberitox group showed a stimulated uptake of oxygen when tested in vitro. The humoral defence seems also to be improved due to the elevated bactericidal activity of sera from Esberitox treated rats.


Comparison of the hypotensive and diuretic effects of 1,4-dimorpholino-7-phenylpyrido[3,4]pyridazine (DS-511) and hydrochlorothiazide in Doca, renal and spontaneously hypertensive rats.

The hypotensive and diuretic activities of a new diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d] pyridazine (DS-511), were compared with those of hydrochlorothiazide (HC) in DOCA, renal and spontaneously hypertensive rats. The results obtained were: 1. During the developing stage of DOCA-hypertension the daily treatment of rats with DS-511 and HC showed significant hypotensive action. During this period the diuretic activity of both agents was clear. 2. During the equilibrium stage of DOCA-hypertension the hypotensive action of DS-511 was indistinct despite its diuretic activity. The hypotensive and diuretic action of HC was not clear. 3. In renal-hypertensive rats the daily treatment of DS-511 and HC caused significant, but weaker hypotension than that in the developing stage of DOCA-hypertension. In these animals the diuretic activity of both agents was clear. 4. In spontaneously hypertensive rats the daily treatment with DS-511 and HC exhibited a similar hypotensive and diuretic action. 5. In all three kinds of hypertensive rats the diuretic activity of DS-511 was similar to that of HC in the excretion of urine and sodium, but the former was less kaliuretic than the latter.


Effect of diltiazem on coronary blood flow of the heart with experimental coronary sclerosis and on regional myocardial blood flow of the heart with acute myocardial ischemia.

Effects of 3-acetoxy-2,3-dihydro-5[2-(dimethyl-amino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one hydrochloride (diltiazem) on coronary circulation of the heart with experimental coronary sclerosis induced by i.v. allylamine (Group A), and on regional myocardial blood flow in acutely-induced ischemic myocardium (Group S) were studied in anesthetized open-chest dogs. Regional myocardial blood flow was continuously measured with heated cross thermocouple method and following results were obtained: 1. In Group A coronary blood flow and coronary flow resistance remained unchanged essentially after the injection of diltiazem, whereas coronary blood flow markedly rose and coronary flow resistance decreased in the normal heart. 2. Local blood flow in both of the inner and outer thirds of the ischemic myocardium was not affected by diltiazem in Group S. In the normal myocardium, however, it increased definitely. 3. From these findings it is concluded that the clinical effectiveness of diltiazem is independent of its vasodilator properties.


Antagonizing effect of aspartic acid on the development of physical dependence on and tolerance to morphine in the rat.

As free amino acids in the brain have a role in the development of physical dependence on and tolerance to morphine, and in the mechanism of action of some drugs, the effects of aspartic acid which antagonizes some effects of the single dose of morphine were studied during the development of the physical dependence on morphine and after the withdrawal of morphine. 108 rats were given morphine and aspartic acid in different combinations in drinking water for 30 days. Every tenth day the dose of morphine was increased: At the end of this period some of them in each group continued or began to receive aspartic acid depending on the experimental conditions after the withdrawal of morphine. During the experiments body weight, spontaneous motor activity and analgesic threshold were determined. Aspartic acid prevented the alterations induced by morphine during the development of physical dependence and tolerance. Furthermore the rats that received aspartic acid after the withdrawal showed no body weight loss.


Distribution of S-adenosyl-L-(methyl-14C)methionine in animals.

The distribution of i.v. injected S-adenosyl-L-(methyl-14C) methionine was studied in the whole body of mice and in the cat brain using an autoradiographic technique. The drug was concentrated, at shorter survival times, mainly in the blood stream and in highly vascularized organs. Low concentration of radioactivity was found at longer times in the central nervous system (CNS). The quantitative analysis by means of organ radioassay was carried out in rats and confirmed the autoradiographic data.


A comparison between the morphologic changes in the livers of hamsters and rats after galactosamine treatment and their correlation with altered serum transaminase levels.

Galactosamine caused changes in the livers of rats that were similar to those seen in human viral hepatitis. In hamsters the changes were characteristic of a typical toxic hepatitis. The response by the liver to galactosamine was very variable in both the rat and the hamster and there was a degree of correlation between the raised transaminase levels and the liver cell damage.


A pharmacokinetic study of 3H-diosmine.

A pharmacokinetic study of 3H-labelled 7-rhamnoglycoside of 5,7,3'-trihydroxy-4'-methoxyflavone (3H-diosmine) administered both i.v. and orally, shows the great ease with which it is absorbed in digestion. A very sharp difference in elimination between the two modes of treatment must be associated with a difference in metabolism. A study of fixation confirms this conclusion. In particular the fixation on the tunica vascularis, perhaps due to a metabolite, appears relatively late. Furthermore the existence of an enterohepatic cycle assures a permanent hepatic binding.


[The effect of silybin dihemisuccinate on cholesterol biosynthesis in rat liver homogenates (author's transl)].

The effect of silybin dihemisuccinate on the hepatic biosynthesis of cholesterol was studied by measuring the incorporation of [1-14C]-acetate and [2-14C]-mevalonate in the postmitochondrial supernatant of liver homogenates. 2. Under absolute in vitro conditions, silybin dihemisuccinate inhibits the biosynthesis of cholesterol in dependence on its concentration. With [1-14C]-acetate or [2-14C]-mevalonate the concentrations of silybin for 50% inhibition are 0.37 mM or 0.40 mM, resp. 3. 30 min after i.v. injection of 150.6 mg silybin dihemisuccinate/kg with both precursors the biosynthesis of cholesterol studied in vitro is diminished in comparison to controls. 60 min or 24 h after i.v. injection of silybin no effects on in vitro biosynthesis of cholesterol can be observed.


Antagonism of non-steroidal anti-inflammatory drugs and narcotic analgesics against ethacrynic acid induced writhing.

Thiol-group reactive agents [alloxan, N-ethyimaleimide (NEM), ethacrynic acid, p-chlormercuribenzoate (PCMB)] were shown to induce a writhing syndrome in mice and rats when injected i.p. in appropriate dosage. Non-steroidal anti-inflammatory agents, narcotic analgesics and also psychotropic drugs inhibit the syndrome elicited in rats by ethacrynic acid. Rats pretreated with cysteine i.p. show a greatly reduced nociceptive response to ethacrynic acid or alloxan.


[Collected findings of long-lasting chemical stimulation of the immune system by N-(2-cyanethylene)-urea derivatives (author's transl)].

The present paper describes our findings so far on the long-lasting chemical stimulation of the immune system by means of various batches from the synthesis of N-(2-cyanethylene)-urea (BA 1). These findings were also supported by results of other authors. Furthermore some recent findings have demonstrated that 2-cyanaziridine, 2-cyanethyl-urea and a bicyclic isomer represent examples for immunologically effective BA 1-derivatives or BA 1-isomers, respectively.


[On the determination of azapropazone from plasma by direct quantitative thin-layer chromatography (author's transl)].

For the purpose of investigating drug interactions, a new selective method for determination of 5-dimethylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a] [1,2,4]benzotriazine-1,3(2H)-dione-dihydrate (azapropazone, Prolixan 300) was developed. The method is based upon the direct quantitation of the drug by thin-layer chromatography using remission measurement. The method is well suited for routine analysis of numerous samples, because of its simplicity and rapidity. The standar deviation of the method is about +/-4% at therapeutic plasma concentrations.


Oversaturation of urine with sulphadiazine during treatment with a small therapeutic dose.

The urinary crystallization of N1-pyrimid-2-yl-sulfanilamide (sulphadiazine, Sulfolex) during treatment with a small therapeutic dose (600 mg/day p.o.) for 6 days was evaluated in seven voluntary female subjects. In 5/7 and 3/7, respectively, of the urine supernatants obtained from samples collected 6 and 24 h after the last dose of sulphadiazine, the sulphonamide concentration exceeded the experimental solubility of the drug in 37 degrees C urine at the same pH. However, only in 3 sediments of the 6-h urine samples could a few sulphadiazine crystals be found. The findings suggest that the urine often can be oversaturated in respect to sulphadiazine, without any marked crystallization.


[Indications for determining serum levels of antiepileptic drugs (author's transl)].

Measurement of the serum levels of antiepileptic drugs is an important progress in managing the patients with epilepsy. The determination of serum levels has become indispensable in special indications such as assessing the compliance in taking medication and identifying the responsible agent in intoxicated patients on multiple drug therapy. The long-term prognostic value of the routine determination of anticonvulsant drugs is related to the validity of the concept "therapeutic serum level".


[The role of cytochrome P450 in the activation of drugs (author's transl)].

Unspecific microsomal monooxygenases have been found in many organisms of different developmental stages. In higher organisms liver is the main organ of drug metabolism but smaller intestine, lung and skin also show this activity. The corresponding membrane-bound enzyme system could be isolated by modern chromatographic techniques and was found to consist of a reductase and a series of cytochrome P450 enzymes. Each of these cytochromes has a different, but with other forms overlapping substrate specificity. The steady-state concentrations of the various forms is regulated by induction with drugs and foreign compounds. The unspecificity of the systems is also reflected in the varying pattern of metabolites. In general stable and more polar metabolites are formed by the monooxygenation reaction, but reactive and unstable products may also appear, e.g. N-hydroxy compounds, 1,2-diphenols, epoxides and a new class of compounds which have been characterized as carbenes.


[Activation mechanisms in chlorinated aliphatic compounds/experimental possibilities and clinical significance (author's transl)].

Chemical reactivity, biotransformation and toxic effects of chlorinated aliphatic compounds are decisively determined by type and number of chlorine substitutions. In saturated compounds, chlorine substitution exerts a destabilization; metabolic reactions are free radical formation and dechlorination or dehydrochlorination, respectively, under formation of olefins. In saturated alkenes, Cl-substitution leads to a stabilization of the olefinic double bond. Biotransformation of this class of compounds starts with epoxidation. The epoxides are prone, among other reactions, to intramolecular rearrangement; more stable aldehydes or acid chlorides are formed. In the series of chlorinated ethylenes, the rearrangement mechanisms have been studied systematically in vitro and in vivo. As judged from the identified metabolites there is accordance in vitro and in vivo, with one important exception: trichloroethylene. The only formation of chloral in vivo may be due to a catalysis by the iron in P450. In a modified Ames test system the unsymmetrically substituted chlorinated ethylenes are found mutagenic (tri-,1,1-dichloroethylene and vinyl chloride), whereas symmetrically substituted molecules are inactive. The reason for this is seen in the high instability of the unsymmetric molecules caused by the electron withdrawal effect of chlorine.


[Mechanisms in inactivating reactive metabolic products of drugs (author's transl)].

An in vitro test system was used to study the relative contribution of epoxides metabolically produced from aromatic or olefinic drugs to the total of mutagenically reactive metabolites. As an epoxide-specific tool the enzyme epoxide hydratase was purified to homogeneity. Using several aromatic and olefinic hydrocarbons as model substrates the following was observed, exceptions being discussed in the main text: 1. Epoxides represent the most important and generally the almost exclusive metabolites responsible for the observed toxic endpoint. 2. These epoxides generally are efficiently inactivated by epoxide hydratase. The rather narrow limitations of exceptions are outlined in detail. 3. Amongst the enzymes metabolizing epoxides, for the substrates investigated epoxide hydratase represents the system which is most critical for the control of tissue levels of epoxides. 4. Several practical consequences following from these facts are outlined in the last paragraph of this paper. 5. A generalization from these model experiments will be justified only after further experimental validation.


[Polymorphisms and deficient drug metabolism as triggers of toxic reactions (author's transl)].

The influences of polymorphisms and pharmacokinetic defects of drug metabolism as causes of toxic drug reactions are presented. The different mechanisms of toxic side effects mediated by alterations of the metabolism and excretion of drugs are discussed.


[Capacity limited pharmacokinetics, a mechanism of drug toxicity (author's transl)].

In the past drug elimination was described mainly by two different laws. Zero-order kinetics postulates that the speed of elimination be constant and independent of drug concentration; in first-order kinetics which describes satisfactorily the elimination of all drugs except ethyl alcohol it is assumed that the speed of the elimination is proportional to the plasma drug concentration. This can only be interpreted biologically in the case of polar drugs eliminated by diffusion or filtration. Non-polar drugs, however, bind reversibly to macromolecules such as albumin and enzymes. This means that elimination should be saturable as predicted by the law of mass-action. Saturation phenomena have clearly been demonstrated with several drugs eliminated by tubular and biliary secretion, or by enzymatic transformation. It is shown that zero-order and first-order kinetics are consequences of the validity of the mass-action law in two extremely different drug concentration ranges. When the affinity between drug and biological macromolecules is high the possible clinically relevant consequences are abnormal drug accumulation and drug interactions such as mutual displacement from the plasma albumin binding sites, inhibition of active drug transport and metabolism, or enzyme induction.


[Drug-induced disorders of lupus erythematosus type (author's transl)].

Drug induced Lupus erythematosus (LE)-like syndromes are generally observed after long-term and/or high-dose therapy with so called "principal inducers" procainamide, hydralazine, isoniazide, chlorpromazine, anticonvulsives and possibly with D-penicillamine, too, and even so in some cases after some additional 26 drugs. The rare pseudo LE syndrome appears after combined drugs which usually contain pyrazolone derivatives used especially against venous diseases. The mechanism of induction of autoimmune reactions in these disorders varies and is after all still unknown. There are individual differences in drug metabolism, genetic disposition for increased autoantibody formation and sometimes humoral and cellular immune reactions against the drug itself. Essentially involved in the indication of autoimmune reactions is often the production of hapten carrier complexes between drugs and body constituents and drug induced changes of autoantigen elimination as well as drug mediated immunologic imbalance.


[Mechanisms of photoallergies (author's transl)].

Photoallergic reactions represent a special form of allergic contact dermatitis. The immunological aspects of the delayed-type sensitivity are fairely well known, whereas information on the photochemical antigen formation is still scarce. This is illustrated by two examples.


Pathology of intracerebral hemorrhage.

Spontaneous intracerebral haemorrhages are dealt with on the basis of a great number of clinical and neuropathological cases. They amounted to 4.9 per cent of the patients admitted to the hospital and 5.2 per cent of the autopsies. In two thirds hypertension was found about 20 per cent were ruptured aneurysms. In 3 per cent of the respective autopsies no cause was found. The clinical courses are dealt with in greater detail. Eighty per cent of the hypertensive haemorrhages are located in the cerebral hemisphere; among these, 60 to 80 per cent show ventricular perforations. This percentage is still higher in thalamus--brain stem haemorrhages. Two theories on the aetiology are discussed. Traumatic haemorrhages are especially dealt with in connection with late apoplexy. Deformations of the cerebral vessels, too, are described in detail. Among the aneurysms, 82 per cent belong to the circulus willisi. Angiomas were found in 15.2 per cent of the autopsies in case of cerebral haemorrhages, but in 58 per cent of the surgically treated intracerebral haemorrhages. These figures are higher than those given in the relevant literature. Among 1600 cerebral tumours, there were 2.2 per cent massive cerebral haemorrhages. The cases are compiled in a table.