Anemia of azaribine in the treatment of psoriasis. Azaribine is an effective agent in the treatment of psoriasis. In this investigation the extent of clinical dermatologic remission appeared to correlate with the degree of metabolic block induced by 6-azauridylic acid, as quantitated by the urinary excretion of orotic acid and orotidine, and the development of anemia. Following azaribine therapy there was a coordinate rise of the specific activities of erythrocyte orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. There was no correlation between the pretreatment activity of these enzymes and the clinical response to azaribine. The anemia of azaribine therapy was mile and of a megaloblastic type. Uridine effectively corrected the azaribine-induced anemia, but led to exacerbation of the patients' psoriasis. Following uridine therapy there was a reduction in the urinary excretion of orotic acid and orotidine, presumable reflecting end-product inhibition or repression of the first steps of a repeated pyrimidine biosynthesis.


Ultrastructural study of testis in testicular feminization. Testicular tissue was investigated by electron microscopy in a case of testicular feminization. The seminiferous tubules were lined by spermatogonia and by Sertoli cells. Spermatocytic maturation was not observed. Leydig cells were numerous and contained well developed, abundant vesicular smooth-surfaced endoplasmic reticulum and large mitochondria with tubulovesicular cristae. Reinke crystalloids were absent. The ultrastructural findings were consistent with the assumption that Leydig cells were under adequate stimulation and were in a stage of active secretion. Hence, the results seem to indicate that testicular endocrine function was maintained in the studied case.


[Study of the HL-A system in Basedow's disease (author's transl)]. HL-A typing has been carried out in 100 caucasians with Graves' disease and compared with 270 healthy controls. 25 HL-A antigens were characterized using a lymphocytotoxicity microtechnique. Analysis of the results reveals an increased incidence of HL-A8 antigen (35% in patients as compared to 16,3% in controls), with a high degree of statistical significance: p=0.0002 and corrected p X 25) = 0.005. We did not observe a clearcut correlation between the presence of HL-A8 and different characteristics of the disease: sex, age of onset, familial history, exophtalmia, goiter, severity. The knowledge of the relationships between the HL-A8 gene and several auto-immune diseases is a strong argument in favor of the auto-immune nature of Graves' disease. The association between HL-A8 and Graves' disease could be explained by a close linkage between the second HL-A locus and one or several Ir-IgG loci occupied in predisposed individuals by predisposing alleles. In these subjects, an antigenic contact with an exogenous etiological agent would induce a pathological immune response, with production of thyroid stimulating IgG.


The ultrastructure of the interstitial cells in human fetal ovaries. Steroid-active interstitial cells (stromal lutein cells) in human fetal ovaries of 12, 15 and 22 weeks of gestation were studied by means of electron microscope. The large cells, which are predominantly situated in the vicinity of capillaries, show high structural similarity to Leydig cells (type A) of the fetal testis. Both are characterized by extensively development of smooth endoplasmic reticulum, accumulation of lipids, and numerous mitochondria of the tubular type containing osmiophilic inclusions. Whether the interstitial cell system of the fetal ovary has any specific function in developmental physiology of the genital system cannot be decided on the basis of the present results. Its differentiation may only indicate adequate response of competent mesenchymal cells to gonadotropic stimulation.


[Morphological study of a prolactin-secreting pituitary adenoma after therapy with 2-bromo-alpha-erogocryptine (CB154) (author's transl)]. After treatment with CB 154 of a prolactin-secreting pituitary adenoma a morphological study reveales that many cells present a positive immunofluorescent reaction with anti-ovine prolactine antibody. At the ultra structural level, many granulations and vacuolated dense bodies can be observed.


[The ratio birth-weight, placental weight and the term of delivery. A contribution to the problem of a relative placental insufficiency in late pregnancy (author's transl)]. It is suggested, that a relative placental insufficiency in late pregnancy is one of the releasing factors of childbirth. Under this assumption 1027 deliveries in term pregnancy (266th-294th day of pregnancy) were inquired on the interrelationship between the ratio brith-weight: placental-weight and the duration of pregnancy. The average birth-weight increases slighly but significantly with the duration of pregnancy just as the average placental-weight. The average ratio birth-weight: placental-weight decreases significantly: The more unfavorable the ratio birth-weight: placental-weight is, the shorter remains the fetus in utero. This underlines the assumption of a relative placental insufficiency as one of the releasing factors of childbirth.


[Experimental candida vaginitis in the mouse (author's transl)]. Manifest Candida albicans infection of the vagina of mice was achieved only after oestrogen treatment. Histologically, different phases of vaginal candidiasis could be observed: the mycotic infection began with a massive colonization of Candida albicans in the horny layers of the vaginal epithelium and an early immigration of granulocytes. Abscess-like changes followed when high number of yeast cells were used for infection. One to two weeks after onset the inflammatory changes decreased and fungi were no longer identifiable in epithelial micro-abscesses by the methods employed. In contrast, yeast cells could be detected within the vaginal skin exhibiting weak inflammatory lesions up to the 57th day. Chemotactic studies showed that the fungi considerably stimulated the migration of mouse granulocytes in the presence of serum. Since mannan isolated from the Candida cell wall also possesses strong chemotactic activity, certain components of the fungal cell wall may play a pathogenic role in Candida colpitis.


[Histological diagnosis, DNA-content and chromatin pattern of breast cancer cases with positive and negative 17-beta-oestradiol receptor binding (author's transl)]. The DNA-concent of cell nuclei of 45 breast cancer cases of various histological structure has been determined cytophotometrically. With the exception of two gallert carcinomas no DNA-histogram of peridiploid range was found. The average DNA-content was 2--3 times higher as in the control tissue. The standard deviation of undifferentiated solid mammary tumors was the highest measured in this series. 24 of 45 cases had a negative oestrogen receptor binding. This was true in 60% of the undiffierentiated solid breast cancer cases, in 69% of the adenomatous and in 89 respectively 67% of the ones of special histological structure. The heterochromatin content of nuclei was lowest in the group of differentiated mammary cancer (50--60%). In the group of undifferentiated tumors it was 60--70%. So much for now is known about the mechanism of cellular action of 17-beta-oestradiol and the function of eu- and heterochromatin of cell nuclei it is discussed that positive or negative oestrogen hormone receptor binding in mammary tumor cells is probably a biochemical parameter of cytological desintegration. From this point of view these hormon receptors could be of the same value as the index of Barr bodies in breast cancer cells with respect of selection of cases for hormonal therapy. But this has to be analyzed in further studies extensively.


Investigations into the preservation of human ovaries by means of a cryoprotectivum. Human ovaries in the phase of follicular ripening were treated by means of a cryoprotectivum immediately after their removal. They were kept at --18degrees C for up to 8 weeks. After having gradually been thawed the ovaries were in vitro connected to a perfusion system. When completely revitalized they were examined in the steady-state for their metabolic behaviour. It was found that in comparison with the untreated controls, depending on the period of preservation, the oxygen consumption and the estrogen secretion had decreased, while the glucose absorption and lactate production had increased. As a morphological substrate a minor oedema was established in the tissue in the histological control after a preservation period of 2 months. This was mainly localized around the arteries. The method can be regarded as suitable for the preservation of ovaries for a limited period of time. It is possible to maintained a metabolism that can still be regarded as functioning.


[Asteroid plastic surgery as optimum management of complete and partial vaginal occlusion (author's transl)]. Opinions differ about the type of surgical procedure to be applied in cases of complete or partial vaginal occlusion. The large percentage of postoperative vaginal stenoses and functional disorders necessitated a search for a new technique. The mucous membrane of the introitus vaginae is incised in the shape of a lying cross and the four flaps thus made are detached. Then an exactly lateral incision is made on each side of the crossing point described above resulting in a broad access to the vagina. Once the opening is wide enough, a second group of triangular flaps is formed vertically to this horizontal incision; the dimensions of the triangular flaps in the inner and outer group must be identical. Then the outer four flaps are turned inward and the four inner flaps are turned outward and interlinked so that a zig-zag line is formed which encircles the vagina in the area of the former stenosis. Thus far this surgical technique has been applied five times and yielded satisfactory results in every instance.


A trend in the therapy of Amanita phalloides poisoning. Recent experimental evidences have been produced on the protection afforded by penicillin G in rats poisoned by Amanita phalloides extracts. A therapeutic trend which combines penicillin G infusions to the classical supportive measures was applied to 33 cases of severe A. phalloides poisoning, with 100% survival rates. The possible mechanism of the protective effect of penicillin G in A. phalloides poisoning is discussed.


The effect of N-alkyl groups of substituted phenyl-N-alkyl carbamates on the inhibition of human plasma cholinesterase. The inhibition constants for human plasma cholinesterase (dissociation, carbamylation, decarbamylation, overall bimolecular rate constants) were determined for two series of substituted phenyl-N-alkyl carbamates. N-propyl carbamates were found to be better inhibitors than the corresponding compounds carrying smaller N-alkyl groups. In both series the carbamylation constants of N-ethyl carbamates were lower than those of the N-methyl and N-propyl analogues, whereas the decarbamylation constants of the former were found to be higher than those of the latter carbamates. The experimental results obtained with human plasma cholinesterase are compared with published inhibition constants determined for several types of acetylcholinesterases.


A death case involving tilidine.

A death case involving tilidine. A fatal poisoning case due to the combination of a relative overdose of barbiturates (600 mg daily) and 750 mg of tilidine is reported. The concentrations of barbiturates and tilidine with its metabolites were determined in blood, liver, and urine.


Metabolic and toxic behavior of phthalimide derivates. I. Fate of imidan in the fetus. The organophosphate insecticide imidan includes a phthalimide group. Because of the structural relationship to the teratogenic compound thalidomide we have investigated its placental transfer and metabolic fate in rats. Its passage to embryonic tissues could be confirmed. After intraamniotic injection to the first amniotic cavity of the left uteri we could establish a distribution of imidan and 32P compounds throughout the uteri, the concentration depending upon the incubation time and the distances from the place of injection. The half-life of imidan, detected in the exterioized fetuses or in newborns, was 50--70 min. Imidoxon, i.e., the oxidized form of imidan, has a diminished half-life. This fact explicates the presence of imidoxon only in small concentrations after application of imidan.


Therapeutic effects of some cholinolytics in organophosphate intoxications. The therapeutic effects of pipethanate (sycotrol) and two newly synthetized cholinolytics, DPX-8 and ANC-51, were compared with atropine in mice poisoned by DDVP, fluostigmine, phospholine, and paraoxon. The antagonistic activotagonistic activity of tested drugs against acetylcholine-induced contraction of rat ileum and oxotremorine-induced salivation and tremor in the mouse was also studied. The anticholinergic activity of pipethanate, DPX-8, and ANC-51 was weaker than that of atropine. However,the therapeutic effect of pipethanate was higher than that of atropine in mice poisoned by the organophosphates. DPX-8 and ANC-51 afforded a better antidotal effect than atropine only in DDVP-poisoned mice.


Experimental manganese lymphadenopathy in guinea pigs. Experimental manganese lymphadenopathy was produced by guinea pigs by intratracheal inoculation of manganese dioxide (50 mg/300 g body weight) and histopathologic changes in the tracheobronchial lymph nodes were studied up to 180 days. There was slow extracellular transport of manganese dust into the nodes, which did not provoke any significant reaction at early periods. However, at later periods the nodes exhibited a significant increase in the density of dust particles and the reaction consisted of phagocytosis, degeneration of dust laden macrophages, slight proliferation of fibroblasts, together with some reticulinosis corresponding to deposits of dust particles. The significance of these findings have been discussed from the chronic toxicity viewpoint.


Biotransformation of As(III) to As(V) and arsenic tolerance. The paper deals with excretion of As(III) and As(V) in the urine of mice exposed to a toxic concentration of As(III) (250 mg/1) in drinking water. After the exposures of 2, 6, and 8 days, the mice were given i.m. a solution of 74As(III) labeled sodium arsenite in a dose of 1.3 mg As(III)/kg b.w. and an activity of 3 muCi/l ml. After the sacrifice of the animal, the urine was drawn off directly from the bladder. The urine samples were subjected to separation of As(III) from As(V) by using a paper radiochromatography technique. The results showed that unexposed control mice excreted one-half of the administered As(III) in the form of As(V). Mice exposed to arsenic in drinking water exceted already, after 2 days of exposure, four-fifths of the applied As(III) in the form of As(V), after 4 days of exposure the proportion of As(V) was more than 95%, and after 8 days of exposure only traces of As(III) were present. The authors discussed the possibility of the biotransformation of As(III) to As(V) on arsenic tolerance.


In vitro system for toxicological studies on the development of mammalian limb buds in a chemically defined medium. In organ culture systems using the Trowell setup, morphogenetic differentiation (which largely mimics the development reached in vivo within 2--3 days) can be obtained in limb buds of mouse embryos during a culture period of 6 days. We succeeded in improving the technique and in achieving good differentiation of the limb buds in a chemically defined culture medium from which all additions of the heterologous serum used in previous studies were omitted. With this technique of using a chemically defined medium, the following results were obtained: (1) A high degree of reproducibility can be obtained in the grade of differentiation if the experimental conditions are standardized and limb buds of the same developmental stage (somite stage) are used. (2) The technique is applicable to species other than mice, such as rats and rabbits, however, the results obtained so far are not so satisfactory as those acquired with mouse limb buds. (3) In an attempt to offer some colloid osmotic pressure, macromolecules like polyvinylpyrrolidone (Periston), polydextrans (Macrodex) or polypeptides (Haemaccel) were added to the culture medium. None of these macromolecules had a beneficial effect on the differentiation of the limb buds in vitro; in the case of Macrodex the differentiation was even impaired. (4) In comparison with the development in a serum-containing medium, the results attained with a chemically defined medium are just as good when judged from microscopical and some biochemical studies (total content of DNA, RNA, protein, and protein-bound hydroxyproline in the explants). The applicability of the test system for the evaluation of embryotoxic effects is discussed.


[The application of nitrogen detectors for arsenic determination in biological material (author's transl)]. An easy gc-determination of arsenic in biological samples with a nitrogen phosphorous detector is described. AsH3 is produced by reduction with NaBH4, and a sample introduced by the usual head space technique. The sensitivity of the method comes up to the concentration limits, which is of toxicologic interest.


Determination of dextropropoxyphene and norpropoxyphene in autopsy material by gas chromatography. A gas chromatographic method for the simultaneous determination of dextropropoxyphene and norpropoxyphene in autopsy material is described. The esters were hydrolyzed before the final determination. The mass spectra of the hydrolyzed esters are presented together with the results of an investigation of 6 cases of fatal intoxications.


X-ray crystallographic and gas chromatographic--mass spectrometric studies on norpropoxyphene. The crystal structure of norpropoxyphene maleate is presented. The conformation is discussed in relation to similar compounds. A gas chromatographic--mass spectrometric investigation indicates that earlier proposed metabolites may be formed during the gas chromatographic separation.


Circadian fluctuations in the activity of DNA-dependent RNA polymerases I and II in the nuclei isolated from mouse tissues and the significance for pharmacological and toxicological studies on transcription. For pharmacological and toxicological studies on the effect of drugs on transcriptional processes the basic fluctuation in activity during a 24-h period must be known. We have measured the activity of nuclear and mitochondrial DNA-dependent RNA polymerases in cell fractions from mice kept under defined dark/light and feeding schedules. The following results have been obtained: 1. Circadian variations in the activity of RNA polymerases are especially pronounced in the nuclei of liver tissue. These changes depend predominantly on feeding habits and they are comparatively independent on the dark/light schedule. A maximum in the activity of nuclear DNA dependent RNA polymerases can be observed shortely after the beginning of the feeding period. 2. The nuclei isolated from other tissues, such as brain, kidney or embryos during the late stage of embryogenesis shown considerably smaller, if any, fluctuations in connection with the feeding habits. These tissues seem to be especially suitable for pharmacological or toxicological studies on transcriptional processes. 3. While both nuclear DNA-dependent RNA polymerases shown a strong dependence on the feeding habits no obvious circadian viriations can be observed in the activity of the DNA-dependent RNA polymerase localized in the mitochondrial fractions of the same tissue. The regulation of these polymerases in different cell compartments apparently occurs quite independently. The conclusions for the design of experiments on induction processes occurring in liver tissues, drawn from the results presented, are discussed.


Possible influences of circadian rhythms in experimental carcinogenesis. The induction of tumours by chemical carcinogens depends not only on the chemical structure of the substance but also on biological properties of the target cell population, such as enzyme patterns, DNA repair mechanisms and the proliferative state of the cells. Interference with any of these processes can theoretically affect the tumour yield, as can variations due to biological rhythms. A series of investigations of circadian and circannual rhythms in the hairless mouse epidermis (hr/hr) is reviewed. DNA synthesis as well as the mitotic rate undergo great variations in the course of a 24-h period. The respiration and glycolysis in this epidermis undergo strong circannual variations. Evidence that the eventual tumour development after methylcholanthrene application to the skin is modified by circadian variations in DNA synthesis is presented and discussed in relation to pertinent data from other cell systems.


Genetic and hormonal regulation of steroid hydroxylases and drug metabolizing enzymes in rat liver. Two microsomal steroid hydroxylase activities (cholesterol-7alpha-hydroxylase and progesterone-16alpha-hydroxylase) were measured in the livers of Sprague-Dawley and Wistar rats and compared to three other monooxygenase activities (aryl hydrocarbon hydroxylase, p-nitro-anisole-O-demethylase and aminopyrine-N-demethylase). Cholesterol-7alpha-hydroxylase behaves in a very unique manner. It is the only one of the studied enzymes to be more active in the female than in the male, it is very poorly induced by phenobarbital and methylcholanthrene, but responds quickly to the administration of glucocorticoids. In fact, the cholesterol-7alpha-hydroxylase activity presents a very pronounced circadian rhythm which is under the control of the hypothalamo-adrenal axis. Marked differences are also found in the response of the various enzymatic activities to the administration of inducers as well as in their relative activities in untreated male and female animals.


The manipulation of circadian rhythms.

The manipulation of circadian rhythms. In a study on male Wistar (TNO) rats kept under phase-shifted light-dark (12:12) conditions, it was demonstrated that the circadian rhythms of the following functions were effectively synchronized to the new lighting regimen: (a) body temperature, gross motor activity (after 1 week of acclimatization); (b) stomach weight, liver weight, liver glycogen, liver protein and acid phosphatase activity; serum corticosterone, glucose, total protein and inorganic phosphatase (after 4-6 weeks; as concluded from the data pooled of a sex of identical experiments); (c) the in vivo toxicity of approximately LD50 amounts (i.p.) for antimycin A and of E 600. In the individual experiments the various normal functions appeared to be different with respect to sensitivity to light. The overall pooled results indicated that, except for glycogen, the 24-h means of the normal values in the stomach, liver and serum were slightly decreased when compared to the respective means obtained from standard LD (= light: 6:00-18:00)-conditioned control groups (P less than 0.001 for liver weight, liver protein, serum protein and inorganic phosphate). The experimental animals revealed an intermediate or persisting decrease of the growth rate. From the serial biological and toxicological studies performed in the course of 1 year, it is concluded that the synchronizing effect of an altered lighting regiment may be influenced by seasonal factors...


The circadian rhythm of synthesis and catabolism of cholesterol. The circadian rhythms of HMG-CoA reductase and cholesterol-7 alpha-hydroxylase (low values, during light, rising in the evening with maximum at 12.00 p.m.) are investigated in rats under diverse conditions. Intragastral administration of cholestyramine (bile acid-absorbing resin) leads to an increased rhythm of both enzymes. Feeding of cholic acid (or cholesterol) reduces the activity of both enzymes (of HMG-CoA reductase and cholesterol-7 alpha-hydroxylase, respectively). In starved rats enzyme activity and time of day is proportional to the metabolism of a substrate.ies are lowered, too; a damped rhythm reappears after 24 h. A 20% fat diet (containing saturated fatty acids predominantly) markedly reduces the high values. Enzyme activities inhabited after thyroidectomy can be normalized by thyroxin substitution. Thyroxin administration in the normal remains without effect. Four-day insulin treatment of the normal inhibits cholesterol-7 alpha-hydroxylase, has no effect on HMG-CoA reductase. In the untreated diabetic rat cholesterol-7 alpha-hydroxylase is increased, HMG-CoA reductase significantly inhibited. Insulin treatment of the diabetic animal results in normalized values of HMG-CoA reductase whilst cholesterol-7 alpha-hydroxylase is nearly completely suppressed. The rate-limiting enzymes of cholesterol turnover are peripherally regulated by their products via a negative feedback. In contrast, hormones may have synergistic or opposite effects; thus they may represent means of higher regulation. All regulative possibilities discussed (except hypophysectomy) do modifiy the circadian rhythms. This cannot be demonstrated after hypophysectomy. After hypophysectomy circadian rhythms are not detectable any more. To get valid data about biochemical or pharmacological effects on these enzymes the circadian viriations have to be considered by measuring at different times of day (e.g. fat diet); for only the area of enzyme activit


Circadian rhythm of the renin-angiotensin-aldosterone system in the rat. The 24 h-course of plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma corticosterone concentration (PCC) and of the urinary excretion of sodium, potassium and aldosterone was investigated in male Sprague-Dawley rats under different experimental conditions. The data obtained can be summarized as follows: 1. The renin-angiotensin-aldosterone system (RAAS) of the rat is subject to a circadian rhythm which is largely in phase with the well-known rhythm of the pituitary-adrenal axis. This rhythm can be demonstrated in PRA as well as in plasma concentrations and urinary excretion rates of aldosterone. The rhythm of urinary excretion of electrolytes is unlikely to be due to the rhythm of aldosterone secretion. 2. The light-dark cycle is the main synchronizer for these rhythms: inverting the light-dark cycle for 5 weeks entirely inverts the rhythms of all the parameters cited. 3. A dissociation of the rhythms of PRA and PAC can be observed following sodium restriction or dexamethasone treatment. A role of ACTH IN regulating the rhythmic pattern of aldosterone secretion is suggested by the finding that PAC and PCC follow the same pattern of circadian variations under every experimental condition tested. 4. The responsiveness of the RAAS to stimulation or suppression varies with the time of day. 5. It is suggested that experiments ought to be performed not only during the inactive (light hours) but also during the active (dark hours) phase when investigating the RAAS in the rat. This can conveniently be achieved by the use of an animal room with a reversed lighting regime.


Circadian influences on clinical values in man. 1. The circadian patterns of clinically relevant parameters were studied in 109 young, healthy soldiers. 2. Erythrocytes, hematocrit, creatinine and cortisol exhibited very stable rhythmic patterns which were found by continuous examinations of the same persons as well as in examinations of different persons at different times. 3. The rhythmic patterns of leukocytes, blood glucose and body temperature were strongly influenced by stress caused by the first confrontation with an unknown hospital-like situation or by pain caused by blood sampling.


The relevance of drug-induced organ pigmentation in animals. Postmortem examination of animals from long-term safety evaluation studies often reveals pigment deposition in tissues. A review of several such observations is given and the possible chemical backgrounds of their origin are described, in an attempt to aid the determination of relevance in individual cases. It is suggested that one may be fairly broad-minded in the interpretation of the relevance of such pigments, especially if they are found only in one species, and have no influence on the function of the organs involved. A final answer comes only after administration of the particular drug to man, although he is normally dosed at all events one should not overvalue the relevance of pigmentation found in long-term animal studies.


Teratogenicity and embryotoxicity of some maleinimides. Maleinimide, the teratogenic structural "central part" of the thalidomide molecule, and 5 of its dichloro- and dibromo-derivatives have been investigated teratologically by tests on SWS mice. According to both the electrophilic properties and the spatial requirements of the substituents, the effects were found to be up to 100 times stronger than those of thalidomide, and up to 10 times stronger than those of phthalimide respectively. The results are referred to the distinct electron-acceptor behavior of the maleinimide compounds, which--due to their flat molecular structures--are able to intercalate into the DNA double helix forming EDA complexes with nucleic acid bases as electron-donor molecules. The results can be interpreted as another confirmation of Jönsson's intercalation hypothesis of the thalidomide action.


Neurotoxic effects of dichloroacetylene. In inhalation tests involving lethal as well as sublethal doses of dias examined in rabbits by means ofhistologic and neurofunctional methods. Histologic examination revealed chromatolysis, disintegration of Nissl bodies, and cell shrinkage in proportion to the doses employed in the nuclei of the unpaired brain stem, in the sensory cortical regions and especially in the sensory cranial nerve nuclei. The sensory trigeminal nucleus was involved most severely, followed in decreasing intensity 0y the facial and oculomotor nerves and the motor trigeminal nucleus; the least changes were observed in the acoustic nerve. By testing the protopathic sensitivity of the facial skin it was possible for the first time to produce evidence of a sensory loss in the distribution of the trigeminal nerve by animal experimentation. The neuropathological and functional deficits observed may explain the cranial nerve lesions in human DCA intoxication; however, these lesions seem to be less distinct in experimental animals.


Differential pulse anodic stripping voltammetry as a rapid screening technique for heavy metal intoxications. This paper describes a relatively simple and rapid analytical procedure capable to carry out systematic screening for 10 heavy metals, namely mercury, bismuth, antimony, copper, lead, tin, thallium, indium, cadmium and zinc. Differential pulse anodic stripping voltammetry was chosen because of its simplicity, speed, low cost, low detection limits, screening potential for a wide selection of metals and the combined qualitative and quantitative output. The method of identification is based on measuring peak potentials in 2 different types of electrolyte solution, using 2 different electrodes. Complexing agents are used to mask certain elements.


Binding of inorganic mercury by subcellllar fractions and proteins of rat kidneys. Inorganic mercury, administered to rats in a single dose of 0.5 mg Hg/kg is accumulated in the kidneys mainly in the soluble (54%) and nuclear (30%) fractions, showing decreasing tendency with time. Mitochondrial and microsomal fractions, initially accumulating approx. 11 and 6% of total Hg, show a tendency to increase the absolute level of Hg for the first week after administration. In the soluble fraction low-molecular weight, metallothioneinlike proteins are mainly responsible for the accumulation of mercury, in other fractions proteins of higher molecular weight prevail.


[A rapid carboxyhemoglobin determination by means of non-dispersive ultra-red gas analysis (author's transl)]. A rapid and reliable method of carboxyhemoglobin determination is described. Hemoglobin-bound carbon monoxide is released chemically into a continuous nitrogen stream and transported to an infrared gas analyser. The total amount of released CO is determined electronically. 100% CO Hb values are obtained in the same way from diluted blood samples after flushing with pure CO in special saturation vessels. The method described yields results with a standard deviation of +/- 2.5%.


Irreversible protein binding of 14C-imipramine in rats in vivo. Forty-eight hours after a single dose of 14C-imipramine to rats, 14C-radioactivity could be measured in the following organs: liver greater than kidney greater than serum greater than fat greater than spleen greater than duodenum greater than lung greater than muscle and brain. Liver microsomes contained the main part of radioactivity derived from 14C-imipramine. After exhaustive extraction, only the proteins of liver, kidney, spleen, lung and serum contained measurable amounts of radioactive labeling. The greatest amount of 14C-imipramine irreversibly bound to proteins was detected in liver microsomes. The question, as to whether the irreversible protein binding of imipramine, if it occurs during therapy, results in toxic side-effects, is discussed.


[Synthesis and Quaternation of Pyridine-aldoxim Alkylethers (author's transl)]. Using known procedures, alkylethers of pyridine-aldoxime not described as yet were prepared and transformed into pyridinium salts. The application of a solution of a,a'-di-iodo-dimethyl-ether proved especially useful in the synthesis of bisquarternary salts with formaldehyde-acetal bridge. All the new substances are ineffective in a paraoxon poisoning. On the other hand, some salts show protective action in soman intoxication.


Release of highly soluble substances from inert matrices in cases of two-sided attack of the solvent. The present work is an extension of some of our earlier investigations on the release of soluble substances in inert matrices. There have been described the cases of two-sided attack on the inert matrices (PVC and PE) by the solvent. The theoretical considerations of the cases for the two-sided attack were experimentally confirmed. The values of the diffusion coefficients, which correspond to the calculated ones in the cases of one-sided attack, were calculated as well.


Spectral mapping, a technique for classifying biological activity profiles of chemical compounds. A mathematical technique is described that separates potency from spectral information in biological activity spectra. The technique is a preliminary step in the classification of chemical compounds and in the structuring of pharmacological assays. The method is illustrated using previously reported results on 40 neuroleptics in 12 assays on rats. Principal component analysis and cluster analysis are shown to provide complementing information.


[On the simultaneous effects of ionising radiation and chemical agents on animal cells. 1st communication. Cytogenetic studies on X-rays and isonicotinic acid hydrazide in the Chinese hamster, Cricetulus griseus (author's transl)]. In bone marrow cells of Chinese hamsters enhanced chromosome damage is observed after 48 h treatment of the animals with isoniazid (INH) combined with X-rays only at much higher doses than normally applied in human therapy. Compared to X-ray-induced aberration levels, 125 mg/kg INH and 50 R given simultaneously increase the number of gaps and breaks, the latter being increased over-additively. This points to an interaction between both agents. The combined treatment changes the mitotic rate of the bone marrow as well.


Classification of psychoactive drugs by visually evoked potentials in rabbits by means of multiple discriminant analysis. A possible way of predicting the clinical efficacy of new psychoactive drugs. The influence of representatives of various groups of antipsychotic drugs on the visually evoked potential (EP) was investigated with the aid of a modified recording and evaluation technique for the rabbit EEG from cortical and subcortical structures. The starting point was the hypothesis that changes in the EP in animal experiments caused by representative members of these "substance groups" (neuroleptics with predominantly antipsychotic or predominantly sedative effect, and antidepressants with predominantly mood-brightening or predominantly sedative main components) make predictions of the clinical efficacy of "unknown" substances possible on the basis of clinical therapeutic principles of classification. Experiments were carried out with haloperidol and fluphenazine, chlorpromazine, amitriptyline and doxepin, and with imipramine and clomipramine, as representatives of these classes of substances. The hypothesis was checked by attempts to assign amitriptyline and chlorprothixene in varying dosage, haloperidol, benzperidol and mianserine to appropriate classes. As classification and assignment procedure we used stepwise multiple discriminant analysis (SWDA) according to our modification of the BMD 0 7 M Program. The purpose of the latter program, and its applicability to our studies, are described and discussed. It was found 1. that with EP data from animal experiments it is possible to classify various groups of psychoactive drugs on the basis of clinical therapeutic findings, using SWDA; 2. that assignment of "unknown" compounds can be based on this classification; 3. that hence with some caution predictions of the clinical effect of newly developed substances may be made on the basis of findings in animal experiments. The EP variables which contain most information for making up the separation formula and hence are of special importance, are investigated with respect to their possible neurophysiological evidential value, and their significance is discussed. It was found that the EP from the visual cortex are of particular significance for the separation of groups in the form presented here.


[Pharmacological Properties of Fendiline in Cardiac and Smooth Muscle (author's transl)]. The pharmacological properties of fendiline N-(1-phenylethyl [1])-3,3 - diphenylpropylamine-hydrochloride; Sensit, were investigated in the isolated guinea pig heart and in isolated circular smooth muscle strips of bovine coronary arteries, pulmonary arteries and trachea. 1. Fendiline dose dependently increased coronary flow by up to 200% but, different from verapamil, did not inhibit contraction. 2. Fendiline dose dependently relaxed  coronary strips and, more powerfully, tracheal and pulmonary arterial strips. 3. In cardiac muscle, fendiline was almost completely retained for a prolonged period of time. In the smooth muscle tissues under study, fendiline accumulated twenty-fold above the concentration present in the organ bath. 4. In paced hearts, fendiline non-competitively inhibited the positive inotropic effect of isoprenaline in doses that did not significantly depress the amplitude of isotonic contractions. 5. In the guinea pig heart, adenosine uptake becomes progressively inhibited when coronary flow increases. This "washout" effect was definitely counteracted by fendiline and by NaNO2, but was augmented by papaverine, hexobendine and dipyridamol. The counteraction of the "washout effect" by fendiline as well as by NaNO2 is most likely due to the opening of additional (previously closed) capillaries.


Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine. 1. It was investigated whether the calcium antagonistic coronary drugs verapamil and nifedipine have similar antiarrhythmic properties. Their effects on functional refractory period and contractile force in the isolated left guinea pig atrium were compared. To assess their influence on myocardial excitability the relation between threshold voltage and pulse duration was studied in the left guinea pig atrium. Furthermore, the influence on AV conduction was investigated in the conscous dog in haemodynamically equieffective dose ranges. 2. Verapamil as well as nifedipine cause a dose-dependent prolongation of the functional refractory period in the isolated left guinea pig atrium. The slope of the dose-response curve of nifedipine is, however, significantly less steep than that of verapamil. Maximum prolongation of refractory period which can be induced by nifedipine is significantly inferior to that occurring after verapamil; under nifedipine this prolongation is, however, accompanied by a significantly greater reduction in contractility. 3. In the isolated left guinea pig atrium the voltage-duration curve is shifted to the right and the chronaxia value is significantly increased by verapamil. Even in the highest dose possible nifedipine has no effect on atrial excitability. 4. In the conscious dog verapamil considerably prolongs AV conduction time whereas a moderate yet dose-dependent shortening of PQ duration is observed with equieffective nifedipine doses regarding the decrease in blood pressure and increase in heart rate. 5. The results indicate that nifedipine does not exert antiarrhythmic effects comparable to those of verapamil.


[The effect of n-butanol on the metabolic status of some organs of rats and the circulation of rabbits]. Rats received n-butanol i.m. in a dose of 0.1 g/kg body weight/die during 50 days. The metabolic status of some organs was examined and compared to that of rats which in control experiments had received 0.9% NaCl-colution in an equivalent volume (double blind experiments). The tissue levels of metabolites of the adenylic acid-creatine phosphate system, of glycogen, glucose and lactate exhibited no significant differences in both the groups. In the liver the tissue level of glycogen, free creatine and total creatine was significantly elevated in rats which had received n-butanol. In concious rabbits the effect of n-butanol on circulatory parameters was investigated in double blind experiments. n-butanol was without a significant effect in a dosage of 0.008 g/kg. A dosage of 0.033 g/kg and particularly of 0.1 g/kg resulted in a transitory decrease in the heart rate and the systolic and especially diastolic blood pressure.


Experiments on the detection of the carcinogenic N-nitroso-dimethylamine in the urine of rats after oral administration of the analgesic amidopyrine and nitrite. N-Nitroso-dimethylamine (NDMA) was excreted unchanged in the urine of rats after oral administration of the compound in amounts ranging from 0.003% at a dose of 2 mg/kg to 0.08% at a dose of 15 mg/kg. By measurement of the NDMA excreted after oral administration of amidopyrine and nitrite, the extent of nitrosation in vivo was estimated to be about 30%. For clinical investigation of NDMA formation in patients treated with amidopyrine, however, we consider this method to be too insensitive.


[Isolation and structure determination of metabolites of xantinol from rat urine (author's transl)]. In the urine of rats as metabolites of the theophylline-derivative 7-[2-hydroxy - 3 - (N-methyl-N-2-hydroxyethyl)-amino-propyl]-1,3-dimethylxanthine (xantinol), the two stereoisomeric 2-coffeinyl-N-methyl-6-hydroxy-morpholines were found. These compounds represented about 7 to 8 percent of the eliminated xantinol and can be described structurally as semiacetals of a terminal aldehyde formed from Xantinol. Their structure has been elucidated by combined NMR- and mass-spectrometry. After oral application of xantinol-nicotinate in therapeutic doses to male test subjects, the same substances were detected by thin-layer chromatography. Both compounds could be synthetized by treatment of 7-[2,3-epoxypropyl]-theophylline or 7-[2-hydroxy-3-chloro-propyl]-theophylline with methylami-noacetaldehyde-dimethylacetal and subsequent hydrolysis of the reaction product with hydrochloric acid.


Secretion and irrigation of gastric mucosa during disulfiram effect. Experimental study in the dog. The effect of ethyl alcohol and disulfiram (Antabuse) on the secretion and the irrigation of an isolated and denervated gastric pouch has been studied in the dog. In these conditions, disulfiram increased the differential acidity; the association of ethanol with disulfiram impaired the proteolytic activity of the secretion and induced a hyperirrigation of the gastric mucosa more definite than with ethanol alone. Effects on ethanol absorption from stomach are discussed.


Pharmacological properties of thiazolinobutazone (LAS 11 871). III. General pharmacology, ulcerogenic effects and acute toxicity. 2-Thiazoline - 2 - ammonium-4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedionate (thiazolinobutazone, LAS 11 871, Fordonal) has been compared with phenylbutazone in a variety of pharmacological tests with a view to side effects and toxicity. Thiazolinobutazone was the less toxic (acute LD50) and the less ulcerogenic molecule of the two and, in contrast to phenylbutazone, was not antidiuretic. Some signs of activity on the autonomic and somatic nervous systems were seen following high doses of thiazolinobutazone which appeared to be related to inhibition of cholinesterases.


Bromperidol, a new potent neuroleptic of the butyrophenone series. A comparison of the effects of bromperidol and haloperidol in intracranial self-stimulation. Bromperidol, a new potent and long-acting neuroleptic of the butyrophenone series, and haloperidol were injected s.c. at the doses 0.01, 0.02, 0.04 and 0.08 mg/kg, in rats implanted with electrodes in the lateral hypothalamic region of the medial forebrain bundle. A dose-related response inhibition was found with both compounds and the graphically estimated ED50 value was 0.041 mg/kg for bromperidol and 0.047 mg/kg for haloperidol. These data are in complete agreement with our previous findings that bromperidol is a new potent and specific neuroleptic.


[Cholinergic contraction of the dog urinary bladder by electrical stimulation of the n. pelvicus and the ligamenta lateralia nerves and its affection by atropine and scopolaminebutylbromide (author's transl)]. As is well known contraction of the urinary bladder induced by electrical stimulation of the N. pelvicus-hypogastric plexus in the dog can only be diminished by atropine but not completely abolished. The result of stimulation can, however, be quantitatively abolished by the quaternary ammonium base hyoscine-n-butylbromide (scopolaminebutylbromide, Buscopan). Apart from antimuscarine-like peripheral effects, Buscopan also possesses, in contrast to atropine, antinicotine-like ganglion-blocking properties. Since Buscopan possesses only anticholinergic properties the contraction triggered off by stimulation of the nerve can be considered as being purely cholinergic. In the collateral ligaments of the urinary bladder of the dog there is another nervous system which when electrically stimulated contracts the bladder. Depending on the dosage the effect of stimulation can be diminished or abolished by atropine as well as by Buscopan. The result of stimulation can be diminished by hexamethonium and increased by eserine (physostigmine). Because of the effect of atropine-Buscopan (inhibition) and eserine (increase) this nervous system can be characterised pharmacologically as cholinergic.


The effect of rifamycin SV on the wound-healing process. The influence of rifamycin SV on the healing process of a wound was studied in animal experiments. Measurement of the degree of cicatrization, determination of the free hydroxyproline in serum, and histological findings helped to demonstrate that local application of rifamycin SV leads to an increased fibrinous conglutination of the lips of the wound at an early phase of the healing process and the subsequent formation of fibres in the regenerative tissue is not impaired.


[Penetration, permeation and resorption of heparin. In vivo studies on human skin]. The penetration and permeation of radioactive heparin into human skin was investigated as well as absorption and excretion. Heparin concentrations and vehicles were those that are in common use in practical therapy. It was shown that in spite of its high molecular weight, heparin can penetrate through the intact horny layer barrier. The concentration of heparin found in the skin, e.g. 10 I.U./ml in the epidermis and 0.6 I.U./ml in the corium are biologically relevant and are expected to be able to exert an influence. The penetration rates have shown a clear dependence on the kind of vehicle.


[Isolation and characterisation of two main metabolites of ifosfamide from human urine (author's transl)]. Two main metabolites of the cytostatic agent 1,3,2-oxazaphosphorine-3(2-chloroethyl)-2-[(2-chloroethyl)-amino]-tetrahydro-2-oxide (ifosfamidd as two different dechloroethylated derivatives. They both can also be derived from ifosfamide in vitro by means of KMnO4-oxidation. The metabolites are stable in organic solutions and they show no cytotoxic activity in biological test systems. In the urine of a patient treated with ifosfamide, nearly 50% of the applied dose were excreted as dechloroethylated derivatives. In the urine of other patients "carboxyifosfamide" was the main metabolite. It is assumed that the therapeutic effect of ifosfamide depends partially on whether side chain oxidation or ring oxidation is the predominant way of biotransformation.


[The geriatric pharmacology of cefazolin, cefradin and sulfisomidine]. Clinical pharmacology of 3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-8-oxo-7-(tetrazol-1-ylacetamido)-5-thia-1-azabicyclo-(4,2,0)oct-2-en-carbonic acid (cefazolin) and D-7-[2-amino-(cyclohexa-1,4-dien-1-yl)-acetamido]-3-methyl-8-oxo-5-thia-1-aza-(4,2,0)-oct-2-ene-2-carbonic acid monohydrate (cefradine) was compared in young and old adults without renal disease after i.v. injection of 1 g. Mean serum levels of cefazolin after 4 h and 6 h were significantly higher in old persons (25.0 and 14.7 mug/ml, resp.) than in young persons (16.2 and 7.8 mug/ml, resp.). Serum concentrations of cefradine after 2 and 4 h were found also higher in the aged (11.2 and 4.4 mug/ml, resp.) than in young adults. Half-life of cefazolin was prolonged from normally 94 min to 189 min, half-life of cefradine from 32 min to 72 min. Skin blister fluid punctured once for antibiotic assay contained less cefazolin in old persons (after 4 and 6 h only 22.4 and 17.4 mug/ml, resp.) than in young persons (32.7 and 27.6 mug/ml, resp.). Cefradine levels in skin blister fluid 0.5 and 1 h after i.v. injection showed also a significant difference (11.4 and 11.9 mug/ml, resp.) in old persons, 17.3 and 16.5 mug/ml, resp., in young persons). Elimination constants (alpha, beta, kel, k12, k21) were always lower in geriatric patients. Renal clearance of cefazolin was reduced from 83 ml/min to 43 ml/min, and renal clearance of cefradine from 378 ml/min to 152 ml/min. After i.v. injection of 1 g 6-sulfanilamido-2,4-dimethyl-pyrimidine (sulfisomidine) total content of the drug in blood was higher in elderly people than in young persons, but proportion of acetylated sulfisomidine was nearly the same in both groups (15%). It is supposed that higher serum levels of some drugs in old persons (over 70 years) can be explained by impaired renal excretion and slower tissue penetration of the compound from the blood.


Pharmacokinetics of coumarin upon i.v. administration in man. The disposition pharmacokinetics of coumarin has been studied after i.v. administration in man, and might be described best by an open two-compartment model. Three dose sizes have been studied, 0.125, 0.2 and 0.25 mg/kg. The mean biological half-life was found to be 1.81, 1.45 and 1.49 h, respectively, for the three dose sizes. Coumarin is extensively distributed. The volume of the central compartment apparently comprises the extracellular and intracellular fluid. The study indicates dose-dependent (non-linear) pharmacokinetics with respect to distribution.


Cobalt-induced experimental epilepsy in cats pharmacologically immunodepressed. An EEG and histological study. The authors made 11 adult cats epileptic by implanting cobalt powder on the left sensorimotor cortex. Some of the animals were treated with the immunodepressant drug, cyclophosphamide (Endoxan), before and after surgery, and others were not. Then the two groups of animals were compared in terms of EEG and histopathological findings. The treatedanimals showed a definite reduction of focal electrical activity both primary and secondary, and a much milder perifocal parvicellular infiltration and cerebral edema. In view of these findings, the authors suggest that in addition to other well-known factors, the pathogenesis of cobalt-induced experimental epilepsy involves immunological mechanisms triggered by the release of nerve tissue antigens as a result of tissue injury caused by cobalt. This would result in the formation of antibodies directed against several brain constituents. Last, the authors submit that a similar autoimmune mechanism may be at play also in the pathogenesis of some forms of focal epilepsy of traumatic origin.


[Animal studies on the tolerability of NAB 365 (clenbuterol) (author's transl)]. The findings of acute, subacute and chronic toxicity studies in rats and dogs with the new beta-mimetic agent 4-amino-alpha-[(tert.-butylamino)methyl]-3,5-dichlorobenzyl alcoholhydrochloride (NAB 365, clenbuterol) are reported. The longest period of investigation, with daily oral administration of the substance, was 18 months (rats) and 12 months (dogs). No abnormalities of any kind were found in the rat studies which could be attributed to the substance. The administration of clenbuterol to dogs produced microscopically small lesions in the myocardium which were not dose-dependent and which were localised entirely in the papillary muscle of the left ventricle. The reason for these lesions was that dogs react to the substance with severe tachycardia, as a consequence of a reduction in diastolic blood pressure produced even by very low oral doses. Oxygen deficiency occurs which affects particularly the papillary muscle. The response to hypoxia is better capillarisation. This causes an improvement in the oxygen supply, which in turn prevents the spread of existing necroses and the development of further lesions.


[Reproduction-toxicologic tests with a new beta-mimetic agent clenbuterol (NAB 365) (AUTHOR'S TRANSL)]. The reproduction-toxicologic tests on rat and rabbit yielded no indication of a teratogenic potency of the beta-mimetic agent 4-amino-alpha-[(tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol-hydrochloride (clenbuterol, NAB 365). The fertility test showed no signs of reduced fertility. Excessive dosage of NAB 365 to pregnant rats led to an increased mortality of the pups during the neonatal period. A dosage of 1 mg/kg is regarded as the maximum tolerated dosage in perinatal toxicity tests.


[Electron microscopic study of guinea pig tracheal epithelium after administration of NAB 365 (author's transl)]. After application of 4-amino-alpha-[(tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, NAB 365) the following changes in the secretory cells of the tracheal epithelium of the guinea pig can be visualised by electron microscope: 1. increase of membrane-bordered structures which might be regarded as primary lysosomes, 2. a faster and more pronounced loosening of secretion granula. These findings suggest a selective site of action of the substance at the lysosomal system. It is stimulated, loosens the secretion intensively already within the cell, and possibly develops some activity even in the lumen. These conceptions can serve as an explanation of the clinically and experimentally demonstrated secretolytic effect.


[Pharmacokinetics and metabolite pattern of clenbuterol in the rat]. Pharmacokinetics and metabolite pattern of the beta-sympathomimetic 4-amino-alpha-[tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, NAB 365) have been investigated in the rat. After a single i.v. dose of 2 mg/kg 14C-NAB 365 up to 10 min p.a. the blood level falls very steeply and 15 min p.a. there is an increase to be observed. A maximum blood level of 0.85 mug eq. NAB 365/ml is achieved. Then a biphasic elimination of radioactivity from the blood occurs. After a single oral dose of 2 mg/kg the maximum blood level of 0.5 mug/ml is attained 2 h p.a. Again a biphasic elimination occurs. 26 h is the half-life of the slower of two elimination processes for i.v. and p.o. administration, respectively. Elimination predominantly takes place via the kidneys. After i.v. administration 85% and after p.o. administration 80% of the radioactivity applied are eliminated in urine and faeces. The main portion of radioactivity had been eliminated by 48 h p.a. As can be seen from the urinary radioactivity absorption is complete. Following i.v. dosing the excretion is slightly faster than after p.o. administration. Whole-body autoradiography and the distribution of radioactivity in the organs show a relatively slow absorption after p.o. dosing. In the pregnant mouse the placenta barrier is passed but the fetuses contain far less radioactivity than the mother animal. Clenbuterol is metabolized in the rat. 70% of the radioactivity represents the unchanged parent compound in urine (38% of the administered radioactivity). 8 metabolites have been established in urine (extracts). Faeces radioactivity mainly contains unchanged clenbuterol and only traces of metabolites. The metabolite pattern of the maximum plasma level (2 h after p.o. administration) and the metabolite pattern of the collected urines are identical. 38% of the administered radioactivity represent unchanged NAB 365 in the urine, whereas there are 45% in the plasma.


[Comparison of the pharmacokinetic profiles of clenbuterol in rat and dog during toxicological studies (author's transl)]. The pharmacokinetics of the beta-sympathomimetic 4-amino-alpha-[(tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, NAB 365) have been investigated in two animal species during the chronic toxicological studies after single and multiple dosing. After oral administration of 2.5 mg/kg (dog) and 5 mg/kg (rat) the plasma levels showed significant differences. Moreover, a marked sex difference was to be seen in the plasma levels of the rat. The excretion, established only in the dog, showed no difference after single or multiple administration. The elimination occurs predominantly via the kidneys, and the main urinary elimination product is the unchanged clenbuterol. Each of the 8 metabolites is formed only in minor quantities. The biotransformation is not altered by long-term administration. The differences in the plasma levels that are observed with larger doses can be explained by the biological adaptation of the gastrointestinal tract during multiple administration.


[Elevated creatine kinase activity in serum following oral application of a beta2-mimetic broncholytic drug (NAB 365) (author's transl)]. In 25 patients with chronic bronchitis it was shown by a study of 9 months' duration (3 months before treatment, 6 months under treatment) that after peroral application of 4-amino-alpha-[(tert.-butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, NAB 365) elevations of the activity of creatine kinase occur without other recognizable signs and symptoms. The isoenzyme of creatine kinase were differentiated by immunological means and proved to be of the MM-type in additional 9 patients. The significance of the elevations of creatine kinase activity in serum even after peroral intake of drugs has been discussed.


[Biotransformation of diflucortolone valerate in the skin of rat, guinea pig and man (author's transl)]. The biotransformation of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, DFV, Nerisona) was examined in vitro in the skin of rat and man and in vivo in the skin of guinea pigs. In the investigations with rat skin DFV in ethanolic solution (0.1 mumol) was added and the ester hydrolysis in buffer monitored in relation to the incubation time. In the experiments with guinea pigs and with human skin DFV was applied topically in the form of a 0.1% W/O emusion employing a dose of 6 mg/cm2 skin. After the substance which had not penetrated had been recovered by means of cotton wool and adhesive film at the end of the period of exposure the portions of skin were homogenized, extracted and the extracts separated by thin-layer chromatography. DFV is hydrolysed in the skin of rats and guinea pigs with a half-life of about 30-60 min to diflucortolone 6alpha,9-difluoro-11bets,21-dihydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione) and valeric acid. In excised human skin degradation of the ester proceeds much more slowly. Even 7 h p. appl. about 80-90% DFV and only 5-15% DF were identifiable in the skin extract. Despite the estremely low absorption rate the slow hydrolysis of DFV in human skin guarantees an adequate level of active ingredient in the skin over a long period.


[Toxicological examination of pure diflucortolone valerate and its formulations as ointment, fatty ointment and cream in animal experiments (author's transl)]. On the basis of absolute DL50 values 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) is virtually non-toxic after single oral administration (mouse greater than 4 g/kg, rat ca. 3.1 g/kg, dog greater than 1 g/kg). Given s.c. (LD50 mouse ca. 180 mg/kg, rat ca. 13 mg/kg) and i.p. (LD50 mouse ca. 450 mg/kg, rat ca. 98 mg/kg) it is highly active and therefore produces also toxic effects. The formulations Nerisona ointment, fatty ointment and cream have proven practically non-toxic in rats after single oral gavage (LD50 greater than 33 g/kg). The daily s.c. administration over 6 weeks revealed systemic glucocorticoid effects in rats at 0.0004 mg/kg and in dogs at 0.04 mg/kg. Similar effects were seen in dogs after daily dermal treatment for 13-14 weeks with Nerisona ointment at 100 mg/kg body weight. On the skin of rabbits and dogs there were no differences in the reaction at the application site between Nerisona ointment, fatty ointment and cream and the corresponding ointment, or cream bases by daily dermal administration for 28 days. However, the 13-14 week dermal study in dogs with Nerisona ointment revealed atrophy of the epidermis at the application site in several cases. The daily dermal application of Nerisona ointment during organogenetic phases of pregnancy caused embryotoxic effects in rats at 500 mg/kg and in rabbits at 50 mg/kg. All of these findings are discusses as well-known glucocorticosteroid effects.


[Percutaneous absorption of diflucortolone valerate in guinea pigs and man (author's transl)]. Percutaneous  absorption of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (difucortolone valerate, Nerisona) as dependent on the base, the concentration in the base and the condition of the skin was investigated in man and in guinea pigs. In addition the distribution of the corticoid in the stratum corneum, epidermis and corium was determined by stripping the skin and by horizontal thin-section technique. 2. In man diflucortolone valerate from all of the formulations tested (0.1 and 0.3% cream, ointment and fatty ointment) was only absorbed to a slight extent by both the intact and the stripped areas of skin on the subjects' backs. In the case of the 0.1% formulations a total of about 0.2% of the dose was absorbed within 4 h via intact skin and about 0.4% via the stripped skin. After application of the 0.3% formulations the percutaneous absorption from the ointment, fatty ointment and cream were examined separately. This revealed percutaneous absorption within 7 h of 1.7% from the ointment, 0.7% from the fatty ointment and 0.5% for the cream by combined determination through 1 intact and 1 damaged area of skin. 3. Percutaneous absorption via intact skin is slight in the case of the guinea pig also. Absorption is accelerated considerably by the removal of the stratum corneum, however, and shows a characteristic dependence on the concentration of the corticoid in the base. Whereas the corticoid from the 0.03% ointment is almost quantitatively absorbed within 7 h, absorption from the 0.5% ointment is reduced to about 30%. 4. The absolute concentrations of active ingredient in the epidermis are approximately 10(-6) mol/l and drop to approximately 10(-7) mol/l in the corium (guinea pig in vivo, man in vitro). An active ingredient flow equilibrium (inflow = outflow) is reached in the skin of the guinea pig after only 1 h.


[Pharmacokinetics and biotransformation of diflucortolone valerate in man (author's transl)]. Two male normal subjects were each given 1 mg of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione1,2,4-3H (3H-diflucortolone valerate, Nerisona) by i.v. injection. The pharmacokinetics and biotransformation of the corticoid were examined by measurement of the total activity in the blood, plasma, urine and faeces and by thin-layer chromatographic analysis of the spectrum of the metabolites in plasma and urine. The compound is very rapidly degraded. No more intact ester was identifiable in the plasma 5 min after injection while, at the same time, 6alpha,9-difluoro-11beta,21-dihydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione (diflucortolone), the product of hydrolysis, was present in a concentration of 6-8 ng/ml plasma. The half-life of diflucortolone in the plasma was 4-5 h, that of the total 3H-steroids about 9 h. 80-40% of the 3H-steroids in the plasma were in unconjugated form. Besides diflucortolone and two unidentified metabolites chromatographic comparison demonstrated the presence of 6alpha,9-difluoro-21-hydroxy-16alpha-methyl-1,4-pregnadiene-3,11,20-trione (11-keto-diflucortolone) as a further metabolite in the plasma. The elimination was rapid and complete: by 24 h after injection approximately 56% of the dose had been eliminated with the urine and by 7 days after administration 98 and 93% of the dose had been recovered in urine and faeces. The ratio of elimination urine to faeces averaged 3:1. Within 48 h after the injection about 30% of the dose was eliminated in the form of unconjugated 3H-steroids, about 20% as 3H-steroid-glucuronides and about 10% as 3H-steroid-sulphates. Diflucortolone was demonstrable both in the unconjugated form and as glucuronide and 11-keto-diflucortolone as glucuronide and as sulphate. A total of 7 metabolites were characterized in the urine by means of chromatography.


[Comparative studies in man on the percutaneous absorption of diflucortolone valerate, betamethasone-17-valerate, beclomethasone dipropionate and fluocinolone acetonide]. Percutaneous absorption of 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadience-3,20-dione (diflucortolone valerate, DFV, Nerisona), betamethasone 17-valerate (BV), beclomethasone dipropionate (BDP) and fluocinolone acetonide (FA) by damaged skin was examined on the backs of 4 healthy males from whom the stratum corneum had been removed by "stripping". The determination of percutaneous absorption was performed on the one hand by a method employing radioactive labelled compounds (DFV, BV) and measuring the elimination with the urine and faeces and on the other hand by photometric determination (DFV, BV, BD, fa) of the corticoid remaining on the skin immediately following application and at the end of a 24-h period of exposure. Direct measurement of the radioactivity in the urine and faeces revealed that percutaneous absorption from a new W/O emulsion takes place up to 2.2+/-0.8% in the case of DFV (0.1%) and to at least 12.2+/-3.3% in the case of BV (0.12%) within 24 h. The determination of percutaneous absorption via recovery from the skin produced the following results for the 4 corticoid preparations examined: DFV (14.8+/-4.2%) and BDP (14.0+/-4.3%) approximately equal, BV (23.5+/-4.1%) a marked increase and FA (39.2+/-2.4%) the highest level of absorption. This order for percutaneous absorption appears to correlate to the frequency of systemic side effects.


[Efficacy of diflucortolone valerate in the vasoconstriction tests]. The efficacy of a new topical corticosteroid, 6alpha,9-difluor-11beta-hylerate, Nerisona), as a 0.1% cream, ointment and fatty ointment was investigated in the vasoconstriction test in two series of studies after application to human skin in which hyperaemia had been experimentally induced. The diflucortolone valerate W/O emulsion proved to be 100 times more effective than fluocortolone in an identical base. In a further study diflucortolone valerate as well as in the three preparations was compared with nine known corticosteroids or their commercial preparations. In the comparison of the preparations only the cream with 0.05% betamethasone-17,21-dipropionate was superior to the diflucortolone valerate cream. As regards all the other preparations of formulations the new substance proved to be more or at least equally effective.


[Reactivation of phosphorylated acetylcholinesterase (AChE): quaternary salts of vinylogous pyridinaldoxims (author's transl)]. Application of Wittig reaction to 4-pyridinecarboxaldehyde leads to 4-beta-formylvinylpyridine (62%). The corresponding oxime (4-(2)) can be quaternized with alpha,alpha'-bis-(chloromegonin), and with methyliodide one to 4-PAM (4-(3)). In this case the formal insertion of an ethylenic double bond between the pyridinium ring and the aldoxime group decreases the ability to reactivate phosphorylated acetylcholinesterase (AChE).


[Binding of sisomicin and gentamicin to serum proteins (author's transl)]. The binding of sisomicin and gentamicin to the proteins of human serum was investigated by the dialysis method at 37 degrees C. The antibiotic concentrations were determined by the disc diffusion assay as well as by measurements of the optical rotation of the antibiotics in the buffer solutions. Serum was dialyzed against buffer solutions to obtain the standards for the antibiotic assay with regard to the electrolytical exchange at dialysis. In studies on protein binding of sisomicin and gentamicin no measurable binding to human serum proteins could be found, neither in the therapeutically possible concentrations nor at higher ones. Therefore a different binding of the two antibiotics cannot be the reason of the advantage of sisomicin over gentamicin in tests in vivo with animals described in literature nor of its higher activity against several bacterial strains of different species tested in the presence of serum.


[Synthesis of a water-soluble orotic acid salt. Short communication. (author's transl)]. Description of the synthesis of thiaminedisulfide-monoorotate, the first salt of the orotic acid soluble in water with neutral action.


The uptake of potassium ions into isolated heart mitochondria in the presence of calcium ions and k-strophanthin. The conditions of potassium transport were investigated in isolated rabbit hear mitochondria. In the presence of 5 to 40 mM potassium chloride there is a rapid initial phase of potassium influx of less than 2 min duration in which 65-75% of the total K+ uptake occurs. This is followed by a slow phase of K+ uptake of about 45 min during which 25 to 35% of the total potassium was taken up. While the rapid phase is due to passive diffusion, the slow phase is an active process which requires either ATP or respiratory substrates as an energy source. It can be totally abolished by 0.5 mM antimycin A. An increase of the calcium concentration in the incubation medium to more than 5 X 10(-5)M resulted in an inhibition of the energy-dependent uptake of potassium which was directly proportional to the calcium level. k-Strophanthin induced a distinct inhibition only at very high concentration  (greater than 10(-4)M). The inhibition of potassium uptake by 1. 3 or 5 mM calcium chloride was gradually cancelled by increasing k-strophanthin concentrations above 10(-8)M. Maximal cancellation was found with 10(-5)M of k-strophanthin. This concentration almost completely prevented the inhibition by calcium ions. On the other hand, 10(-5)M k-strophanthin had no inhibitory effect on the energy-dependent uptake of 0.5 mumoles of calcium chloride or on the oxidative phosphorylation of 0.5 mumoles of ADP added to the incubation medium.


Cardiovascular effects of an antiarrhythmic aminosteroid ORG 6001 in the anesthetized pig. The hemodynamic effects of 3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride (ORG 6001), an aminosteroid possessing antiarrhythmic properties, were studied in 14 anesthetized pigs. ORG 6001 was administered i.v. cumulatively until a toxic level was reached. Doses less than 20mg/kg had, in spite of the negative inotropic properties of ORG 6001, no effect on the pump function of the heart, as the afterload was reduced and the filling pressure was not significantly altered. After administration of 40 mg/kg A-V conduction was depressed and second degree A-V block appeared. This was associated with deterioration of the pump function and for 6 of the 14 animals this was fatal. In the survivors, the alterations were reversible after cessation of drug administration. Since ORG 6001 has been shown to be effective against arrhythmias at doses less than 20 mg/kg, though in a different species (dog), it seems likely that it can be used safely for antiarrythmic treatment.


[Acute myocardial infarct and pindolol. Effect of a beta sympatholytic with intrinsic sympathomimetic activity on hemodynamics and contractility]. After acute circumscribed myocardial infarction the effects of the beta-sympatholytic agent 1-(indol-4-yl-oxy)-3-isopropyl-amino-propan-2-ol (pindolol; Visken) on hemodynamics and contractility were examined. Hemodynamic changes after application of pindolol are of small extent only. Heart rate shows a rising tendency whereas systolic and diastolic aortic pressure decreases only after higher doses. Left ventricular end-diastolic pressure (LVEDP) does not change remarkably. Cardiac output is reduced by small doses of pindolol and reaches starting values again before the administration of higher doses. Changes of the contractility parameters (dp/dt)max, t-(dp/dtmax, and PEP in the sense of a beta-sympatholysis appear only in the lower range of the doses given. Thus maximum decrease of contractility is 20% measured at (dp/dt)max, which consequently reaches the starting value again. The other contractility parameters change accordingly. These typical dose-response relations between pindolol and contractility parameters are considered to be due to lacking cardiac depressive properties combined with significant so-called positive intrinsic activity. Our results show that no contraindication can be derived from the small influence of pindolol on contractility in acute myocardial infarction.


Effects of cinepazide, a new vasoactive substance, on heart and circulation in the dog. The authors report on the action of a new drug, 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-trimethoxycinnamoyl)-piperazine-maleate (cinepazide), on the heart and systemic and coronary circulation. At doses of 1--3 mg/kg i.v. (n=6), systemic blood pressure decreased by 4%, and heart rate increased reflexly by 8%...


Influence of cinepazide, a vasoactive substance, on canine coronary circulation after acute constriction of the left anterior descending coronary artery. The left anterior descending coronary artery was variably constricted mechanically in nine dogs. Blood flow in the left anterior descending (LAD) and circumflex coronary arteries (CCA), aortic pressure and peripheral, i.e. post-stenotic coronary pressure were measured. Myocardial perfusion was determined from the clearance of radioactive xenon injected at a depth of 7 mm into the underperfused area supplied by the LAD artery. The vasoactive drug 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-tri-methoxycinnamoyl)piperazine-maleate (cinepazide) was given at doses of 5-10 mg/kg by i.v. route. 1. Blood flow in the LAD was decreased stepwise to 50% of its initial value. There was practically no more coronary reserve. After drug injection, diastolic aortic pressure, that normally falls, was kept constant by clamping. Heart rate, perfusion pressure, post-stenotic pressure, and blood flow and resistance in the LAD showed practically no change. In the CCA, blood flow increased significantly (p less than 0.005) and flow resistance decreased (p less than 0.001). 133Xe clearance showed an increased myocardial perfusion (p less than 0.02) in the territory supplied by the LAD artery. 2. The lumen of the LAD was narrowed by 53%, i.e., coronary reserve was decreased. This constriction was followed by no haemodynamic reaction. After injection of cinepazide, mean and diastolic aortic pressure (p less than 0.02) and post-stenotic coronary pressure (p less than 0.005) decreased. Blood flow increased by 41% in the CCA and by 31% in the LAD. Coronary resistance in these vessels decreased (p less than 0.001 and 0.005, respectively). Here, too, the 133Xe clearance curve showed an increase in myocardial perfusion in the territory supplied by the LAD artery (+78%).


The distribution and excretion of 14C- and 3H-labelled 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370) in the rat. The distribution and excretion of radioactivity following a single or multiple oral administration of 3H-and/or 14C-4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370) has been determined in rats. The daily excretion of radioactivity following a single administration (3H and 14C) or multiple doses (3H) fell to less than 1% of the dose in 4 days. A similar fall was observed at the end of 10 days continuous administration. The radioactivity in plasma reached a maximum between 2 and 4 h after administration of the drug (14C). Tissue levels were found to be effectively zero 24 h after administration of the drug for up to 10 days. The very large amounts of radioactivity lost in bile were found to correlate with blood, tissue and faecal levels.


Acute toxicity of various solvents in the mouse and rat. LD50 of ethanol, diethylacetamide, dimethylformamide, dimethylsulfoxide, glycerine, N-methylpyrrolidone, polyethylene glycol 400, 1,2-propanediol and Tween 20. The LD50's of various solvents frequently used in toxicological work to improve the solubility of otherwise poorly soluble compounds were determined in the mouse and rat. The substances investigated were ethanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, glycerine, N-methylpyrrolidone, polyethylene glycol 400, 1,2-propanediol and Tween 20. The substances were administered under standardized conditions to groups of 10 animals (5 females, 5 males) (mice and rats) at doses that supplied at least 3 values lying between the LD16 and LD84. The median lethal dose and slope were determined with the aid of Finney's programmed probit analysis. The results are tabulated as LD50 ml/kg with 95% confidence limits. It is recommended that when using these solvents for pharmacological and toxicological investigations not more than a quarter of the LD50 should be used because otherwise there will be confusion between the deaths due to the substance being investigated and those due to the solvent.


[Influence of an antispastic, analgesic combination on blood pressure, dynamics and contractility of the left ventricle in the dog]. The following cardiovascular parameters were continuously measured in 12 dogs anaesthetized with sodium pentobarbital following i.v. application of Baralgin, a combination of 1-beta- piperidino-ethoxycarbmethoxy-benzophenone-hydrochloride with diphenylpiperidino-ethyl-acetamide-bromomethylate and 2.3-dimethyl-4-methylamino-1-phenyl-5-pyrazolone-N-methanesulfonic acid: Mean arterial blood pressure, left ventricular pressure, dp/dt-value in the left ventricle, the parameter (see article), told peripheral resistance, cardiac work, heart rate, cardiac output and stroke volume, flow rate in the A. femoralis and the repiration volume. In this experimental series dosages of 0.1, 0.25, 0.625 and 1.56 ml Baralgin/kg i.v. were tested and the subsequent cardiovascular activity was recorded for a period of 90 min following application. 1. The mean arterial blood pressure remained practically unaltered following low doses of Baralgin (0.1 and 0.25 ml/kg i.v.), whereas higher doses (0.625 and 1.56 ml/kg) led to an initial drop in blood pressure corresponding to the fall in total resistance. 2. The cardiac output rose slightly in correlation with rise in stroke volume. In the dosage range of 0.25 ml Baralgin/kg i.v. the rise in cardiac output was accentuated by an increase in heart rate. 3. The cardiac work remained relatively stable following small Baralgin doses, however, a slight diminution in cardiac work due to the fall in blood pressure and decrease in cardiac output, resulted from application of 1.56 mg/kg i.v. 4. A slight positive inotropic stimulation of the heart became apparent in the initial period following small doses of Baralgin (0.1 and 0.25 ml/kg i.v.), higher i.v. dosages caused a marginal reduction in cardiac contractility.


Assessment of Hypervitaminosis D during the first trimester of pregnancy on the mouse embryo. Preliminary report. The effect of hypervitaminosis were studied in pregnant mice during 0-3 and 4-7 days of gestation. After pregnancy was determined, mothers received 50 000 I.U. of vitamin D2 during the first gestational period. During the first half of the first trimester, the vitamin D treatment did not significantly influence maternal weight, fetal weight, implantation rate and survival of the embryo. The number of mothers with malformed fetuses significantly increased during critical treatment periods (from 4-7 days of pregnancy.


Effect of short- and long-term administrations of some drugs on rat intestinal flora. Short communication. Two schedules of treatment were adopted for an experimental evaluation of drug induced alterations in mid-small intestinal flora of normal rats. Test substances were given orally twice daily for 3 days at large doses and once daily for 30 days at lower doses. Indometacin, benzydamine, phenylbutazone, pheprazone, picosulfol, magnesium sulfate, tolbutamide, phenformin, dexamethasone acetate and prednisolone acetate were tested. Drug-induced alterations in rat intestinal flora resulted more evidently following multiple short-time treatments.


Antagonism of maximal metrazol seizures in rats and its relevance to an experimental classification of antiepileptic drugs. The antagonism of various components of maximal Metrazol-seizures (MMS) (i.e. tonic hindpaw extension, tonic backward extension of the forepaws, generalized clonic seizures and tremors), ataxia and loss of righting reflex-activity have been studied in a standardized procedure comparing 41 antiepileptics and related compounds. Appropriate analyses (Cluster Analysis and Principal Component Analysis) resulted in the distinction of seven clusters which could be considered along two continua. A first continuum is characterized by a progressive strengthening of loss of righting reflex-inducing properties, a decreasing dissociation of ataxia and loss of righting reflex and the disappearance of a selective anticonvulsant effect. The second continuum is characterized by an increasing relative potency of ataxia-inducing properties, an increasing dissociation of ataxia and loss of righting reflex and a decreasing antagonism of tremors. Three main types of anticonvulsants could be defined: drugs with a complete anti-MMS effect antagonizing both clonic and tonic seizures; drugs selectively abolishing tonic seizures, i.e., tonic extension of hind- and forepaws; and drugs exclusively blocking tonic hind-paw extension. The neurological and clinical significance of these different types of anticonvulsant activity has been discussed. Finally, the described modification of the maximal Metrazol-seizures test is proposed for routine screening purposes.


Influence of silymarin on drug metabolizing enzymes in rat and man. Male rats weighing 100-130 g were treated orally with a daily dose of 1 X 10 mg Legalon (active principle: silymarin)/100 g b.w. daily for 4 or 10 days. 4 and 10 days after the beginning of the pretreatment a significant increase of the activity of the mixed function oxidation system (Cytochrome P-450, aminopyrine demethylation, p-nitroanisole demethylation) was observed. No alteration of the body weight, the liver wet weight, the microsomal protein content, the cytochrome b5 content and the activities of glucose-6-phosphatase (G-6-Pase) and of a glucoronidase (4-methylumbelliferone) took place after the Legalon treatment. 4 h after the oral administration of 0.5 ml CCl4/kg b.w. the activity of the mixed function oxidation system and of the G-6-Pase was markedly decreased. This effect could not be prevented by the oral administration of 1 X 10 mg Legalon/100 g b.w. 6 h prior to CCl4 application. In human subjects the treatment with daily doses of 3 X 70 mg Legalon during 28 days had no influence on the metabolism of aminopyrine and phenylbutazone. From our results it is concluded that Legalon despite its effects in experimental animals has no influence on drug metabolism in man, when applied in therapeutic amounts.


Studies of the kinetics and metabolism of 17 beta-heptanoyl-17 alpha-ethinyl-4-oestren-3-one-7-3H (norethisterone enanthate) in humans following intramuscular injection. The kinetics and metabolism of 17 beta-heptanoyl-17 alpha-ethinyl-4-oestren-3-one-7-3H (7-3H-norethisterone enanthate, NET-En) after i.m. injection in two female subjects is described. 177.4 mg and 174.5 mg NET-En were injected. Maximum 3H-activity in plasma was reached 8 to 14 days after the injection. In terms of NET-En it amounted to 70-100 mug/100 ml. Maximum NET concentration was reached on the 4th to 8th day and amounted to about 1 mug/100 ml. After 4 weeks NET concentration was still about 0.05 to 0.1 mug/100 ml and even after 6 weeks NET was still detectable in plasma. In 14 days the two subjects excreted about 13% of the administered dose in the urine and about 15% and 21%, respectively, in the faeces. On the basis of a rough calculation, the subjects eliminated about 60% and 55% of the radioactivity with urine and faeces within 42 days.


Experimental evaluation in man of analgesic effects. A device operated by compression has been studied in order to define a method of measuring analgesic effects. Three analgesics (metamizol, acetylsalicylic acid and ketobemidone) and placebo have been tested in man to verify the adequacy of this apparatus and its sensitivity.


A study of the EEG sleep patterns and the sleep and dream experience of a group of schizophrenic patients treated with sulpiride. The modifications of spontaneous sleep in schizophrenic patients following N-ethyl-2(2-methoxy-5-sulfamido-benzamidomethyl)-pyrrolidine (sulpiride, Dobren) administration are reported in this study. No significant modifications in the quantitative distribution of the various sleep phases (LST, SWS, REM) were observed, while a significant percent increase of SWS was noted, together with a significant decrease in the number of awakenings during the night and an increase of the sleep onset time. The patients' own difficulty to fall asleep, however, decreased significantly, and also a significant increase of dream recall could be observed.


[The autoradiographic distribution of 3H-spironolactone in whole-body slices of the mouse (Short communication)]. The autoradiographic localisation of H3-spironolactone in whole-body sections of mice is shown. The drug is enriched in the liver, bile-ducts and in the content of the small intestine, which probably indicates a biliary excretion.


Vitreoretinal reactions and persistent hyaloid vessels. In cases with persistent primary vitreous in full-term infants there were vitreoretinal reactions including vitreoretinal anastomoses of blood vessels, vitreoretinal strands, traction folds of the retina, avascular retinal areas, hypoplasia of retinal blood vessels, rarefaction of retinal ganglion cells, and ischaemic structural changes of the retina. New vessel formation on the surface of avascular retinal areas was supplied from persistent hyaloid blood vessels. This finding may be of some importance in explaining those cases histologically resembling classical retrolental fibroplasia with no history of prematurity or oxygen treatment.


Malignant lymphoma of the thyroid.

Malignant lymphoma of the thyroid. Two cases of malignant lymphoma are reported and the clinical features of a further 6 cases collected over a 10-year period are presented. The literature is reviewed and the treatment, prognosis and relationship to Hashimoto's disease are discussed. It is suggested that lymph node biopsy at the time of operation is important in confirming the diagnosis and that the prognosis may be more hopeful than has previously been suggested.


Some aspects of sexually transmitted disease in Swaziland. A survey of sexually transmitted diseases was attempted in Swaziland. Time and the terms of reference limited its scope, but much interesting information was gathered. Neither the prevalence nor the relative frequency of the different diseases in the community could be ascertained, but there was evidence to support the local impression that the sexually transmitted diseases present an increasing problem in Swaziland. An important problem was that of case finding and two aspects of this are stressed: (1) A general lack of knowledge concerning the venereal diseases; (2) The large number of men infected by 'casual' girl friends who cannot easily be traced, and who form a reservoir of infection in the community.


[Association of Hashimoto's disease with carcinoma of the thyroid]. The Authors describe a case, which came under their observation, of indifferentiated neoplasia of the thyroid associated with Hashimoto's disease; treated surgically by total thyroidectomy, at a distance of over four years it did not show signs of recurrence. Consideration is also given to pathogenetic and clinical problems, as well as those of surgical therapy, which such a combination between autoimmune thyroditis and a neoplastic process may raise.


Bromocriptine potentiation of gastric acid secretion in cats. Bromocriptine administered both orally and intravenously potentiated gastric acid secretion in response to submaximal pentagastrin stimulation in cats. Bromocriptine did not increase the maximum acid secretion in response to pentastrin, not did it stimulate basal acid secretion. Potentiation was observed in normal and vagotomized animals which precludes involvement of the vagi in the response. The mechanism of action of this compound on the stomach does not appear to be mediated through stimulation of dopaminergic receptors as no potentiation was observed with dopamine infusions. It is argued that the bromocriptine potentiation of gastric acid secretion may be a demonstration of 5-hydroxytryptamine or alpha-adrenergic antagonism. However, the potentiation observed with daily oral bromocriptine treatment had disappeared by the eighth day and may correlate with the disappearance of gastric side effects noted in patients on bromocriptine  treatment.


Studies on shigella isolated in southern Taiwan. During 1969, a total of 1,476 fecal and rectal swab specimens was collected from children with diarrhea and 249 strains of shigella were isolated. The incidence was 16.9%. The serotypes of 249 strains were: Shigella dysenteriae, 1.6% (4 strains); S. flexneri, 73.1% (182 strains); S. boydii, 3.2 (8 strains) and S. sonnei, 22.1% (55 strains). There was no marked difference of the isolation rate throughout the whole year. The susceptibility of shigella isolates to chemotherapeutic agents were also investigated. The percentage of the strains susceptible to gentamicin was 97.2%; to cephaloridine, 93.2%; to kanamycin, 91.9%; to colistin, 91.6%; to hetacillin, 88.4%; to ampicillin, 82.4% and to nalidixic acid, 79.9%. The other tested chemotherapeutic agents were less effective.


Determination of mycelial steroids with the aid of polyene antibiotics. II. Quantitative determination of the mycelial steroids of Mucor hiemalis. UV absorption spectrum of polyene antibiotics was dramatically altered in the presence of steroids. The introduction of a steroid to an aqueous solution of polyene antibiotics resulted in a change in the ratio of absorbance of peak 3 (with shorter wavelength) to peak 1 (with longer wavelength), E3/E1. Interactions between 28 steroids and 4 polyene antibiotics were studied and the results revealed that the structures of steroids essential for the optimal interaction with polyene antibiotics were C-17 side chain, substitution C-3 hydroxyl group, intact steroid nucleus and aromatic A-ring. The ratio of E3/E1 was used for the determination of steroids in mycelium of Mucor hiemalis and the result was in good agreement with that obtained from gas chromatograph. The (-) strain had a greater change in the ratio of absorbance, E3/E1, than that of the (+) strain. The ratio of absorbance, E3/E1, decreased in the following order: the (-) strain, the (-) strain with the addition of the filtrate of (+) strains, the mated strains, the (+) with the addition of the filtrate of (-) strain and the (+) strain.


Treatment of Taenia saginata infection with mixture of areca nuts and pumpkin seeds. In January and February 1974, 32 adults (20 males and 12 females) and a 13-year-old girl with taeniasis saginata were treated with the mixture of boiled areca nuts and pumpkin seeds at Mastoban, Jen-ai District, Nantou County, Taiwan. A total of 48 worms including 42 scolices were recovered from 29 cases. Side-effects were observed in 4 cases including 3 with complaints of dizziness, tinnitus, nausea and vomiting, and one with coma and abdominal pain. Mixtures of 75-150 g areca nuts and 50-100 g pumpkin seeds were judged effective and safe.


Mycoplasmal pneumonia in Chinese veterans. From 1967-1973, a total of 54 strains of Mycoplasma pneumoniae was isolated from patients suffering from different acute respiratory diseases, with an average positive isolation rate of 4.7%. Most mycoplasmas were isolated from patients aged 40-60, and with pneumonia of primary atypical pneumonias. The highest frequency of isolation was found in sputum collected 4-8 days after onset of illness. Colony formation on PPLO medium usually occurred 7-12 days after incubation. Serological tests were methods of choice for diagnosis of mycoplasmal pneumonia. In the 6 years period, 163 patients were diagnosed: 74 were positive only by metabolic inhibition test (MIT), 55 were positive only by cold agglutination test (CAT), and 34 gave positive by both tests. Of the above 2 tests, the CAT is nonspecific, but the MIT appears to be more sensitive and specific. Of the 94 sera positive by MIT, 42 (48.2%) were also positive by CAT; of those negative by MIT, 45 of 507 (8.8%) were positive by CAT. Of 45 sera with positive mycoplasma isolation, 37 (82.2%) were also positive by MIT, but only 22 (48.9%) showed the rises of CAT titers. Clinical features of mycoplasmal pneumonia were almost similar to those described by the other investigators. The chief symptoms were fever, coughs, chills, rales, malaise, sore throat headache and chest pain. The sedimentation rate of erythrocytes was accelerated. White count was normal in most cases. Both leucocytosis and leucopenia were found in 10% of the cases. Seasonal variation in incidence of mycoplasmal pneumonia was not obvious, however the lowest incidence occurred during summer. A roentgenogram of the chest was necessary for diagnosis of mycoplasmal pneumonia, and the lung infiltration was mainly located on right side (57.1%), segmentally, and limited to one lobe, especially the lower lobe.


Antithiamine factor in cotton seed (Bombex malabericum)--its isolation and characterization. 1. The antithiamine factor isolated from cotton seed (Bombex malabericum) was a light yellow amophous substance. 2. 1 mg of this antithiamine factor inactivated 20.5 mug of thiamine hydrochloride. 3. The antithiamine factor was characterized as 3,5-dimethoxy salicylic acid.


Social aspects of venereal disease aboard a U.S. navy destroyer. This paper describes the social characteristics of venereal disease patients aboard a US Navy destroyer. The research team administered questionnaires to 247 crew members at the outset of the ship's 7 month-overseas deployment. When the ship returned to home port, the research staff gathered demographic and occupational information plus disciplinary records, job performance ratings, and complete dispensary visit information for the deployment period. The morbidity data indicated that 48% of the entire crew experienced at least one case of VD, and of these VD patients, 38% had multiple infections. A set of variables that best predicted VD incidence was determined by means of multiple regression analysis. These variables included disciplinary record, pay grade, division or type of job ("blue-collar" versus "white-collar"), and education. Other variables that correlated with VD incidence were age, length of service, marital status, performance ratings, and verbal aptitude scores.


Study of rickettsioses in Slovakia. III. Experimental infection of Apodemus flavicollis Melch. by rickettsiae of the spotted fever (SF) group isolated in Slovakia. Experimental studies of infection of Apodemus flavicollis, and for comparison of rickettsiaemia in Clethrionomys glareolus and of susceptibility and antibody formation in white mice, with rickettsiae of the SF group isolated in Slovakia, gave the following results: the species A. flavicollis reacted by the formation of antibodies on subcutaneous administration of rickettsiae, strain B, in an amount of 10(0.5) EID 50/0.25 ml, whereas the white mouse only in an amount of 10(2.5). Rickettsiae, strain B, administered in an amount of 10(3.5) EID 50/0.25 ml subcutaneously to A. flavicollis were found in smears from the liver and spleen of the inoculated animals up to the 25th day following infection, on detection by the isolation test on chick embryo yolk sacs in the spleen on day 5 and 7, in lymph nodes on day 7 and in the brain on day 15 following infection; on detection by the method of injecting suspension from the organs into the haemocoelom of ticks regularly in the spleen and liver up to the 10th day, in the brain, kidney and lymph nodes regularly up to the 15th and irregularly in the lungs also up to the 15th day, then regularly in the testes up to the 5th day and in the heart, blood and peritoneum up to the 3rd day after infection.