[Influence of tribenoside on spontaneous osteoarthrosis in mice (author's transl)]. 1. In 15- to 21-month-old male mice of the C 57 black strain that had been treated with a placebo (olive oil), the incidence of gonarthrosis was found to be 19% in the youngest and 61% in the older animals. If the very early stages are included, the incidences range from 36% to 65%. 2. Only the most severe degrees of arthrosis could be diagnosed radiographically; mild stages were only detectable by histological examination under the light-microscope. 3. The motility of the older animals severely affected with arthrosis (as measured by reference to their ability to run over a grid) was for the most part limited. 4. The percentage of mice with gonarthrosis was diminished by treatment with ethyl-3,5,6-tri-O-benzyl-D-glucofuranoside (tribenoside, Glyvenol) in doses of 150, 500 or 1200 mg/kg p.o. weekly over a period of three months. Comparison of the animals that had received tribenoside with those given the placebo (olive oil) revealed that the incidence of lesions was 36-60% less in the former. If the very early stages of arthrosis were included in the evaluation, the differences were statistically significant (P less than 0.05) at the two higher dose-levels. 5. Under the given experimental conditions, no clear-cut dose-effect relation on the part of tribenoside was demonstrable, since the youngest animals with the least marked arthrosis were treated with the smallest dose of the preparation and the older animals, in which the incidence of arthrosis was higher, with the larger doses.


[Study on the protective effect of vitamin A on stress ulcer of the rat (author's transl)]. The protective effect of vitamin A on "restraint stress" ulcer formation was studied in rats. Animals receiving i.m. injections of 1000 or 2000 IU vitamin A, respectively, every 6 h after 19 h of immobilisation had significantly fewer and smaller ulcers than had the controls. There was no difference between the 2 doses. Only a few rats had no gastric ulcers at all, that means the protection was not absolute. Therapeutic use of vitamin A in the prophylaxis of stress ulcer is discussed.


A new route of heparin administration--the lung. Instillation of a single dose of heparin into the lungs of the dog resulted in a steady prolonged hypocoagulability as measured by the Lee and White clotting time, partial thromboplastin and activated partial thromboplastin times. 15 mg of heparin/kg increased clotting time three to five times control values. The anticoagulant effect occurred within one hour and lasted 48 h or more, in contrast to the short effect of intravenous heparin. For doses of 8, 10, 12, 15 and 20 mg/kg, there was a corresponding increase in the area under the response curve. The very prolonged moderate anticoagulant state with intrapulmonary heparin did not show the wide fluctuations in coagulation test values which occur with intravenous heparin.


[Acute liver injury in rats by praseodymium nitrate (author's transl)]. After acute intoxication with praseodymium nitrate (10 mg/kg body weight i.v.), time functions of enzyme activities of GOT, GPT, ChE, AP and of free fatty acids concentration in rat serum were analysed and the results subjected to significance and correlation analysis. Time functions of free fatty acids concentration corresponded with those of enzyme activities of GOT and GPT. In the early state of intoxication serum concentrations of palmitoleinic and oleic acid were more increased than those of stearinic acid. There seems to be an alteration in the correlations of analysed measures with regard to their temporal changes parallel to the progress of intoxication.


[Possible therapeutic influences on experimentally induced edemas (author's transl)]. In pathogenetically different models the antiedemic effect of extractum hippocastani semen (EHS) for intravenous and oral use was to be demonstrated. The histamine-induced edema of the skin, the postischemic edema of muscle and the cerebral edema provoked by cold injury were used. In all the models tested, it was possible to obtain reproducible numerical results which made statistical evaluation of the experiments possible. Antiedemic protective effects could be demonstrated in all investigations, whereas in one model a curative effect could be proved, too.


[Experimental comparison of the tuberculostatic activities of INH, INHG and INHG-Na (author's transl)]. In a comparative experimental study the glucuronic acid derivatives of isonicotinoylhydrazone (INH), isonicotinoyl-hydrazone d-glucuronic acid lactone (INHG, Gluronazid) and INH-sodium glucuronid (INHG-N-A, Gluronazid pro infusione) were shown to have the same tuberculostatic activity as INH both in vitro and in vivo. As judged by the serum inhibitory activity the serum level shows a different temporal pattern. After the administration of INHG or INHG-Na, the inhibitory activity reaches its peak later than does INH but remains in the active range essentially longer. The most substantial and, with regard to therapy, most significant difference between INHG or INHG-Na and INH lies in the varying toxicological properties. Both the oral and intravenous LD50 increase in the sequence INH, INHG and INHG-Na. The i.v. LD50 of INHG-Na exceeds the oral LD50. As compared to INH the lower toxicity permits a higher dosage of gluronazide. Thus a continuously higher serum inhibitory activity can be achieved than with a corresponding INH therapy.


Interference of sulpiride with the mitogenic activation of lymphocytes cultured in vitro. The action of a psychotropic substance, N-ethyl-2(2-methoxy-5--sulfamido-benzamidomethyl)-pyrrolidine (sulpiride, Dobren), on cellular metabolism has been studied by means of the in vitro lymphocyte activation technique. The effect of the continuous presence of the compound in the culture, at a concentration permitting cellular vitality was evaluated. Furthermore the effect of the drug on the culture during the lymphocyte stimulating phase and during the incorporation phase of 3H-thymidine was separately evaluated. The results indicate that the sample population can be divided into two different groups depending on the modality of the response to the drug in vitro taken as activity index (A.I.). Whether our conclusion has any practical significance remains to be elucidated.


Effect of single and repeated administration of sulpiride on the restraint ulcer in the rat. Preventive activity of N-ethyl-2(2-methoxy-5-sulfamido-benzamidomethyl)-pyrrolidine (sulpiride, Dobren) upon restraint ulcer has been studied using two strains of rats (Wistar and Sprague-Dawley) treated with single or repeated administration of 5, 10, 20, 40 mg/kg i.p. of the drug. Wistar strain was shown to be less sensitive to the ulcerogenic procedure and a significant preventive effect of sulpiride occurred only at the dose of 10 mg/kg i.p. In the Sprague-Dawley strain a preventive effect was present not only at this dose but also at the dose of 20 mg/kg i.p. and 5 mg/kg i.p., the latter dose giving the greatest effect. Animals receiving the dose of 40 mg/kg i.p. did not differ significantly from the control in both strains. Results are discussed in relation to possible changes of the cerebral mono-amine turnover during the establishment of stress ulcer, particularly in terms of restoration of the balance between dopamine (DA) and norepinephrine (NE) neuronal activity.


Effect of sulpiride on serum gastrin in duodenal ulcer. The effect of N-ethyl-2(2-methoxy-5-sulfamido-benzamidomethyl-pyrrolidine (sulpiride, Dobren) on serum gastrin in patients with duodenal ulcer was evaluated. A statistically significant decrease in gastrinemia was observed. The possible mode of action of sulpiride is discussed. It is suggested that sulpiride by acting on the hypothalamus could possibly normalize the alterations of the mucosal barrier and restore the feed-back mechanism implicated in the autoregulation of antral gastrin secretion.


Absolute concentrations of an antimycotic agent, econazole, in the human skin after local application. The absolute concentrations of an antimycotic drug, econazole, 1-[2,4-dichloro-beta-(p-chlorobenzyloxy)-phenethyl]-imidazole nitrate, in the different layers of the skin are reported when the agent is applied to human skin in vitro and in vivo. The drug was tritium-labelled and incorporated into an ointment to give a 1% concentration as it is used in the therapy of dermatomycoses. This ointment was applied to the skin surface. After fixed time intervals, the skin was sliced parallel to the surface and the amount in each layer determined by liquid scintillation counting. In the in vivo investigations, the excretion of the drug in the urine was also determined. The results reveal that though up to 90% of the drug remain on the surface, about 20 mug/ml epidermal tissue and 1.5 mug/ml dermal tissue can be achieved. The amount which is excreted in the urine is equivalent to the quantity which enters the skin, i.e., the penetrating drug is absorbed by the circulatory system.


A new oral contraceptive based on the normophasic method. 62 women were treated for 554 cycles with normophasic oral contraceptive Fisioquens. A treatment cycle consists of 7 tablets of 0.05 mg ethinyloestradiol, followed by 15 tablets with a combination of 0.05 mg ethinyl-oestradiol and 1 mg lynestrenol. No pregnancies occurred. Both tolerance of the preparation and cycle control were good. Irregular bleeding occurred sporadically. Various side-effects diminished during treatment and even disappeared completely. Fisioquens appears to be a reliable contraceptive with a minimum of side-effects.


A model for studies of dermal surface epithelization: with observations on the effects of dexamethasone and nandrolone decanoate. Experiments were designed to study the events of cell proliferation and migration during epithelization of an intact dermal surface in man. Epidermis was removed by prolonged suction and epithelization was followed by serial skin biopsies. DNA-synthesis and migration of labelled cells were followed by radioautography. Migration and cell proliferation were not found to be exclusive events in this model. Dexamethasone applied locally in a cream base was found to delay epithelization and nandrolone decanoate was found to counteract this to some extent. The model can be used in studies on effects of drugs on events involved in epithelization.


Pharmacokinetics and relative bioavailability of vinylbital in man after oral and rectal administration. A sensitive and specific method for the quantitative determination of 5-vinyl-5-(1-methylbutyl)-barbituric acid (vinylbital) in plasma was developed, by using gas chromatography with alkali flame ionization detection. The method is suitable for measuring vinylbital plasma levels in man after administration of therapeutic doses. The pharmacokinetics and relative bioavailability of vinylbital after oral and rectal administration were studied in man. Tablets (Bykonox) containing 150 mg vinylbital, were used for the oral experiments and suppositories (Suppoptanox, polyethylene glycol base) containing 200 mg vinylbital, were used for rectal administration. Six volunteers participated in a cross-over way in the study. Vinylbital plasma concentrations were determined at regular intervals after drug administration. Absorption and elimination of vinylbital appeared to occur according to a single first-order process and the plasma concentrations were fitted by computer according to the equation intrinsic to the one-compartment open model after oral or rectal administration. The lag time was shorter for the suppository than for the tablet, whereas the absorption rate was faster for the tablet (mean absorption half-life 0.24 h compared with 0.64 h for the suppository). The elimination half-life of vinylbital varied from 17.6 to 33.5 h, with a mean value of 23.5 h for oral administration and 23.8 h for rectal administration. The half-lives were not considerably different on the two occasions for the individual volunteers. The average bioavailability of vinylbital for the suppository, relative to the tablet, was approximately 93%. Three volunteers collected their urine during 3--4 days after administration of a tablet. Unchanged vinylbital was determined and approximately 1.6% of the administered dose was excreted as unchanged drug. Some preliminary experiments of repetive vinylbital administration showed that self-induction of metabolism did not occur.


Passage of diazepam and desmethyldiazepam into breast milk. The aim of this investigation was to study whether and to what extent 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (diazepam, Valium) passes into the breast milk during repeated oral administration to nursing mothers. It was shown that diazepam and its main and also active metabolite desmethyldiazepam passed into the milk. Their concentrations, however, remained small as compared to plasma values. Desmethyldiazepam levels  in the milk were consistently higher than those of diazepam. These results are explained by the relative binding of both substances to plasma proteins. The maximum quantities of diazepam + desmethyldiazepam that can possibly be absorbed by a newborn with the milk of a mother receiving 10 mg Valium daily, are considered to be too small to cause any untoward effects in the baby. If, however, high doses of Valium must be administered repeatedly, breast-feeding should be discontinued for safety reasons.


[On the efficacy of a spleenic dialysate (M 40,412) in disturbed potency (author's transl)]. By means of a combined phallographic-exploratory method and using statistical classification we were able to confirm clinically the potency enhancing action of a spleenic dialysate (M 40,412, Solcosplen). The remarkable alleviation of chronic and acute disturbances of potency can be explained not only by the elevated serum testosterone levels but likewise by biochemical mechanisms of action in the target organ, as was demonstrated by a research group. The treatment of potency disorders of different genetical origins yielded as the outstanding conclusions: 1. The interdependence of dream- and erection phases, usually injured in disturbed potency, could be restored by M 40,412. 2. The effect of 40,412 was the more striking the more pronounced were the initial values. 3. A particular type of experiencing (feeling of inferiority and disturbed contact) appears to respond prevailingly well to M 40,412. Further clinical studies are suggested.


[EEG spectral analysis of caffeine effects]. Spectral EEG analysis is shown to quantify the centrally stimulating effects of caffeine. Comparing the effects of coffee, decaffeinated coffee, caffeine solution and placebo results in two groups of substances: coffee and caffeine solution on one side, decaffeinated coffee and placebo on the other. The within-group differences are negligible, whereas the between-group differences are highly significant. It may be concluded that caffeine is the effective factor. This study gives no valid evidence confirming possible effects of other coffee ingredients.


[The reactions of embryonic tissues and cells to xantinol-nicotinate in the culture (author's transl)]. The influence of xantinol-nicotinate (Complamin) or with its chemical designation 7-[2-hydroxy-3-(N-2-hydroxy-ethyl-N-methylamino) propyl]-1,3-dimethylxanthinepyridine-3-carboxylate and its formula: C19H26N6O6, on 2500 tissue cultures of embrynic epithelium, bone and connective tissues from the domestic chicken was examined. It was found that xantine-nicotinate at high concentrations strongly inhibits cell proliferation. It seems possible that this substance is insolubly bound to the nucleic acids. With the diminution of the concentration to values corresponding those in the human organism, the stimulation effects on mitosis and cell proliferation were striking, in bone and connective tissues stronger than in the epithelial tissues. In tissue culture there appeared eventually remarkable effects with very high doses not applied in human medicine.


Tolciclate against dermatophytes.

Tolciclate against dermatophytes. 0-(1,2,3,4-Tetrahydro-1,4-methanonaphthalen-6-yl)-m-N-dimethylthiocarbanilate (toliciclate; KC 9147) is a new topical antimycotic having an in vitro activity on dermatophytes between 0.1 and 0.01 mug/ml. It is fungicidal after some day's contact. It has the advantage over dyes used in the past for topical treatment of dermatomycoses in that it is colourless and is soluble in well tolerated excipients. It is more liposoluble than tolnaftate. In the guineapig skin infections with Trichophyton asteroides and Microsporum canis, it is usually 3 times more active than tolnaftate and, in some tests, up to 10 times.


[Studies on the excretion of various aminoglycosides in rat milk (author's transl)]. 10 mg/kg of strepto-, neo-, kanamycin, genta- and sisomicin were applied s.c. to rats in lactation. After 0.5, 1, 2, 4, 6, 8 and 24 h the animals were milked. The antibacterial concentrations in the milk were determined in comparison to the serum concentrations. Strepto-, neo- and kanamycin showed the highest concentrations in the serum, genta- and sisomicin the highest in the milk.


[Comparison between the pharmacokinetics of epicillin and ampicillin (author's transl)]. To anesthetized rabbits 6-[D-2-amino-2-(cyclohexa-1,4-dienl-yl)-acetamido]-penicillanic acid (epicillin, Spectacillin) and ampicillin were administered i.v. at doses of 50, 100 and 200 mg/kg, and up to 5 to 8 h thereafter the concentration was estimated in the plasma, urine and bile. Within 5 h, the blood levels took biexponential courses so that a two-compartment open model could be assumed. With epicillin all the different doses a more slowly decreasing tissue level and a higher total volume of distribution are obtained as well as a tissue volume of distribution higher than that with ampicillin. The clearance shows that both antibiotics are eliminated in the urine by glomerular filtration as well as tubular secretion and reabsorption. After 200 mg/kg of either antibiotic a three-compartment open model could be assumed, on the base of which only the volumes of distribution for epicillin could be completely determined. The total volume and the tissue volume of distribution are the same after each different dose of epicillin, whilst in the case of ampicillin both volumes are smaller and decrease with rising doses.


Specifity and sensitivity of the inhibition of drug metabolism following inhalation of carbon disulphide-air mixtures. A single 8-h exposure of adult female Wistar rats to 20 ppm carbon disulphide (CS2), the threshold limit value (TLV) in several countries, was sufficient to cause inhibition of the following drug-metabolizing reactions: formation of trichloroethanol and trichloroacetic acid from trichloroethylene (aliphatic C-hydroxylation), formation of 4-hydroxyantipyrine from antipyrine (quasi-aromatic C-hydroxylation), formation of acetaminophenol from acetanilid (aromatic C-hydroxylation) and phenacetin (oxidative odealkylation), respectively, and formation of 4-aminoantipyrine from aminopyrine (oxidative N-demethylation). The behaviour of these effects was dependent on the dose of CS2 administered in that the inhibitory process was enhanced when increasing the concentration to (50), 100, 200, and 400 ppm. The respective changes could be demonstrated by a short-duration (6-h) reduction in the urinary excretion of the metabolites. In the case of trichloroethylene the limitation in metabolite formation persisted for as long as 36 h due to the varying rate of formation of trichloroethanol and trichloroacetic acid. This deficiency in excretion was compensated in part during the subsequent elimination phase (up to 24 and 36 h, respectively), an observation which suggests the rapid reversibility of the alteration. As shown by the respective prolongation of the hexobarbital sleeping time in the rat, the side-chain oxidation of hexobarbital to ketohexobarbital was increasingly inhibited by rising concentrations of CS2 in the range of 20 to 400 ppm/8 h. On the basis of the present results it is concluded that CS2 also inhibits various oxygenases of the microsomal enzyme system. In adult female NMRI mice a significant inhibition of the microsomal procaine-hydrolyzing esterase of the liver was observed only after 400 ppm/8 h; however, this limitation did not affect the LD50 of procaine-HCl, particularly as the corresponding serum esterase activity also remained uninfluenced. The aromatic N-acetylation of sulphisomidine and the quasi-aromatic N-acetylation of 4-aminoantipyrine in rats failed to be significantly reduced by CS2 even after 400 ppm/8 h, nor did the same dose of CS2 affect the glucuronidation of 4-hydroxyantipyrine in the same animal species. It is concluded from the above results that the specificity and sensitivity of the inhibition of drug metabolism observed in small laboratory animals is probably similar to that prevailing in man. This assumption has already been substantiated for the oxidative N-demethylation of aminopyrine.


[On pharacokinetics and metabolism of the choleretic agent febuprol (author's transl)]. The pharmacokinetic behaviour as well as metabolization of 3-butoxy - 1 - phenoxy-propanol-(2) (febuprol) in rats and mice were studied. In addition, binding on human protein and in vitro absorption were determined. The distribution of tritium labelled Febuprol in the body after oral administration was studied in rats and mice: the product was found to circulate in enterohepatic circulation, including the intestines, liver and kidney, and, in the case of mice, also the gall bladder, whereas other organs or tissues show no activity. Upon oral adminstration over 90% Febuprol are absorbed via gastro-intestinal tract and as metabolites 85% of the substance were eliminated via bile, 4% via urine. The rate of metabolisation is high. Via bile only 0.2%, via urine only 0.6% unaltered Febuprol are excreted. Mainly conjugated Febuprol and hydroxy-Febuprol are found as metabolites. By means of the Sartorius absorption model Febuprol yeilded a rate constant common to pharmaceutical substances which are absorbed at a medium rate. This constant does not depend on the pH-range. The buccal tests and the distribution coefficients show the same results.


Studies on Vaccinium myrtillus anthocyanosides. II. Aspects of anthocyanins pharmacokinetics in the rat. Vaccinium myrtillus anthocyanins adminstered by i.v. or i.p. route to the rat undergo a rapid body distribution and in part also are easily eliminated such as to fit a three-compartments pharmacokinetic model. The anthocyanins elimination occurs mostly through urine and bile. The slight difference between the amount of anthocyanins eliminated after i.v. and after i.p. application shows a modest liver extracion of these substances. Vaccinium myrtillus anthocyanins possess a greater affinity for some tissues, namely kidneys and skin rather than for plasma. This fact could explain the long-lasting activity of anthocyanins on capillary resistance which is still elevated when plasma levels of these substances are no more detectable.


Interaction of pentobarbital, diphenylhydantoin and digitoxin with ethanol in the isolated perfused guinea-pig liver. In the isolated guinea-pig liver the interactions of ethanol with the metabolism of three drugs (14C-pentobarbital, 14C-diphenylhydantoin, and 2H-digitoxin) has been investigated. The disappearance of ethanol could be described by zero-order kinetics and was not influenced by the three drugs. In the case of 14C-pentobarbital and 14C-diphenylhydantoin after a short period of distribution disappearance of radioactivity was faster under the influence of ethanol, whereas radioactivity in liver tissue was increased. The radioactivity accumulated in the liver tissue predominantly represented the unchanged drugs suggesting that the inhibition of drug metabolism by ethanol was the cause of the altered distribution. In the case of 3H-digitoxin ethanol did neither significantly influence the distribution of radioactivity nor the pronounced biliary excretion. However there exists some evidence for a minor inhibition of 3H-digitoxin's metabolism by ethanol.


Pharmacological studies on a new 1-benzoyloxy-alkylaminocycloalkane derivative (YAU-17) with special reference to its mucosa anesthetic activity. A new compound, dl-cis-1-benzoyloxy-2-dimethylamino-1,2,3,4-tetrahydronaphthalane (YAU-17) was found to produce sciatic nerve block, corneal and intradermal anesthesia in guinea-pigs, which markedly exceeded the effect of procaine and lidocaine. YAU-17, when given orally to mice, was much less toxic than any other drugs tested, though YAU-17 showed a considerably high acute toxicity by i.v. route. Oral administration of YAU-17 was effective in antagonizing the emetic response of dogs to intragastric phenylalanine isopropyl ester, but produced no distinct inhibition against vomiting elicited by oral copper sulfate. Furthermore, it possessed a spasmolytic activity which was comparable to that of papaverine, and showed an effect of suppressing the mucosal intrinsic reflex in the dog intestine. These pharmacological properties of YAU-17 were qualitatively similar to those of oxetacaine which was used as one of the reference compounds.


General pharmacological properties of a new non-opiate antitussive: zipeprol (3024 CERM). II. Actions on the cardiovascular system, intestinal transit and central nervous system. The effects of 1-(2-methoxy-2-phenyl)-ethyl-4-(2-hydroxy-3-methoxy-3-phenyl)-propyl-piperazine-dihydrochloride (zipeprol, 3024 CERM, Respilene), a new nonopiate antitussive agent, have been studied on the cardiovascular system, intestinal function and the central nervous system. Most of these studies were performed comparatively with reference antitussives, particularly codeine, whose activites in these fields are the basis of its undesirable side effects. In the dog, zipeprol showed no hypotensive or cardiac-depressant activity. It did not alter pulmonary arterial pressure. An important antiarrhythmic action was apparent in studies on rhythm disturbances induced by ouabain and coronary ligation. Intestinal function, measured by the recording of peristaltic movements in the dog and the speed of intestinal transit in the rat, was not modified by the product. Zipeprol showed no characteristic action on the central nervous system. Analgesic activity was seen only at doses just below toxic levels. Finally in the rat and the mouse, no evidence of physical dependence was seen after prolonged treatment. This together with the absence of chemical similarity to the morphinics, leads to exclude the possibility of zipeprol treatment leading to addiction. The results of these studies allow zipeprol to be clearly distinguished from the opiate antitussives.


Improvement of perfusion-flow in the isolated rat liver, under the influence of streptase. Accumulation of radioactive material in the isolated rat liver was noted when 125I-fibrinogen was added to the perfusing medium. Owing to an enhanced production of fibrinogen and to a diminished fibrinolysis, fibrin deposits were found to occur in the capillaries of fhe isolated liver. This would cause a decrease of hepatic flow and an impairment of the nutrition of this organ which leads to subsequent necrosis. Administration of streptase removed the fibrin deposits and restored the perfusive flow in the isolated liver.


Influence of four agents (tibric acid, DH 990, oxandrolone and Sch 9122) on aspects of lipid metabolism in rats). We have investigated the effects of four drugs on aspects of lipid metabolism in rats. The four drugs used were: tibric acid = 2-chloro-5-(cis--3,5-dimethylpiperidonosulfonyl)benzoic acid; DH 990 = 2-[(3,5-di-t-butyl-4-hy-droxyphenyl)thio]hexanoic acid; oxandrolone = 17beta-hydroxyphenyl-17a-methyl-2-oxa-5a-androstan-3-one; and Sch 9122=2-(p-anisyl)-3(2-pyridyl)pentane hydrochloride. Serum and liver triglycerides and liver cholesterol, 7a-hydroxylase and 26-oxidase were determined. Tibric acid (0.015%) was hepatomegalic and hypotriglyceridemic. It did not affect normal 7a-hydroxylase or 26-oxidase activity. In the absence of cytosal, this drug resulted in normal mitochondrial cholesterol-26-oxidase activity whereas none was observed with preparations from control rats. DH 990 (0.075%) did not affect liver size. It had a slight (10--20%) hypolipidemic effect. The effects of DH 990 on the two liver enzymes were similar to those of tibric acid. In view of the absence of a hepatomegalic effect of DH 990, its influence on mitochondrial oxidation of cholesterol in the absence of cytosol is noteworthy. Oxandrolone (0.15%) had a slight (11%) hepatomegalic effect but did not influence serum of liver lipid levels. This drug caused a 19% increase in liver 7a-hydroxylase activity but did not affect cholesterol-26-oxidase activity in the presence or absence of cytosol. Sch 9122 (0.03%) caused significant weight loss. Serum and liver cholesterol levels were unaffected, but serum triglyceride levels were significantly elevated in rats fed this drug. Cholesterol-7a-hydroxylase activity was slightly (11%) higher than normal, but 26-oxidase was significantly lower.


[Experimental studies on the mechanism of action of carbocromen on the isolated cat papillary muscle (author's transl)]. 1. In isotonically shortening cat papillary muscle 3-(2-di-ethylaminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen; Intensain¿) (1-30 mug/ml) slightly increases contraction amplitude. 2. At low stimulation rates (6-12/min) the positive inotropic effect is more pronounced. 3. The maximal velocity of depolarization of the monophasic action potential is slightly reduced. 4. At all stimulation frequencies investigated (15-90/min) the total duration of the action potential -- especially at late repolarization level -- is strongly increased. Hence, functional refractory period is prolonged and maximal follow frequency reduced.


[Actions of carbocromen of toxic effects of digitalis (author's transl)]. Experiments an anaesthetized dogs, rabbits and guinea pigs show that with clinically relevant doses of 3-(2-diethyl-aminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen, Intensain¿) the LD100 of digoxin (+50%) and ouabain (+60%) considerably increase. The positive inotropic effect of digoxin is not influenced by carbocromen. The appearance of arrhythmias is significantly delayed, the coupling between atrial and ventricular activity continues for a longer time. Besides effects on myocardial metabolism a membrane effect of carbocromen could be responsible for the improvement of the therapeutic range of digoxin and ouabain.


A systematic antilipidemic structure-activity relationship study was carried out on a series of alcoyl- and benzoyl-phenoxy-carboxylic acids. A systematic antilipidemic structure-activity relationship study was carried out on a series of alcoyl- and benzoyl-phenoxy-carboxylic acids. The introduction of a p-chlorobenzoyl moiety into the original phenoxy-isobutyric acid enhanced antilipidemic activity significantly. Chlorine meta substitution or chlorine disubstitution abolished activity. Among the esters synthetized, the isopropylester has been selected for further studies.


Antilipidemic drugs. Part 2: Experimental study of a new potent hypolipidemic drug, isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF178). Pharmacological investigations have been carried out on a new p-chlorobenzoyl substituted phenoxy-isobutyric acid derivate with potent antilipidemic activity, isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]propionate (LF 178; procetofene; Lipanthyl¿). The compound depressed total lipids and total cholesterol significantly in the normal rat from 15-20 mg/kg upwards. At 100 mg/kg, the drug-induced depression of total lipids was twice the effect observed with 300 mg/kg of clofibrate. Significant depression of lipid parameters was induced in the senescent rat, in the dietary hyperlipidemic and in the triton hyperlipidemic rat. In the two last models clofibrate failed to affect lipid parameters at 300 mg/kg. The absence of pharmacological side effects indicates a high pharmacological specificity with respect to lipid metabolism. It might be concluded that LF 178 presents an antilipidemic profile different from the well known hypolipidemic drug clofibrate.


Antilipidemic drugs. Part 3: On the synthesis of 14C-radiolabelled isopropyl-[4'-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF-178). Isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2 methyl]-propionate (LF 178; procetofene; Lipanthyl¿) was labelled with 14C. The carbon atom of the ketone function was chosen for the study. The obtained product has a total specific radioactivity of 8.79 mCi/mM. Its structure was proved by NMR.


Antilipidemic drugs. Part 4: The metabolic fate of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-protionate (LF 178) in rats, dog and man. The excretion and plasma concentrations of radioactivity and chromatographic patterns of radioactive components in plasma and excreta have been compared in rats, dogs and man after oral doses of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF 178; procetofene; Lipanthyl¿). 2. In rats, 48.1% of a single dose of 25 mg/kg was excreted in the urine, and 48.6% in the faeces. In dogs, 23.1% of a single dose at the same level was excreted in the urine, and 71.8% in the faeces, but 88.1% of a dose of 300 mg to man was excreted in the urine, and only 5.1% in the faeces. Peak levels of radioactivity in the plasma of all three species studied were similar (20--30 mug/ml) after doses at these levels and concentrations declined thereafter with half-lives of 7--24 h in rats and dogs, and 7 h in man. The half-life of radioactivity concentrations in rat plasma was not altered by repeated daily doses for 7 days. 3. Whole-body autoradiography of rats showed that radioactivity was largely associated with the liver, kidneys and gut, which are the organs of biotransformation and excretion, although relatively high levels were present in lungs and blood, and small amounts of radioactivity had a widespread distribution into some peripheral tissues during 2--7 h after dosing. 4. The available chromatographic evidence indicated that the most important biotransformation pathway appeared to be ester hydrolysis to LF 178 acid and formation of water soluble conjugates of this acid. This pathway appeared similar to that of the related drug clofibrate (ethyl p-chlorophenoxyisobutyrate).


[Influence of digitoxin on isolated segments of lateral branches of human vena saphena (author's transl)]. The effect of digitoxin on isolated segments of lateral branches of the human saphenous vein perfused in vitro with constant volumes is reported. Digitoxin, depending on concentraion, effected rise in perfusion pressure and intensification of reaction to norepinephrine. Some venous segments showed spontaneous activity. The tests were supported by histological studies.


[Pharmacokinetics of cyproterone acetate in normal subjects after i.m. and oral application (author's transl)]. Sixteen volunteers were given cyproterone acetate-2'-14C (6-chloro-17-hydroxy-1alpha,2alpha-methylene-pregna-4,6-diene-3,20-dione acetate; Androcur¿) in single doses of between 2 and 12 mg i.m. and p.o. in 19 investigations. The plasma radioactivity was then determined at suitable intervals. Urine and faeces were collected quantitatively for 12 days. After oral administration the highest concentrations in plasma were found 1--4 h after administration. The mean amounts were 2--3% of the administered dose in the plasma volume. Plasma concentrations of more than half the highest values were measured for a period of 2--8 h. Cyproterone acetate was eliminated from the body with a half-life of about 1 1/2 days for men and about 2 days for women. After oral administration in single doses of 2--12 mg the compound was almost completely absorbed.


Metabolism of hydroxyethylrutosides (HR): metabolism of [14C]-HR in man. 1. following oral administration of a [14C]-hydroxyethylrutoside (Paroven, Venoruton) preparation (HR) to three subjects, 3.05--5.97% of the administered [14C] was excreted in urine. Unchanged urinary [14C]-hydroxyethylrutosides represented 1.57--1.96% of the total dose. 2. Significant levels of [14C] were detected in plasma within 1 h of oral administration of HR. Peak levels were observed from 2--9 h. 3. The presence in urine of [14C]-3',4',5,7-tetra-O-(beta-hydroxyethyl)rutoside, [14C]-3',4',7-tri-O-(beta-hydroxyethyl)rutoside and [14C]-4',7-di-O-(beta-hydroxyethyl)rutoside was shown by radioscanning and/or spectal methods. 4. Administration of a second oral dose of [14C]-HR to each of the three subjects following extended dosage of nonlabelled HR did not result in any increase in urinary [14C] excretion over that observed after administration of a single oral dose. 5. Observations on urinary excretion in man are compatible with the finding in experimental animals that the major route of hydroxyethylrutoside excretion is via the biliary-enteric route.


[On respiratory stimulation by aminophenazol in global insufficiency due to chronic-obstructive diseases of the lungs (author's transl)]. For evaluation of a respiratory analeptic as supplementary therapy in global insufficiency blood gas analyses were performed on 19 patients under normal room air conditions as well as under oxygen breathing. It could be proved that with 2,4-diamino-5-phenylthiazol (aminophenazol; Daptazile) respiratory depression associated associated with chronic obstructive pulmonary diseases can be influenced and that here is statistically significant improvement of respiration. Effects of mechanical breathing and hyperventilatin are discussed -- basing on the present evaluation results they need not be expected. Side effects were not registered. With simultaneous and exhaustive application of all therapeutic means for the remedy of pulmonary obstruction amiphenazol is recommended for use in cases of pulmonary hypoventilation and primary central respiratory depression.


[A method for studying pupilomotorics under the influence of neurolepic medication (author's transl)]. A pupilostatic method of measuring the pupillary diameter after standardized exclusion of retinal impulses is described. The pupil is photographed by a polaroid camera at a 1 : 2 scale. On the photographs the pupillary diameter is measured under a magnifying lens. We then present data of application of the method in a clinical experiment. The question we investigated was to determine physical effects of neuroleptic drugs in changes of the pupillary diameter. Our patients were 40 acute schizophrenics treated with two different neuroleptic drugs. It was found that already after a single dose of 1 mg 4'-fluora-4-[4-hydroxy-4-(4-chlorophenyl)-piperidyl-(1)]-butyrophenone (haloperidol) or 10 mg 2-chloro-11-(4-methyl-1-peperazinyl)-dibenz[b,f]-1,4-oxazepine (loxapine), respecitvely, a distinct change in pupillary diameter was measureable. The statistically significant differences in the effects of the two neuroleptics point as a further finding to the sensitivity of the developed method. This difference was paralleled by our clinical observation that loxapine showed more distinctly sedative effects in comparison with haloperidol.


Polygraphic sleep studies in rats and humans: their use in psychopharmacological research. The effects of selected centrally acting drugs on sleep after single administration to rats and humans were studied using polygraphic sleep recording techniques. D-Amphetamine, a stimulant, had similar effects in both species: reduction of total sleep time, of N(non-)REM- and particularly REM (rapid eye movement)-sleep, increased restlessness during sleep. The psychodepressants mesoridazine and, in particular, nitrazepam had relatively little effects on sleep stages. In doses which did not cause side effects they reduced restlessness during sleep. The most typical effect of the antidepressant imipramine was a dose dependent reduction of REM-sleep duration in both species, without impairment of NREM-sleep. The central dopamine agonist, bromocriptin, had little effect on sleep and did not reduce total sleep and REM-sleep. These examples suggest that polygraphic sleep studies are a sensitive and stable method for the study of centrally acting drugs. The specificity of the model is illustrated by its ability to differentiate chemically and pharmacologically different drug classes. The validity of the model, i.e., its ability to allow predictions from the laboratory conditions to the therapeutic situation, varies in different drug classes. Investigations in normal subjects and animals appear to be relevant for the study of CNS-stimulants, whereas for CNS-depressants studies in sleep-disturbed subjects or animals are more likely to provide dependable results.


[Problems of circadian periodicity and its disorders (author's transl)]. The human circadian system controlling the variety of overt 24-h rhythms consists of some different oscillators which are separately self-sustained. Normally, all oscillators run synchronously to each other; under certain external and internal conditions (e.g. increasing score of neuroticism, or old age), however, they run in the steady state with different periods. The necessary synchronization of the endogenously driven oscillators to the environment is effected, in man, essentially by social timing mechanisms; their efficiency presupposes the possibility as well as the ability to establish social contacts. A timing mechanism may synchronize the circadian system only partially; as a result, only several oscillators are synchronized whereas others persist ot run autonomously. The different rhythm disorders, internal or external desynchronizations, when effective for a long time, may be sources of ill health.


[EEG aspects of waking-sleep behaviour and the chronophysiology of endogenous depressions]. 1. The resting EEG in endogenous depressions, characterized by an increase of slow alpha- and subalphacomponents and a change of spatial organization of background activity, indicates a lowered level of vigilance, If the physiological diurnal increase of the dominant alpha-frequency compensates the described slowing of alpha-rhythm, the typical daily mood fluctuation of endogenous depressions will result. 2. Changes in the resting activity occurring during arousal are probably related to the functional alteration of the EEG-sleep activity, especially to the diminishing of phasic REM-activity. 3. It is suggested that the alterations in EEG pattern during sleep and wakeful state, indicating a dissolution of slow sleep activity and a deficiency of the arousal functions, represent a regression towards an immature functioning of the vigilance regulation.


[Adaptation to the sleep laboratory in normal subjects and neuropsychiatric patients (author's transl)]. In 86 subjects (11 healthy persons, 8 suffering from autonomic instability, 11 from endogenous psychosis, 30 from cerebral circulatory disturbances, 26 parkinsonian patients) the problem of adaptation to the sleep laboratory and the persistence of adaptation was investigated. In healthy subjects, less pronounced in patients suffering from autonomic instability, marked, statistically significant differences could be found between the first and second night. In addition there was a further increase in the amount of rapid eye movement (REM)-sleep from the second to the third night. In the other groups a very retarded, or even an absence of, adaptation could be revealed. Adaptation, once gained, outlives an interruption of registration of several weeks and is more marked in healthy subjects than in other groups.


[Liberation of growth hormone and melanocyte-stimulating hormone in natural and melatonin-induced human sleep (author's transl)]. As in the early period of night sleep, plasma levels of human growth (HGH) are markedly elevated in afternoon sleep in healthy young males. Melatonin (50 mg i.v.) induces marked secretion of HGH when sleep is prevented. It decreases latencies for sleep onset and deep sleep significantly, and markedly enhances peak secretion of HGH during slow-wave sleep. Plasma melanocyte-stimulating hormone (betal-MSH) levels were influenced neither by melatonin nor by sleep.


[Inhibition of monoamineoxidase and day-night-rhythm: correlation of physiological and biochemical parameters (author's transl)]. The motor activity of rats following medication with monoamine-oxidase inhibitors was registered continuously over a period of nine days. At the same time the enzyme activity of monoamineoxidase (MAO) form A and B and the concentration of serotonin, tryptophan, 5-hydroxyindolacetic acid and norepinephrine were measured in brain stem and hippocampi. We draw the following conclusions: 1. The rhythmic changes in the levels of serotonin and norepinephrine play a minor role in the circadian rhythm. 2. MAO-inhibitors influence the timing mechanism. A relationship between this finding and the therapeutic effect on depressed patients is discussed. 3 Dopaminergic neurons antagonize the activation by adrenergic neurons during the dark-period.


[Seasonal rhythm of free tryptophan and nonesterified fatty acids in the blood of healthy subjects (author's transl)]. During one year, free and total tryptophan, tyrosine and non-esterified fatty acids were determined in the blood of eight healthy volunteers. No clear seasonal rhythm appeared for any of these parameters. But over this period, the following significant correlations were found: total tryptophan-free tryptophan; total tryptophan-tyrosine; free tryptophan-tyrosine. For the individuals, the quotient tyrosine-tryptophan showed to be constant during this year.


[The effects of lithium ions on circadian rhythms (author's transl)]. Lithium ions lengthen the critical dark period in short-day plants, increase the period length of circadian rhythms in Kalanchoe plants, in the rodent Meriones and influence the activity rhythm of birds. In the case of the Kalanchoe rhythm, mainly the process of the petal opening is affected.


[The influence of mepiprazol on monoamine metabolism in the rat CNS: demonstration of reduced norepinephrine activity and simultaneously enhanced serotonin and dopamine activities (author's transl)]. Biochemical studies of monamine turnover and neuronal reuptake indicate that mepiprazole, a novel psychotropic pyrazole derivative, decreases norepinephrine receptor activity and enhances serotonin and to a lower extent also dopamine activity in the rat CNS. It can be concluded that mepiprazole might be of value in the treatment of certain types of depression and might be helpful to alleviate side effects of L-dopa in the treatment of parkinsonism.


[Receptor-blockade and receptor-hypersensitivity following neuroleptic treatment (author's transl)]. Neurolepitcs induce a receptor-blocking effect at central dopaminergic neurons. This may be demonstrated in mice by inhibition of methylphenidate induced compulsive gnawing. In the post-receptor-blocking phase the receptor is temporarily hypersensitive to dopaminergic agonists like methylphenidate and apomorphine. By repeated dosage a competition is created between receptor-blockade and hypersensitivity, often in favour of the latter.


[Effects of anticholinergics and clozapine on the activation of the striatal dopaminergic system in the rat by haloperidol. Pharmacological findings (author's transl)]. Tardive dyskinesias, often seen in patients treated with classical neuroleptics, have been attributed to the development of receptor hypersensitivity following prolonged blockade of dopamine (DA)-receptors. In rats with unilateral striatal lesions, development of DA-receptor hypersensitivity following a 6-day treatment with haloperidol can be demonstrated by means of the increased turning response to apomorphine. Addition of atropine to the haloperidol treatment schedule resulted in a further increase in receptor sensitivity, but with a delay of 24 h in its appearance. This finding provides pharmacological support for the observation that tardive dyskinesias are more frequent and more severe in patients treated with a combination of a classical neuroleptic and an anticholinergic agent. Clozapine, despite its anticholinergic property, did not enhance the haloperidol-induced hypersensitivity.


[Effects of anticholinergics and clozapine on the activation of the striatal dopaminergic system in the rat by haloperidol. Neurochemical findings (author's transl)]. The increase in the concentration of homovanillic acid (HVA) in the haloperidol for 6 days compared to a single administration of the drug. The induction of tolerance is probably due to a functional modification of the striatal dopamine (DA)-receptors after repeated administration of the neuroleptic. Atropine given in combination with haloperidol enhances the induction of tolerance. Clozapine (20 mg/kg orally) had no such effect.


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


[Relationship between dependence on and tolerance to morphine in the rat (author's transl)]. The same administration schedule of morphine leads to different degrees of tolerance in different test situations. The most intense one was found to depressing effects. Slight tolerance to stimulating behaviour, observed in an open field stiuation at low doses, develops, too. There is a more marked tolerance to the depression of stimulating effects, thus the bell shaped dose-response relationship is broadened and shifted somewhat towards higher doses. All effects observed in dependent animals were also seen after acute morphine administration. Whereas tolerance in all tests was dependent on dose and administration time this was not the case for dependence determined by naloxone challenge on days 10 and 20 of administration. Thus, in the rat no correlation exists between naloxone provoked withdrawal and tolerance.


Identification of opiate/receptor binding in vivo. The displacement of small amounts of tritiumlabbelled antagonists or agonists by increasing amounts of unlabelled antagonists in mouse brain in vivo offered the possibility of characterizing properties of opiate receptors in the intact animal. The displacement effect was stereospecific, saturable and dependent upon the affinity of the substance investigated. At brain concentrations of 0.3 nM, 75% of 3H-diprenorphine, 60% of 3H-naltrexone and 50% of 3H-naloxone were displaced by high amounts of the respective unlabelled drug. Comparison of the in vivo data with receptor binding in vitro revealed similar results in respect to binding sites and receptor affinity. The displacement was different in various brain areas. The time course of the displacement was also different for the various substances used and seems to reflect differences in the speed of association and dissociation to and from the receptors. The displacement of 3H-etorphine by naltrexone could be correlated with the reversal of analgesia.


The role of dopamine in withdrawal jumping in morphine dependent rats. The role of dopamine (DA) in precipitated withdrawal jumping was studied in morphine dependent rats. Pretreatment with various dopaminergic agonists induced a dose-dependent increase in naloxone induced jumping. Pimocide totally blocked the facilitatory effect of piribedil while naloxone induced jumping was not dose-dependently decreased. Biochemical measurements revealed that during precipitated withdrawal the level of DA was elevated and the accumulation of 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) after probenecid as well as the level of 3-methoxytyramine in the striatum was reduced. Unilateral inactivation of the caudate by local injection of KCl induced contralateral circling during withdrawal. Additional systemic haloperidol pretreatment did not change the direction of circling while additional apomorphine pretreatment changed the direction to ipsilateral and increased the circling rate highly. These latter as well as the biochemical findings strongly suggest an inhibition of striatal DA-mechanisms during withdrawal. The apparent contradiction of these findings to the above finding showing a facilitatroy role of DA-agonists on jumping is discussed.


[Proceedings: On the central action of nomifensine (author's transl)]. The central action of nomifensine (NF), a new antidepressive drug, was studied in rats and mice. NF stimulates locomotor activity in normal animals as well as in animals whose motor activity has been depressed by reserpine, alpha-methyltyrosine (alpha-MT), bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)-disulfide (Fla-63) or phenoxybenzamine. The sedation produced by alpha-MT plus reserpine or by spiroperidol is not affected by NF. NF induces stereotypy in the rat and antagonizes the catalepsy induced in the rat by neuroleptics, pilocarpine and arecoline. The catalepsy induced by alpha-MT plus reserpine is not influenced. NF elevates the brain levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the rat. These and previous results indicate that the profile of action of NF differs both from that of known tricyclic antidepressive drugs and that of dopaminergic stimulants.


[Studies with the AMP system: comparison of symptoms from Berlin and Zürich]. Symptoms of 1830 psychiatric patients from Berlin and of 783 patients from Zurich were assessed using the AMP-system. The symptoms were analysed according to their frequency and their potency to differentiate diagnostic groups. The following 4 categories of symptoms proved to be useful: frequently occurring and specific or unspecific, rarely occurring and specific or unspecific. Factor analyses of the frequently occurring unspecific symptoms yielded three general dimensions, i.e., "depression", "disturbance of memory and thinking" and "hostility".


[Rater-specific variables in judging depressive patients (author's transl)]. Four raters judged their sympathy towards 19 depressed patients and also the intensity of their disease using thermometer-scales. It was exmained whether there was a correlation between the two scores. A rater-specifuc varuabke was fiybd fir eacg if tge fiyr raters. The importance of these variables for further investigations is discussed.


[Studies with a behavior-oriented evaluation scale for depressive inhibition and agitation. Results of a video-documented amitriptyline-mianserine study]. This is the first report of a new approach which is concerned with the registration and graded judgement of non-verbal behavior. We have tried to show that this is a method which helps to unveil the role of non-verbal behavior in the process of making a diagnosis and to define the concepts used.


[Signal analysis of EEG-changes induced by nomifensin - a new antidepressant (author's transl)]. Ten healthy volunteers received a single oral dose of 100 mg nomifensive, a new antidepressant (tetragtdriusiqyubikube deruvatuve; Hoe 36-984). The drug-induced effects on the EEG were compared with those of placebo. The statistically proved results show that nomifensine causes a distinct shift in vigilance with two different partial processes. After an initially occurring stabilization of the dominant alpha-frequency there appears a polyrhythmic disintegration of the alpha-rhythm with increase of slower and faster frequencies. At the same time a shifting takes place within the beta-range with increasing of 23.5-32.0 Hz-components. Accordingly it is evident that nomifensine results in a typical pharmaco-electroencephalographic profile.


[Simultaneous recording of visually evoked potentials (VEP) and registration of simple visual reaction times (RT) in the maximum range of ethanol influence (author's transl)]. The method of simultaneous recording of visual-evoked response (1 occipit-vertex) and simple reaction time to periodic foveal visual stimuli of 1/" per sec was applied to 16 normal individuals. On two successive days the conditions were kept constant except for an independent variable, i.e., ethanol with an average peak of 1.32%; the range of 0.1% below the peak being examined. The amplitude of the component N2-P3 (120-170 msec after the stimuli) was depressed in all individuals. The latencies of N2 and P3 were increased concurrently. The latency of P3, for example, was increased by 10.7% (P less than or equal 0.01) and that of the means of simultaneously recorded reaction time by 14.8% (P less than or equal 0.01). The amount of the increase, however, showed no significant correlation between the two when using Spearman's correlation coefficient and t-test.


[Direct quantitative measurement of tremor: first results of a new mesuring procedure in patients under lithium therapy]. The use of a new piezoresistive minature accelerometer as part of an electronic measurement system for the direct quantification of human finger tremor in physical units is described. The system was designed to yield digital values for the mean tremor amplitude in a given period of time. Reliability coefficients were computed for a smaple of 34 patients under lithium therapy. Coefficients ranged between 0.75 and 0.94 for test-retest intervals between 30 min and several days. Some of the usual indirect methods for the assessment of tremor showed very low correlations to the true tremor amplitude and seemed to be only of limited usefulness. It was further demonstrated that situational factors play a dominant role independently of the particular method of measurement.


[Measurement of body temperature in the auditory canal or in the rectum: first experience with a device for continuous registration of body temperature of psychiatric patients (author's transl)]. A method for continuous measurement of body temperature over a 24-h period is presented. the temperature is measured by an active sensor placed in the external auditory canal or in the rectum, and stored on a magnetic tape in a portable cassette recorder weighing 400 g. Rectal temperature is less sensitive to environmental influence and easier to record than ear temperature. With this method possible disturbances of the diurnal temperature rhythm in psychiatric patients can be registered.


[A method for determination of thermally motivated behavior (author's transl)]. Constant body temperature in homeothermic organisms results from autonomic and behavioral thermoregulatory reactions. The input variables for thermally motivated behavior are temperatures of the skin and of the hypothalamus. Our aim was to determine the behavioral side of thermoregulatory reactions under the influence of drugs interfering with normal body temperature. Initial experiments were made with phentolamine, which at an ambient temperature of + 4 degrees C causes a dose dependent hypothermia. Rats were trained in a cold box to press a lever and were rewarded by a certain amount of warm air. Trained rats were able to raise the temperature in the box from -4 degrees C up to + 4 degrees C at a response rate of 0.5 min. Treated with phentolamine (3.7-15 mg/kg) these rats increased the rate of lever pressing dose dependently, i.e. they increased their ambient temperature. The hypothermic effect of the drug was therby reduced to a certain extent. Using this method it can be determined whether a drug influences body temperature at the level of autonomic reactions or at that of thermally motivated behavior or at those of both.


[Internal and external stress and tybamate and secobarbital: an experimental investigation of their interactions (author's transl)]. This investigation was carried out to test the hypotheses that the reactions associated with external stress are better reduced by barbiturates while meprobamat-type tranquilizers reduce principally internal stress. To test the interaction of medication and type of stress a 3X3 plan was used with independent groups. The medication conditions were: placebo, 500 mg tybamate, and 100 mg secobarbital, and the stress conditions were: white noise of 95 dB intensity (external stress), fictitious assessments of the subject with high negative content (internal stress) and a non-stress situation. The paper deals with the main effects on physiological and subjective variables as the result of a covariance analysis. No interactions were found.


[Psychological-experimental study on the effects of tranquilizers (diazepam and a drug under investigation) considering personality variables (author's transl)]. Three doses of a substance from the thieonodiazepine series (BAY g 5653), a drug under investigation, were tested as well as 5 mg of diazepam and a placebo, including a condition with no medication. 180 healthy male student volunteers, previously classified according to emotional stability/lability, took part in the study following a double-blind procedure. All subjects received white noise discontinuously with an intensity of 95 dBA. From the subjective and objective test variables employed, only the results from an adjective check list were evaluated fro the present paper. Diazepam showed some typical but not very strong effects. BAY g 5653 showed also little difference from placebo. There were some positive effects in the group of emotionally stable under stress.


[Clinical relevance of lithium determination in RBC: results of a catamnestic study (author's transl)]. In 34 out-patients Li+- and K+-concentrations were determined in plasma and RBC during 15 months of clinical routine observations. Average frequency of check-ups was 9/patient. Psychopathological state and side effects were documented by the AMP-system. The mean intra-extracellular lithium concentration ratio (LiQ) was 34%. The ratio and the absolute lithium RBC concentration showed a wide intraindividual variability between 5 and 53%. Patients under 50 years old had the same absolute concentration values as the older ones but required a 50% higher average dose. Side effects such as tremor and thirst correlated well the intra-extracellular ratio. No difference was found between unipolar and bipolar depressions. LiQ was slightly reduced and KQ increased in patients with severe relapses or additional psychotropic medication.


[The distribution of lithium between erythrocytes and plasma: in vitro studies on the transport of lithium in human erythrocytes]. Distribution ratiors of intracellular lithium (Lii) and extracellular Li (Lie) were determined in vitro after incubation of Li-free or Li-loaded red cells in media containing varying Li-concentrations (37 degrees C, pH 7.4). The distribution ratios Lii/Lie obtained in vitro after 24 h of incubation corresponded to those found in vivo. The results indicate that Li can be extruded from red cells against an electrochemical gradient. This Li extrusion is inhibited by replacing extracellular Na+ with K+ or choline+, but is not affected by ouabain or by glucose depletion.


[On improved prophylaxis of endogenous-phasic psychoses: aspects of parallel determination of lithium in serum and erythrocytes (author's transl)]. In 30% of the psychiatric patients investigated the lithium concentration in erythrocytes (RBC-lithium) is a more reliable indicator for the evaluation of the clinical response and the risk of toxicity. After lithium administration the lithium RBC levels increased within the first three weeks. Lithium RBC/plasma ratios are not different between unipolar, bipolar and schizo-affective psychoses. It was found that low lithium RBC/plasma ratios correspond with low monoamine oxidase (MAO) activity in platelets.


[Determination of monoamine oxidase and catechol-O-methyltransferase in human blood components: methodical aspects (author's transl)]. Controversal findings are reported with respect to alternations in activity of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in psychoses. Initially we determined the interindividual differences of some biochemical properties of the two enzymes in normal control subjects. Platelet rich plasma and lysate of red blood cells, respectively, were used for assay. Enzyme activity was referred to mg of protein or mg hemoglobin and number of platelets, respectively. Substrates used for COMT assay were: 3,4-dihydroxybenzaldehyde and 3,4-dihydroxybenzoic acid; for MAO determination: tyramine, tryptamine and phenylethylamine. Interindividual as well as intraindividual differences in the biochemical characteristics (apparent Km, Vmax, IC50, meta/para ratio of O-methylation in vitro) were remarkably low, the coefficient of variation was in the range of 30%.


[Thin-layer chromatographic determination of plasma levels of tricyclic psychopharmacological drugs: first results on their relationship to the clinical activity of neuroleptics (author's transl)]. Plasma levels of perazine, clozapine, amitriptyline and imipramine and of their demethylated metabolites can be measured in patients receiving therapeutic doses by UV reflectance photometry of thin-layer chromatograms of plasma extracts, Large inter-individual variations were observed in unselected psychiatric patients treated with comparable doses. An investigation into the relationship between plasma levels and therapeutc effect in acutely schizophrenic patients was carried out for perazine and clozapine. With perazine, a group of patients exhibiting an unsatisfactory response had a tendency to show lower plasma levels than a group with a good response; in some patients of the former group, increase of the dose with concomitant increase of the plasma level led to a satisfactory therapeutic effect. In patients treated with clozapine, such a relationship could not be demonstrated.


[Antipsychotic efficacy in relation to plasma levels of clozapine (author's transl)]. The relationship between antipsychotic effect and side effects and plasma levels of clozapine were investigated in 26 patients. A significant linear correlation was found between dosage and plasma levels of clozapine. All patients were clearly improved. The degree of improvement was independent of the plasma levels in an average range of plasma levels (100 ng/ml-800 ng/ml). Sedation and orthostatic dysregulation occurred most pronounced on the third day of treatment. There was no relationship between plasma levels and these symptoms. After prolonged treatment the degree of both symptoms diminished. The development of tolerance of symptoms is concluded.


[Total and partial sleep deprivation in the treatment of depression: preliminary communication]. Sleep deprivation (SD) has been proved to be an effective measure of antidepressive treatment (especially in endogenous depression). In a new study, 125 SD were examined on 93 depressed patients. The therapeutic benefit of SD on endogenous depression consists not only of the nightly clear up but also of provoking or improving a typical day wave the day after DS. A period of at least 36 h is necessary to survey the total effect of this method. The best results are achieved in patients with severe endogenous depression, especially in those with the typical day wave and distinct somatic symptoms. The effect of partial SD (for the second half of the night) is almost the same as that of total SD. The advantages of partial SD are: the patient can stand it easier, more often, and - in the company of a suited person - even at home. Finally, it is less complicate in clinical routine than selective REM-deprivation.


[Circulatory function in depression with the circadian rhythm uninfluenced or modified (author's transl)]. The effect of sleep deprivation (SD) on the altered circadian rhythm of endogenous-depressed patients has been investigated. 61 patients (39 endogenous- and 22 neurotic-depressed) with normal cardio-circulatory activities were tested: During SD-night pulse rate is less lowered in endogenous than in neurotic depression. The increase of systolic blood pressure is quicker and higher in endogenous than in neurotic depression. - Surveying the patients for 72 h (before, during and after SD), pulse rate in endogenous- and neurotic-depressed is less markedly fluctuating than in normal individuals. There is a close connection between the circadian fluctuationsof the depressive symptoms and of the pulse rates. The more SD improves depressive symptoms the more it also flattens the wave of pulse rates. - The circadian courses of systolic blood pressure in endogenous- and neurotic-depressed and in normal subjects are nearly the same. SD markedly flattens the circadian rhythm of blood pressure. In neurotic depression, SD does not clearly alter the course of pulse and blood pressure rates.


[Combined sleep deprivation/chlorimipramine therapy of endogenous depression (author's transl)]. A sleep deprivation/chlorimipramine therapy was compared to chlorimipramine therapy in endogenous depression. In the sleep deprivation/chlorimipramine group a quick and long-lasting remission of depressive symptoms could be demonstrated. In the chlorimipramine group a marked prolonged onset of action was seen.


[The role of neurasthenic syndrome in depression (author's transl)]. In endogenous depression a neurasthenic syndrome is partially included. In 100 male cases whose diagnoses merely stated "endogenous depression" without further remarks like "neurotic traits" or "reactive influences", we found in 48 cases a clear neurasthenic syndrome. It is suggested that these symptoms often lead to the diagnosis of endogenous depression. Pharmacotherapy is partially directed to the neurasthenic condition. Hereditary factors may play a part in the unability of the later endogenous depressive to relax.


[Study on the role of personality factors for successful lithium long-term therapy (author's transl)]. 20 female manic-depressive out-patients who had been treated with lithium over a long period (average time = 4.3 years), were submitted to a psychoanalytic interview and a personality test (FPI). The interview focussed to changes in personality with special regard to the rise of novel impulses and conflicts. The severity of neurotic conflicts as well as the frequency of specific events preceding a relapse were investigated. The results suggest that a subgroup of out-patients should be given psychotherapy in addition to long-term lithium-treatment. This hypothesis will be tested in a further investigation.


[Neuroleptic effect of baclofen in chronic schizophrenia (author's transl)]. In early 1975, surprising therapeutic effects of baclofen (Lioresal) in patients suffering from severe, chronic schizophrenia were reported from Sweden. We have carried out a study in 24 similar cases which we treated with baclofen in dosages up to 25 mg t.i.d. In rougly half of these patients no effect was observed. Of the remainder, four showed some improvement and another four a further deterioration of their condition. Those responding well were patients with acute symptoms or a history of depression, while in some of those whose condition worsened catatonic symptoms had been noted. This therapeutic possibility appears interesting from both the scientific and the practical points of view. The new class of substances merits further investigation to evaluate its psychopharmacological activity.


[Psychopharmacological drugs and the eye (author's transl)]. Early and late side-effects of psychopharmacological drugs on the eyes are discussed. The action of antidepressants, neuroleptics, tranquilizers and other groups on the eye are discussed separatedly. The importance of early glaucoma detection and treatment as well as that of pigment and metabolites deposits in the eye tissues is emphasized.


[Proceedings: Psychotropic effects of hypothalamic hormones: immunohistochemical indentification of extrahypophyseal connections of neuroendocrine neurons]. Vasopressin (VP) can be shown to exert psychotropic effects independent of its antidiuretic activity, facilitating learning and consolidation of memory in rats. Immunoreactive VP and neurophysin (NP) are localized on serial section of Bouin fixed, paraffi embedded guinea pig, rat and hamster brains. Localization was not restricted to the classical sites of supraoptic and paraventricular nucleus, medianeminence and neurohypophysis...


[Interrelationship between the transport of L-aspartate and potassium ions into the cell (author's transl)]. The mechanisms involved in active transport and intracellular accumulation of amino acids have been reviewed. In particular, the frequently observed interrelationship between the transport of acidic amino acids and potassium ions was discussed. Kinetic studies on the uptake of radioactive L-aspartate and K+ in the microorganism Streptomyces hydrogenans were performed. The following results were obtained:1. L-Aspartate was actively transported into the cells. However, only a part of the aspartate taken up from the medium remained in the pool as free amino acid. Within 60 min, up to 35% of the label was incorporated into protein. By thin-layer chromatography of cell extracts several radioactive metabolites of aspartate were detected. 2. Aspartate was transported by a t least two different uptake systems exhibiting moderate specificity. At neutral pH , the amino acid was transported as anion; its uptake was inhibited by L-glutamate as well as by dicarboxylic acids, whereas neutral amino acids did not have a significant effect. 3. The influx of aspartate into K+-rich cells was stimulated specifically by extracellular Rb+ and K+, whereas Ki+ and Na+ inhibited aspartate transport. 4. Kinetic analysis of the aspartate influx showed that extracellular K+ increased the affinity of the transport systems for aspartate by a factor of three. These results suggest that K+ is bound by the aspartate carrier and is cotransported together with the amino acid across the membrane. 5. Kinetic measurements of the uptake of 42K+ revealed that the influx of K+ as well was stimulated by extracellular aspartate. Likewise the rate of 28Mg2+ uptake was increased by aspartate.


[Effects of pentaformylgitoxin (gitoformate) on the cardiovascular system of anesthetized cats]. In small and medium doses 3 beta, 14 beta-dihydroxy-16 beta-formyloxy-5 beta-card-20-[22]-enolide-3-tetraformyltridigitoxoside (pentaformylgitoxin; gitoformate) shows a greater positive inotropic and blood pressure increasing potency than do digitoxin and beta-acetyldigoxin. In high doses this influence on contractility is exceeded by digitoxin, that on blood pressure is equalled. None of the substances tested changes heart rate. Arrhythmias with gitoformate are only seen in lethal doses, with digitoxin and beta-acetyldigoxin two dose levels earlier.


[A novel method for measurement of cerebral blood flow in the animal experiment]. A method is described for the measurement of cerebral blood flow by coutinuous registration of the venous out-flow from the temporal sinus of anaesthetized dogs. This method can be used advantageously for the screening of unknown compounds because samples of "cerebral" venous blood are obtained by a less complicated and reliable technique. Changes in cerebral blood flow induced with well defined substances, were registered with our method. The results are discussed.


[The influence of naftidrofuryl on 32Pi-incorporation into nucleic acids and adenosine phosphates of the rat brain]. 3-(1-Naphthyl)-2-tetrahydrofuryl-propionic acid-beta-diethylester-hydrogenoxalate (naftidrofuryl) increased after a 15-day treatment with orally 200 mg/kg per day the 32P-incorporation rate of two nucleic acid fractions and of ATP, ADP and AMP of rat brains. In contrast to the findings of other authors no increased ATP content was observed. The increased incorporation of the alpha-phosphate during the de novo synthesis of AMP.


[Concentration of cardiac glycosides in the heart and brain (author's transl)]. In cats the concentration of cardio-active glycosides in the heart and brain were investigated with trititum-labelled substances. Steady-state conditions were achieved by repeated i.v. injections of ouabain, digoxin, beta-methyldigoxin, digitoxin, and oleandrin over 5 days. 5 h after the last application glycoside concentrations were measured in plasma, urine, heart, cerebrum and cerebellum. Furthermore the metabolic pattern in these compartments was determined. 1. The glycoside concentration in the heart per g wet weight ranges only from 0.93 (oleandrin) to 1.88% (ouabain) of the daily administered dose per kg. 2. The concentrations in the brain show much higher differences between the diverse glycosides: ouabain with a concentration of 0.02%/g wet weight in the cerebrum shows the lowest and oleandrin with 1.60% the highest value. 3. By calculating the mean relative weights for the hearts (3.9 g/kg) and the brains (11.1 g/kg) 3.7% of the daily administered ouabain activity were found in the whole heart and only 0.18% in the whole brain. In contrast to these data the content of heart and brain after giving the more lipophilic oleandrin was 3.6% and 17.7% (!), respectively. 4. Under steady-state conditions the glycosides ouabain, digoxin, beta-methyldigoxin and digitoxin in heart and brain are mainly unchanged whereas oleandrin is transformed at a higher rate to polar metabolites.


[The influence of orally applicable antibiotics on the activities of human enterokinase and disaccharidases (author's transl)]. In this study the influence of 14 antibiotics, 12 of them orally applicable, on human enterokinase was investigated. The effects of these substances on the activities of human disaccharidases were also examined. The enterokinase activity is more sensitive to the studied antibiotics than is human lactase, saccharase or isomaltase. Unphysiologically high concentrations of penicillins, cephalexin and chloramphenicol (10(-2) Mol/l) inhibited enterokinase, tetracycline (doxycycline) in a dose of 10(-3) m reduced the activity of this enzyme by 50%, neomycinsulphate and the sulphates of polymyxin B and E have no effect on the disaccharidases. On the contrary, these substances are the best inhibitors of enterokinase among the tested antibiotics. Neomycin or polymyxin (10(-4) Mol/l) causes a 50% inhibition of a physiological quantity of this enzyme. Therapeutic doses of both antibiotics may reduce the enterokinase activity by  70% to 90%, while the activity of trypsin is not affected unless a concentration greater than 10(-2) m is used. The inhibition is not only caused by the anion (SO4) of these antibiotics, since sulphates reduce the enterokinase only in concentrations higher than 10(-3) Mol/l in man. The mechanism of inhibition is not effected by binding cholic acids under test conditions. Both polymyxin and neomycin inhibit the enterokinase activity with and without glycodeoxycholic acid. Further studies showed that the type of inhibition is competitive in both cases. The inhibition constant K2 of neomycin-B-sulphate is 8.7X10(-5) Mol/l, of polymyxin-E-sulphate 8.6X10(-5) Mol/l. The inhibition type of penicillins, cephalosporins and doxycycline is noncompetitive, thus contrasting that of neomycin and polymyxin.


Hemodynamic effects caused by i.v. administration of verapamil in healthy subjects. The hemodynamic data obtained after rapid i.v. administration of verapamil (Isoptin) (7.5-12.5 mg) to 7 healthy subjects are presented and discussed. The drug caused an early and statistically significant increase in heart rate and output with concomitant decrease of blood pressure (mainly diatolic) and peripheral resistance. Negative inotropic effects were not observed by the decreased peripheral resistance probably masks any possible negative inotropic effects of the drug.


[Influence of a pressure agent on blood concentrations of glucose, lactate, pyruvate and free fatty acids (author's transl)]. In 34 unselected patients blood concentrations of glucose, lactate, pyruvate and free fatty acids (FFA) were determined after i.v. injection of a pressure agent containing theophylline esterified with norephedrine and theophylline esterified with norepinephrine (Akrinor) with and without beta-adrenergic blockade. After Akrinor a significant increase of FFA concentration of 32% is observed, which can be abolished by beta-receptor blocking agents. Our findings indicate that the Akrinor-induced lipolysis is mainly due to a direct sympathomimetic effect on the beta-receptors of adipose tissue. there are only slight effects on carbohydrate metabolism (decrease of pyruvate concentration, increase of lactate/pyruvate ratio) which are not influenced by beta-receptor blockade. According to our results there are important metabolic differences between Akrinor and the classical catecholamines.


[Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation (author's transl)]. The time course of 1-butylbiguanide concentration in plasma and the urinary and fecal elimination of the substance were measured in six female elimination of the substance were measured in six female diabetic patients after oral administration of 100 mg of 14C-1-butylibiguanide hydrochloride as Sindiatil. The mean maximum plasma concentration was 37 mug/100 ml and was reached after about 2 1/2 h. At least semi-maximum plasma concentrations (greater than or equal 18 mug/100 ml) were maintained between the 1st and 8th h after administration. Within 24 h 64% of the administered dose were eliminated (36% via the kidneys, 28% with the faeces). After 3 days a total of 80% had been eliminated, one-half each in urine and faeces, respectively. The average time taken for 50% of maximum renal elimination, and thus of the absorbed quantity, to be excreted was 7.2 h.


Early responses to chemotherapy detected by pulse cytophotometry. DNA/cell distributions were recorded by  automated cytofluorometry (=pulse cytophotometry) in bone-marrow aspirates of leukaemia and lymphosarcoma patients subjected to chemotherapy. In most cases, early perturbations in DNA/cell histographs were observed, characteristically reflecting the known mode of action of the drugs. These changes in general preceded the clinical observation of drug response. In a series of 23 measurements in 19 patients, a positive correlation between early cytophotometric changes and clinical effects of chemotherapy was observed in 17 patients. Five patients were negative for both cytophotometric and clinical reactions and one patient was probably false-positive. The validity of the assay for early detection of drug resistance in acute leukaemia and related diseases is discussed.


An immobilized two-enzyme system for the activation of the lactoperoxidase antibacterial system in milk. Lactoperoxidase catalyzes the oxidation of thiocyanate by hydrogen peroxide and an intermediary product is formed with antibacterial properties. The components of this system, with the exception of hydrogen peroxide, are present in milk. H2O2 may be introduced by means of enzymatic generation and thus make the system complete. A two-enzyme system consisting of beta-galactosidase and glucose oxidase has been developed for this purpose. The coupled enzyme reaction is shown to work with high efficiency at the neutral pH of milk although the enzymes as such, particularly lactases suitable for immobilization, have optimal activities at much lower pH values. The results indicate that the lactoperoxidase system may in this way be employed to inactivate bacteria present in milk.


Increased serum immunoglobulin E concentrations in venereal diseases. Total serum immunoglobulin E (IgE) concentrations were determined by a competitive solid phase radioimmunoassay technique in serum samples from patients with a variety of venereal diseases. The mean IgE concentrations for groups of normal persons without venereal diseases was significantly lower then the means for groups of appropriately matched patients with primary syphilis and gonorrhoea. There were also relatively higher IgE values in patients with trichomoniasis. Our data indicate that patients with urogenital infections have higher concentrations of IgE in the serum than matched control patients without such infections.


Structure of the phosphatidylcholines of the lung surfactant at birth in normal full term infants. 1. This investigation was undertaken for the purpose of determining the structure of the phosphatidylcholines of lung surfactant system present at birth in normal full term newborn infants. 2. The procedure, using tracheal aspirates as lung secretions, combines a cold-acetone precipitation and a two-dimensional thin-layer chromatography of the lipid extract. 3. Different species of phosphatidylcholines were isolated and found to account together for over 60% of the total phospholipids in tracheal aspirates. Analysis of the fatty acids esterifying the alpha- and beta-carbon of these different phosphatidylcholines showed palmitic acid as the major component with little myristic acid. 4. This fatty acid analysis revealed furthermore that the major phosphatidylcholine fraction was almost exclusively alpha, beta-dipalmitoylphosphatidylcholine. 5. This study shows that the procedure described provides a useful and simple method for the extraction, isolation and characterisation of the functional components of lung surfactant in living human newborns.


Causes of cervical carcinoma: new ideas. There are many features of cervical cancer that distinguish it from other common human cancers. It is extraordinarily sensitive to environmental variation, thus coming under early notice by the epidemiologists. Its accessibility and the introduction of aids to visualization, such as the colposcope, have enabled us to combine the methods of epidemiology and molecular biology in studying disease. This combination may well untangle one of the more serious conceptual problems in contemporary biology - the real nature of the carcinogenic process and all this in man himself.


Pharmacokinetics and relative bioavailability of cyclobarbital calcium in man after oral administration. The pharmacokinetics and relative bioavailability of cyclobarbital calcium have been studied after oral administration of Phanodorm, of tablets according to the Formularium Nederlandse Apothekers (1968; FNA), and an aqueous solution. Six healthy volunteers participated in the investigation on three occasions and each received the three preparations. The dose administered was 300 mg cyclobarbital calcium. Plasm concentrations of cyclobarbital were determined at regular intervals. Absorption from the three preparations was rapid was faster from the solution. Peak concentrations were usually attained within 1 h. The eleimination of cyclobarbital could be described by a single first-order process with an average half-life of 11.6 h (range 8 - 17 h). There was little intra-subject variation of the half-life. Relative bioavailability for each volunteer was estimated by comparing the areas under the plasma concentration curves. The RNA-tablets and Phanodorm exhibited similar bioavailability, whereas the average bioavailability of the solution was 78% of that of FNA-tablets; the reason for this unexpected finding is unknown. It was concluded that cyclobarbital cannot be regarded as a uniformly suitable drug for the treatment of insomnia. The long half-life that was apparent in some of the volunteers (15 - 17 h) creates a substantial risk of residual effects on the following morning. In principle, however, the calcium salt of cyclobarbital may be used for induction of sleep, because of its rapid absorption.


Bioavailability of tolamolol.

Bioavailability of tolamolol. Bioavailability of capsule and tablet formulations of tolamolol were compared by measuring plasma concentration of tolamolol and reduction in maximum exercise heart rate over a period of twelve hours in eight healthy subjects in a two-way cross-over study. Tolamolol was absorbed more rapidly from capsules than from tablets; this did not result in any significant difference in the reduction in maximum exercise heart rate between the two formulations. There was no significant difference between area under curve of reduction in exercise tachycardia and area under-curve of plasma concentration of tolamolol for the two formulations. Reduction in maximum exercise heart rate was related to logarithm of plasma concentration of tolamolol between two and twelve hours after both formulations.


The human uterotubal junction: a scanning electron microscope study during different phases of the menstrual cycle. Uterotubal junctions from surgically extirpated human uteri were examined. The specimens were obtained during different phases of the menstrual cycle. The interstitial portions of the tubes together with the cornual areas were dissected, excised, and their luminal surfaces exposed. The specimens were then processed for scanning electron microscopy. The surface epithelium of both the cornual endometrium and interstitial endosalpins. Ciliated cells were more numerous in the endosalpinx. Cyclic changes in ciliated cells were minimal, while cyclic secretory activity was demonstrated, especially in the endometrium. The transitional area between the endometrium and the endosalpinx was characterized by a marked increase in the number of ciliated cells, and a tendency of the secretory cells to assume a flattened, polygonal shape. These morphologic features suggest a possible role in the transport and/or maintenance of spermatozoa and/or ova.


[Syncillin in bacterial skin diseases].

[Syncillin in bacterial skin diseases]. A multicentric open clinical trial was carried out by 8 practising specialists in dermatology or paediatrics in patients with bacterial skin diseases who were subjected to a systemic therapy with Syncillin (=Azidocillin). The Syncillin presentation for adults and schoolchildren was tablets of 750 mg each, and sachets of 125 mg or 250 mg for infants. The duration of treatment was 10 days. The parameters analyzed were bacteriological findings and the clinical course of disease. 71 (=74%) of the 96 patients included in this study were considered as cured, 21 (=22%) as improved and 4 patients (=4%) as unchanged. Bacterial identification was still positive in 10 cases after the termination of treatment. However, this did not preclude the assessments of ""cured'' (3 cases) or ""improved'' (7 cases). The tolerance of the preparation was considered as ""very good'' or ""good'' in 91 and as ""poor'' in 5 patients. The most common side effects were nausea and diarrhoea. Exanthema was observed in 2 cases. None of these side effects, however, made a discontinuation of medication necessary. The era of rational and well-directed chemotherapy enables good therapeutic approach also to bacterial skin diseases.


[Case study of 14C-labelled lecithin placental transfer]. Because of the clinical and biochemical state of a 26 years old patient an erythroblastosis was expected. Continuous controls revealed that delivery in the 36th week of pregnancy was necessary. A therapeutic research with lecithine through the maternal circulation in this special case was carried out in order to prevent a respiratory distress syndrome of the premature infant.


Epidemiological and clinical patterns of genital lesions. A 5-year study of 668 patients with genital lesions revealed that teenagers and those in the age group of 20 to 40 are most vunerable. The poor, the uneducated and unmarried persons are at high risk. Chancroid and syphilis are the majority of cases. Inguinal bubo, herpes pregenitalis, condylomata acuminata, erosive balanitis and traumatic ulcers were seen less frequently. Most of the genital lesions had the classic clinical features. The findings of this study suggest that the pattern of genital lesions is showing borderline changes.


Reduced surface tension in lungs of fetal rabbits injected with pilocarpine. After opening the maternal abdomen under methoxyflurane anesthesia, fetal rabbits 25.5-28.5 days gestation were given an intraperitoneal injection of pilocarpine (150 mg/kg) or saline through the intact uterine wall. They were delivered by hysterotomy and sacrificed without breathing 2.5 h later. Newborn rabbits 29.5 days gestation received an injection of pilocarpine or saline at birth and breathed 30-120 min. Other newborn rabbits 29.5 days gestation were alternately sacrificed at birth or after breathing 30 min. Static pressure-volume curves with air showed decreased recoil and improved air retention on deflation in fetal rabbits 25.5-27.5 days injected with pilocarpine. There was no change in the static pressure-volume curve of lungs filled with saline. The data suggest that pilocarpine reduced surface tension by producing secretion of surfactant into air spaces. No change in lung recoil occurred with pilocarpine at 28.5 days, or with pilocarpine or breathing at 29.5 days. This may mean that air spaces at 28.5-29.5 days contained optimal surfactant, so further secretion of surfactant stimulated by pilocarpine or breathing failed to reduce surface tension.


Sensitive colorimetric determination of cholesterol in dairy products. Cholesterol can be determined colorimetrically in dairy products at levels of larger than or equal to 10 mug (coefficient of variation = 5.3%) with an o-phthalaldehyde reagent when non-cholesterol lipids are eliminated prior to color development. Absorbance for 2 mg tripalmitin was found to be equivalent to about 20 mug cholesterol. Saponification followed by hexane extraction removed interfering lipids. Using the described procedure, 238 individual raw milk samples were found to contain 144.4+/-37.9 mug cholesterol/ml, while their skim milk portions had 26.5+/-6.4 mug cholesterol/ml (mean +/- standard deviation). The o-phthalaldehyde cholesterol estimates agreed with those obtained by a gas-liquid chromatographic procedure when cheese and ice cream were analyzed by the colorimetric procedure with and without prior fat extraction.


Differences between mentally retarded and normally intelligent autistic children. Autistic children with an IQ below 70 and with an IQ above 70 were systematically compared. The two groups differed somewhat in the pattern of symptoms, but were closely similar in terms of the main phenomena specifically associated with autism. However, the low IQ and high IQ autistic children differed more substantially in terms of other symptoms such as self-injury and stereotypies and there were major differences in outcome. The possibility that the nature of the autistic disorder may differ according to the presence or absence of associated mental retardation needs to be taken into account in planning studies of etiology.


Infantile autism in dizygotic twins. A case report. This was a case study of a pair of dizygotic twins who both developed psychotic symptoms indicative of infantile autism at the age of 31--32 months. By the age of 5 years, when the children were evaluated, and over the 1 1/2 years they were followed, some improvement could be observed. Certain family events which took place just prior to the outbreak of the psychosis are reported, and the point is made that these may have had some causative relation with the disorder by acting as environmental stress factors. The possibility of a genetic factor also contributing to the appearance of the disorder could not be excluded in view of the existence of a first cousin with autistic symptoms.


A case report of an autistic boy. Selective responding to components of bidimensional visual and auditory stimuli. A case study was reported in which a 9-year-old male autistic boy was initially trained to discriminate between two auditory stimuli and two visual stimuli. He was then tested for overselective responding to bidimensional combinations of the four stimuli. It was hypothesized that the overselectivity results reported in previous studies were partially a function of a procedure in which autistic children were reinforced for responding in the presence of a multidimensional stimulus complex and then tested with individual stimuli. The child in the present investigation, with the alternative procedure, did not demonstrate overselective responding. Two interpretations of the results were presented, neither of which was consistent with an overselectivity theory. Future research should delineate the specific conditions which produce overselective responding, and suggest methods to facilitate more adaptive responding of autistic children.


Identification of consistent responding to auditory stimuli by a functionally "deaf" autistic child. Although the severity of autistic children's unresponsiveness to external stimulation has been frequently reported, little empirical work has been conducted to specifically describe the nature of their unresponsiveness. The child who participated in this experiment was at varying times reported to be deaf, hard of hearing, or functionally deaf; and at other times was reported to have normal hearing. In this experiment, we measured his responses to systematically presented auditory stimuli in order to determine if there was any pattern to his responding. Two types of auditory stimuli were used: (a) white noise, consisting of most of the frequencies within the human range of hearing, and (b) the sound of a candy machine delivering candy. The results showed the following. (1) There was consistent responding to both the white noise and the candy feeder. (2) The thresholds for responding to the white noise were always consistent on a given day, but varied from day to day. (3) Responding to the candy machine stimulus always occurred at sound levels which were well below the threshold for the white noise. These results are discussed in terms of their implications for understanding autism, and in particular in terms of understanding the lack of speech development in mute autistic children.