The effect of the bis-(2-pyridil-1-oxide)-disulfide adduct with Mg SO4 on the scalp and hair lipids. Animal experiments demonstrate that the topical application of the bis-(2-pyridyl-l-oxide)- disulfide adduct with MgSO4(Omadine MDS) increases the mitosis rate and also the size of the sebaceous glands in the Syrian hamster ear. Corresponding results have been obtained in human subjects in whom the secretion of the sebaceous glands was shown to increase after application of the compound. The studies also demonstrate that it decreases the fatty acid content of the scalp lipids. In this way a seborrhoea oleosa is transformed into a seborrhoea sicca. The undesired side effect of a stimulation of the sebaceous gland secretion is thus in part compensated for the patient's subjective feeling.


Venotonic activity of escin on the human saphenous vein. The venotonic effects of escin on the human saphenous vein have been evaluated in vitro on histologically normal venous segments obtained during surgical saphenectomy procedures. It is necessary to use the human preparations because of the great variability in the responses of the veins of different species. By using a standard stimulus and fitting the experimental data to the logistic function, we were able to compare the activity of escin with those of the commonly used venotonic agents. Stimulation with escin always induced an increase in venous tone which was constant for a given dose and stable for some time, and maintained for as long as an hour after removal of the substance from the bath. The maximum contraction obtained with escin was similar to those obtained with serotonin and dihydroergotamine, significantly greater than that obtained with acetylcholine or vasopressin. However, the affinity of escin was found to be lower than those of the other substances studied. An increase in venous tone, and therefore a decrease in the volume of the venous district, would be considered a very favorable result to be obtained with a drug which, like escin, is indicated for treatment of venous diseases leading to irreversible dilation.


The effect of diltiazem hydrochloride upon sodium diuresis and renal function in chronic congestive heart failure. d-3-Acetoxy-cis-2,3-dihydro-5-]2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride (diltiazem HCl) was orally administered to 9 patients with chronic congestive heart failure (Class IIb to III, NYHA) to examine whether the drug induces sodium retention and aggravates congestive heart failure. Renal hemodynamics and urinary electrolytes excretion were measured for 3 h after the medication in 6 out of 9 patients. Four of the rest of patients had received chronic administration of the drug for about 2 weeks. There was a significant increase in urinary sodium excretion without noticeable change in renal hemodynamics after diltiazem administration, demonstrating the presence of its direct inhibitory action on renal tubules. The increase in urinary sodium excretion was more marked in patients with heart failure than in those without. This difference in the response to diltiazem may be due to the functional constriction of renal cortical vessels in heart failure. This constriction may be related to renin-angiotensin system which diltiazem was reported to antagonize. The chronic administration of the drug did not induce sodium retention and edema. There was no deterioration of symptoms due to congestive heart failure such as dyspnea and body weight increase. It may be concluded that diltiazem does not aggravate congestive heart failure through its diuretic action and probably its systemic vasodilating action.


Effects of long-term treatment with suloctidil on blood viscosity, erythrocyte deformability and total fibrinogen plasma levels in diabetic patients. 1-(4-Isopropylthiophenyl)-2-n-octylaminopropanol (suloctidil, Sulocton), a drug introduced into clinical practice for the treatment of cerebral and peripheral vascular insufficiency and its complications, has been shown to decrease blood hyperviscosity after long-term treatment in diabetic patients. Suloctidil was particularly effective in lowering measured blood viscosity at high shear rate (230 s-1). At low shear rate (0.77 s-1) a decreasing effect was also observed but reached a statistically significant level only after one month. Since neither total plasma fibrinogen levels nor red blood cell deformability were modified by suloctidil treatment, its lowering effect on blood hyperviscosity could be due to a hitherto unrecognized mechansim of action.


[Special consideration of clinical and travelling medical criteria (author's transl)]. The pharmacological properties of difenoxin hydrochloride, a meperidine derivative exerting antidiarrheal effect, are presented. The drug is compared with related substances such as diphenoxylate hydrochloride and loperamide. In an open multicentre study including 259 patients with acute or chronic diarrhea of various etiology, difenoxin hydrochloride removed the complaints in 63--75% of the cases and improved them in some further 20%. Mild side effects were seen in 4% of the cases. In view of the necessity to obtain immediate therapeutic results such an antidiarrheal may be prescribed in cases of traveler's diarrhea despite certain doubts. However, the patients should be warned to see a doctor if certain symptoms appeared.


[Studies on percutaneous absorption of flumetasone pivalate and salicylic acid from a corticoid combination for topical use (author's transl)]. The combination of 0.02% flumetasone pivalate and 1% salicylic acid in a water-alcohol solution (Locasalen) is a novel therapeutic for topical treatment of the hairy scalp and also for the cosmetically acceptable treatment of other skin areas, that is, exposed skin. An investigation was carried out in 6 patients with psoriasis capitis and 6 control subjects in order to determine whether the use of Locasalen Tincture on the hairy scalp leads to percutaneous absorption of the corticosteroid and the salicylic acid. In the patients with psoriasis a few slight transient changes in biochemical-endocrinological parameters were observed, but not in the control subjects. However, these changes remained within the normal, non-pathological range so that they are of no clinical consequence. Percutaneous absorption of salicylic acid was not observed in either patient group.


[Vaginal absorption of econazole].

[Vaginal absorption of econazole]. After vaginal application econazol is absorbed to a high degree. Plasma levels are maintained for a relatively long period. Metabolism occurs in the vagina already. As there are no objections concerning toxicology the fact of absorption is considered positive from the therapeutical view-point because this drug does exert its effect not only in the vaginal cavity but also in the epithelium. It is suggested that vaginal absorption is influenced by cervical mucus.


Classification and bioavailability studies with WE 941 by quantitative pharmaco-EEG and clinical analyses. Psychoactivity, pharmacodynamic properties and drug tolerance of 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]1,2-(4-triazolo)[4,3-a][1,4]diazepine (WE 941), a new triazolodiazepine, were studied in 10 normal subjects utilizing quantitative pharmaco-EEG and clinical evaluation methods. In the double-blind, placebo-controlled trial, the subjects received randomized at weekly intervals oral single doses of 0.1 mg, 0.3 mg and 0.5 mg WE 941, placebo, and 30 mg flurazepam as reference substance. Measurements were obtained before and at the 2nd, 4th, 6th h post drug. EEG power spectral density analysis demonstrated no changes after placebo, while WE 941 and flurazepam induced statistically significant alterations characterized by an increase in beta-activity, a decrease in alpha-activity and increase in average frequency ("anxiolytic pharmaco-EEG profile"). In addition, 0.3 mg and 0.5 mg WE 941 and 30 mg flurazepam produced a significant augmentation of delta-activity indicating hypnotic qualities. Considering spontaneous and placebo-induced alterations, evaluation of the time- and dose-effect relationship indicated that all active substances exerted a tranquilizing effect throughout 8 h, while the hypnotic properties of 0.1 mg WE 941 were minimal (up to the 4th h), those of 0.3 mg WE 941 were moderate (up to 6 h) and those of 0.5 mg WE 941 were marked (up to 8 h). The dosage equipotent to 30 mg flurazepam is 0.3 mg WE 941. Heart rate and blood pressure exhibited no relevant changes, while side effects including fatigue, drowsiness and dizziness were mostly observed after the highest dosage of WE 941.


[Comparison of the cardiac effects of triamterene and its phase II metabolite p-hydroxytriamterene sulphuric acid ester (author's transl]. The positive inotropic action of triamterene (TA) on isolated, electrically stimulated left atria was compared with that of its phase II metabolite, p-hydroxytriamterene sulphuric acid ester (OH-TA-ester). It was found that the metabolite also possesses a positive inotropic action, its potency, however, is about 10 times lower than that of triamterene.


Carcinogenic N-nitrosodimethylamine as a contamination in drugs containing 4-dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (amidopyrine, aminophenazone). A total of 68 commercially available drugs containing amidopyrine were investigated for contamination with the strong carcinogen N-nitrosodimethylamine (NDMA). All samples contained varying amounts of NDMA. About half of the drugs contained 1--10 micrograms/kg, 40% contained 11--50 micrograms/kg, 7% contained 51--10 micrograms/kg and one sample had 370 micrograms/kg. NDMA-contents in batches of pure amidopyrine that had been utilized for preparation of drugs were higher than those in the respective drugs: about one-third was in the range of 20--50 micrograms/kg, one-third had 51--100 micrograms/kg, and one-third was above 100 micrograms/kg. There was, however, no correlation between NDMA-contents of batches of the pure substance and NDMA-contents of the drugs prepared from these batched. NDMA concentrations in the samples were inhomogenously distributed. It could be demonstrated that amidopyrine in substance reacts extremely rapidly with nitrogen oxides from the air to form NDMA. Ascorbic acid, which prevents nitrosamine formation in aqueous-acidic solution, under these conditions had no protective effect.


N-Nitroso compound contaminants in prescription and nonprescription drugs. 73 pharmaceutical products, consisteing of both prescription and over-the-counter drugs have been analyzed by gas chromatography-thermal energy analysis (GC-TEA) and high-pressure liquid chromatography-thermal energy analysis (HPLC-TEA) for the presence of N-nitroso compound contaminants. The methods used were designed to detect both volatile and non-volatile N-nitroso compounds at levels down to 1 ng/g (1 ppb). Results presented here indicate that N-nitroso compound impurities are absent from the majority of the products tested. However, for 3 of the drugs, our analysis suggests the possible presence of N-nitroso compounds at levels up to 81 ng/g (81 ppb). The identity of the suspect N-nitroso compounds have not yet been established. In the case of the over-the-counter drugs, two of these have been shown to contain TEA responsive materials (126 ppb, 406 ppb), that may appear to be O-nitroso compounds rather than N-nitroso.


Sugar-oximes, new potential antidotes against organophosphorus poisoning. In attempt to improve distribution and transport qualities of antidotes against organophosphorus poisoning, a new series of pyridine aldoximes linked to glucose moiety were synthesized and studied both in vivo and in vitro. Preliminary results describing the biological activity of the new compounds are presented and discussed in this report.


alpha, beta-Unsaturated gamma-lactones correlations between lipophilicity and biological activity. A homogeneous series of alpha, beta-unsaturated gamma-lactones was prepared. Their in vitro activity against various microorganisms was quantitatively correlated, with the Hansch approach, to their lipophilicity, expressed by Rm chromatographic values. Although all the experimental results show a parabolic dependence, only in few cases the parabolic model calculated by Hansch fits to them. In most cases it was possible to find a good fitting between the ascending side of the parabola and the linear equation of Hansch. The meaning of the results and their utilization for future work are discussed.


Medrogestone: analysis in serum by high-pressure liquid chromatography. A method for the determination of 6,17-dimethylpregna-4,6-diene-3,20-dione (medrogestone) in serum is described using high-pressure liquid chromatography with UV detection. Interfering substances in human or dog serum blanks were removed selectively by reaction with oxalyl chloride followed by an aqueous alkaline borate "wash" of the extract. The method is specific for medrogestone and, based on 5 ml serum, has a limit of detection of 2 ng/ml.


[The effect of carbocromen on the respiratory function of rat heart mitochondria]. Rat heart mitochondria were isolated by a slightly modified method of Sordahl. The influence of carbocromen (Intensaín) on the respiratory function of the tightly coupled or uncoupled mitochondria was tested in the presence of the respiratory substrates pyruvate, alpha-ketoglutarate, D,L-palmitoylcarnitine, L-palmitoylcarnitine, and D,L-acetylcarnitine. Carbocromen (0.089--0.89 mmol/l) did not change the P/O ratio, but reduced the rate of oxygen consumption (QO2) of the coupled mitochondria by about 20% when palmitoylcarnitine was used as respiratory substrate. With ADP in excess (5 mmol/l) carbocromen decreased QO2 in state ST3 by about 35%. This drug induced reduction of QO2 is still much more evident in uncoupled mitochondria (18% with 0.045 mmol/l carbocromen, 70% with 0.89 mmol/l carbocromen). In the presence of pyruvate as substrate the respiratory function of the coupled and uncoupled mitochondria remained nearly unchanged after adding the drug. It is discussed that carbocromen could interact with the complex enzyme dependent transport of long-chain fatty acids through the mitochondrial membrane.


The inotropic and chronotropic responses of isolated canine atrium to 5-(3-tert.-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol). Direct effects of 5-(3-tert.-butylamino-2-hydroxy) propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol) on chronotropic and inotropic activity were investigated in seventeen isolated atrium preparations which were suspended in a bath and perfused with arterial blood from the heparinized donor dog. Carteolol has little adrenergic beta-receptor stimulating effect in doses which block prominent positive chronotropic and inotropic effects of norepinephrine. At relatively larger doses, however, carteolol produced a long-lasting positive chronotrophic and inotropic effect. At extremely larger doses, carteolol produced a negative inotropic effect with little or slight negative chronotropic effect. In propranolol-treated preparations, carteolol induced less positive effects. Propranolol-induced negative chronotropic and inotropic effects were significantly reduced by treatment with carteolol. From these results, carteolol has not only potent beta-adrenoceptor blocking property but also sympathomimetic activity, and different beta 1-type cardiac adrenergic receptors may probably be suggested.


The electrocardiogram of Roman high- and low-avoidance rats under pentobarbitol sodium anesthesia. Strain-sex differences have previously been observed between RHA and RLA male (m) and female (f) rats in the sensitivity to pentobarbital sodium. This present study further investigated the effect of these factors on the electrocardiogram. The heart rate was depressed at all levels of anesthesia, with the maximum effect at 40 min post-infection. Although the heart rate subsequently increased, the P-R and Q-T intervals lengthened progressively throughout the 2 h, accompanied by steady increases in the T-wave amplitude. Some strain-sex differences were seen in the Q-T interval (RHAm, RLAf greater than RLAm), the T wave amplitude (RHAmf greater than RLAmf) and the S-wave amplitude (RHAmf greater than RLAmf, RHLAf greater than RHLAm).


Repair kinetics of DNA, RNA and proteins in the tissues of mice treated with doxorubicin. Experiments in mice treated with a single 10 mg/kg dose of doxorubicin (adriamycin) i.p. revealed considerable reduction in the incorporation of 3H-thymidine in DNA and of 3H-uridine in RNA, in the spleen and liver, and at mitochondrial and non-mitochondrial level in the heart. Although protein syntheses in the heart and spleen were not reduced by the drug to any great degree, they took 10 days to return to normal; conversely, liver protein syntheses were not inhibited at all and indeed presented signs of stimulation.


[The secretory action of various C-5-alkylsubstituted histamines and N alpha-methyl-histamines on anaesthetized cats with Heidenhain pouches (author's transl)]. In particular, the action of N alpha-methyl-histamine has to be considered since its secretory response is approximately 1.5 times greater than that of histamine and its secretion lasted for a longer period of time. After C-5-alkylsubstitution, both 5-methyl-histamine and N alpha,5-dimethyl-histamine showed secretory action comparable to that of histamine; the agonistic activity, however, decreased with increasing chain length.


Semi-complete versus partial venous obstruction, with and without partial lymphatic obstruction, and benzo-pyrone treatment. The alterations in the fine structure of the venous wall are reviewed, and the changes which occur with injury. These are very similar in both arteries and veins, and were also found by us in experiments in which the common iliac veins of rats were completely occluded, with or without partial lymphatic obstruction. It was found that the protein concentration was considerably increased in the vein wall, in the muscle, and in the skin of the leg--especially when the lymphatics were blocked as well as the veins. The effects of various procedures, including partial and semi-complete venous obstruction and lymphatic obstruction were examined. It was shown to be likely that in semi-complete venous obstruction the blood in the occluded vessels is ultrafiltered, causing great increases in protein concentration, which will be transmitted to the tissues in general--although not to the tissue channels and lymphatics. This will not happen in partial venous occlusion. In all of these cases the benzo-pyrones considerably reduced the amount of excess protein in the tissues. This was no doubt partly due to their abilities to cause increased proteolysis, but may also have been due to their effects on blood and lymph vascular tone and functioning.


Antimicrobial agents in rats. I. Serum levels of parenteral cephalosporins. Eleven cephalosporins were tested for their pharmacokinetic properties in rats in order to obtain a basis for experimental evaluation of their in vivo activity. The compounds were administered to female Wistar rats in i.m. doses of 150 or 50 mg/kg. The cephalosporin concentrations in rat serum were determined by the agar-well-diffusion method. Essential differences concerning the serum levels, half-life and the area under the curve could be ascertained. Low serum levels and short half-life could be reported for cephapirin, cephalotin, and cephradin, whereas cefazolin, cefazedone, and cefuroxime produced high and longer lasting serum levels. All cephalosporins were quickly absorbed, most of them were beneath the minimum detectable concentration after 6 h. It is concluded that pharmacokinetic data should be taken into consideration in conjunction with experimental chemotherapy.


[Animal studies on nephrotoxicity of seven aminoglycoside antibiotics during long-term treatment (author's transl)]. In studies on female Wistar rats (n = 133) the nephrotoxicity and kidney concentrations of amikacin, butirosin, gentamicin, kanamycin, bekanamycin, sisomicin, and tobramycin were examined during four weeks therapy and four weeks convalescence. Maximum doses recommended for human therapy were administered i.m. at 12-h intervals. For evaulation of the tubulotoxic effect the excretion rates of tubular cells were determined daily. At weekly intervals animals were sacrificed for determination of the kidney aminoglycoside concentration, which was assayed microbiologically. The application of all aminoglycosides resulted in an increase of excreted tubular cells, but the extent and course of cell excretion varied for the different aminoglycosides. An initial peak after different periods of therapy and later on a decrease of cell excretion was found for all aminoglycosides. These periods of high and low loss of tubular cells corresponded to aminoglycoside accumulation and saturation in the kidneys. During the first week of treatment only gentamicin was tolerated without signs of renal damage. Initially the nephrotoxic effect was strongest for bekanamycin, but at the end of the first week kanamycin and sisomicin produced similar distinct side effects. Thereafter the highest cell excretion rates were continuously caused by sisomicin.


[Netilmicin and tobramycin: comparative evaluation of pharmacokinetics, nephrotoxicity, and therapeutic efficacy in animal studies (author's transl)]. Pharmacokinetics, nephrotoxicity, and therapeutic efficacy of (2S-cis)-4-O-[3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]-2-deoxy-6-O-[3-deoxy-4-C-methyl-3-(methyl-amino)-beta-L-arabinopyranosyl]-N1-ethyl-D-streptamine sulfate (netilmicin) and tobramycin were investigated in rats. The excretion rates of tubular cells and of the urinary enzyme malic dehydrogenase served as parameter of nephrotoxicity. Both compounds were, similar to other aminoglycosides, tubulotoxic within the range of dosages used for human therapy. Netilmicin, however, produced less renal damage than did tobramycin in all dosages applied. Pharmacokinetic studies revealed lower renal concentrations of netilmicin after repetitive administration. Experimental chemotherapy of the chronic E. coli pyelonephritis in rats with both aminoglycosides resulted in a significant reduction of the renal bacterial counts. In spite of approximately identical serum concentration curves and in vitro activity, especially the low dosage of netilmicin led to more favourable therapeutic results than equal doses of tobramycin. These animal experiments suggest higher renal tolerance and efficacy of netilmicin.


Kinetic metabolism of vinpocetine in the rat. The pharmacokinetics of vinpocetine (Cavinton), a new potent vasodilator, and of its main metabolite have been studied in rats by specific extraction and radio thin-layer chromatography following i.v. and p.o. administration. The drug is rapidly eliminated, its half-life was found to be 125 min. The apparent volume of distribution was 3.8 l/kg and the clearance rate 33 ml/min/kg. From the equation describing the concentration-time curve a two-compartement open model was computed. Bioavailability of vinpocetine after p.o. administration was about 50%. The main metabolite, free apovincaminic acid, is formed very rapidly in rats and is eliminated from plasma with a half-life of 360 min.


Pharmacokinetics of vinpocetine in humans. The pharmacokinetics of ethyl-apovincaminate (vinpocetine, Cavinton), a new vincamine derivative has been studied in volunteers after p.o. and i.v. administration. The concentration of the drug was determined by mass-fragmentography in human plasma. There was a biphasic elimination of the substance after i.v. injection with a T1/2 alpha of 0.136 h and with a T1/2 beta of 4.83 h. The value of Vdss (2.1 l/kg) shows a high adsorption of the drug by tissue proteins. The clearance rate of elimination was 0.366 l/h/kg. Oral administration of the drug resulted in maximum plasma concentration 1--1.5 h after the administration with values of 20--62 ng/ml. The bioavailability of the drug--calculated from the ratio of the areas under the concentration-time curves--proved to be 56.6 +/- 8.9%. Unchanged vinpocetine could not be detected in urine. From the results two-compartment open models were constructed and the steady state concentrations after multiple dosing were computed.


[Clinical study on digoxin tablets with high bioavailability (author's transl)]. The relationship between different maintenance doses and the steady-state digoxin blood concentration was studied in 160 patients with heart failure. All patients received digoxin tablets of the same brand (Digacin). The bioavailability of this brand is 82% compared with an i.v. standard. During the treatment with daily doses of 0.2 mg and 0.3 mg average serum digoxin levels of 1.09 +/- 0.45 ng/ml and 1.33 +/- 0.53 ng/ml were measured in patients with normal renal function. The daily dose of 0.4 mg digoxin was in correlation to an average serum level of 1.75 +/- 0.81 ng/ml. 81% and 86% of all patients with normal renal function taking 0.2 or 0.3 mg digoxin every day were found to have levels in the range of 0.7 to 2.0 ng/ml. The influence of sex, age, height, body weight, maintenance dose, serum creatinine and serum potassium on the variance of the digoxin plasma levels was computed by multiple linear regression. The multiple correlation coefficient was r = 0.666, the coefficient of determination (100 r2) being 44.4%. Therefore 44.4% of the total variance could be explained by these variables. Individual variables accounted for the following percentages of the total variance: serum creatinine 29.1%; maintenance dose 14.5%; age 4.3%; and reciprocal of body weight 3.9%.


Pancuronium requirements. With special reference to serum protein pattern. Requirements of pancruonium were evaluated in 50 adult patients undergoing abdominal surgery in halothane anaesthesia. A significant negative correlation was found between gamma-globulin and the apnoeic dose of pancuronium (r = --0.335, P less than 0.02), on the one hand, and the apnoeic period after it (r = --0.311, P less than 0.05), on the other hand. beta-Globulin displayed a significant positive correlation with the apnoeic period after pancuronium (r = 0.344, P less than 0.02). The heavier patients necessitated less drug/kg bw. to obtain apnoea than the leaner ones did. Finally, the females showed a higher sensitivity to pancuronium in comparison to the males.


[Plasma levels, renal excretion and metabolism of orciprenaline after administration in sustained-release form (author's transl)]. A newly developed sustained-release form of orciprenaline-sulfate (Alupent) was tested in 13 patients. Determination of 3H-radioactivity in blood, urine and faeces was used to elucidate its pharmacokinetic properties. Maximum plasma levels of radioactivity were obtained between 8 and 12 h after administration. 10.7 +/- 2.5% of the administered radioactivity were excreted in urine over a period of 72 h. Orciprenaline was mainly excreted as the sulfate-conjugate. Approximately five percent of the radioactivity were excreted as 4,6,8-trihydroxy-N-isopropyl-tetrahydroisoquinoline--the condensation product of formaldehyde and orciprenaline.


Pharmacokinetics of azapropazone following single oral and intravenous doses. The pharmacokinetics of azapropazone (Prolixan) was studied in 7 healthy volunters following single oral and i.v. doses of 600 mg. After i.v. injection plasma concentration declined biexponentially with time. The half-life of the beta-phase was 13.6 +/- 2.6 h (mean +/- SD), the apparent volume of distribution 11.9 +/- 3.5 l, and the total clearance 10.1 +/- 2.1 ml . min-1. Following oral administration peak plasma concentrations occurred between 3 and 6 h and declined with a beta-phase half-life of 14.3 +/- 2.8 h. The binding of azapropazone to plasma proteins was high (ranging from 99.52 to 99.67% at a total plasma concentration of 75 micrograms/ml). The bioavailability of azapropazone when administered as capsules was 83 +/- 19%.


The effects of alcohol and caffeine on concentration test performance. Within a 2 x 2 x 2 factorial design using two treatment factors, alcohol vs. placebo and caffeine vs. placebo, with stratification for sex as a non-treatment factor in 2 x 2 x 2 groups of 7 students each, concentration test performance was measured by an arithmetic test. The interesting result was a second-order interaction between the three factors: alcohol as well as caffeine decreased concentration in males; combined treatment performance was interpreted synergistically. For females, alcohol as well as caffeine increased concentration while the combination of both had an antagonistic effect.


Social distribution of sexually transmitted diseases. A survey of female clinic registrations. Social and medical data on 1672 female patients attending a venereal disease clinic were recorded over a four-year period. Analysis of these data provided a demographic and social profile of female clinic attenders and indicated considerable variations in patterns of diagnosis between different social categories of patients. The probability of diagnosis of different infections varied according to age, marital state, social class, employment status, and previous record of attendance.


Pyrrolo[1,4]benzodiazepine antibiotics. Biosynthesis of the antitumor antibiotic sibiromycin by Streptosporangium sibiricum. The biosynthesis of the antitumor antibiotic sibiromycin by Streptosporangium sibiricum requires the construction of four units: the amino sugar from glucose; the anthranilate ring from DL-tryptophan probably via kynurenine; the aromatic methyl group from methionine; the propylidene proline from L-tyrosine with the loss of two aromatic carbons and addition of a C-1 from methionine. Retention of tritium from DL-[5-3H]tryptophan in sibiromycin suggest an NIH shift during hydroxylation of an intermediate.


Pyrrolo[1,4]benzodiazepine antibiotics. Biosynthetic conversion of tyrosine to the C2- and C3-proline moieties of anthramycin, tomaymycin, and sibiromycin. This paper descirbes biosynthetic labeling experiments on the conversion of tyrosine to the C2- and C3-proline units of anthramycin, tomaymycin, and sibiromycin. The biosynthetic fate of all of the aromatic and side-chain hydrogens has been determined in each antibiotic by using dual tagged (3H/14C) and 2H-labeled tyrosine molecules. In addition, experiments uing [15N]tyrosine and the tritiated D and L isomers of tyrosine have shed some light on the biochemical reactions which take place at tha alpha position of tyrosine. On the basis of results of all these experiments, a biosynthetic scheme had been proposed to rationalize the apparent inconsistencies which occur between the results for the three antibiotics. This scheme proposes that a common main pathway involving proximal extradiol cleavage of Dopa and condensation to form the pyrrolo ring leads ultimately to a C-7 branch point compound. Parallel pathways from this central branch point compound lead by well-known biochemical transformations to the C2-and C3-proline units of anthramycin, tomaymycin, and sibiromycin. The reactions in these parallel pathways are suggested to be "cosmetic or after events".


Is an average viscosity tenable in lipid bilayers and membranes? A comparison of semi-empirical equivalent viscosities given by unbound probes: a nitroxide and a fluorophore. Relative variations of fluidity in bilayers and membranes are currently evaluated by numerous physical methods, but comparison between different systems remain difficult because the effects of order (anisotropy) and fluidity are involved in the diffusion coefficients for correlation times, or frictional coefficients) given by experiment. The present report represents an attempt to generalize the use of isotropic liquids as viscosity standards for disordered lipidic systems. It advances a simple check to verify the quasi-isotropic behaviour of probe environments and avoids the introduction of estimated values of the molecular dimensions in Perrin-Einstein relations. The equivalent viscosities obtained with 1,6-diphenyl hexatriene and with 2-pentyl-2'-butyl-4,4'-dimethyl oxazolidinoxyl are strikingly similar in egg lecithin vesicles above 0 degrees C, while in dipalmitoylphosphatidylcholine dispersions above their transition temperature, a discrepancy of about 30% seems to remain, even at high temperatures.


Fluorescence temperature jump relaxations of dansylphosphatidylethanolamine in aqueous dispersions of dipalmitoylphosphatidylcholine during the gel to liquid-crystal transition. The change of fluorescence of the probe dansylphosphatidylethanolamine embedded in multilamellar liposomes of dipalmitoylphosphatidylcholine was used to investigate the dynamics of the thermotropic gel to liquid-crystalline phase transition by use of the temperature-jump technique. The results are discussed and compared to published observations on the same system in which the phenomenon was reported by turbidity changes.


[Neonatal meningitis: recent results].

[Neonatal meningitis: recent results]. The better outcome of the patients with neonatal meningitis is reported in the last 3 years with ampicillin and chloramphenicol plus one aminoglucoside. (27/51). The use of intrathecal gentamicin was beneficial in 7 out of 9 babies in whom this procedure was used. The mortality rate on the years 1963-1974 in 86 cases was 70.9% in contrast with 43% (51 cases) for the years 1975-1978. Exchange-transfusion was done to 8 patients, with 6 survivals.


The identity and origin of oligosaccharides present in the faeces and urine of sick infants. A systematic identification scheme, based on improved paper and thin-layer chromatography, acidic and enzymatic hydrolysis, and the reaction of carbohydrates with several location reagents, has been applied to the analysis of oligosaccharides present in the urine and faeces of sick children and the diets they are fed. The identity and origin of these oligosaccharides is described and their relevance to the diagnosis and treatment of children with suspected disorders of carbohydrate metabolism is discussed.


Pulmonary vasculitis complicating childhood ulcerative colitis. A case of pulmonary vasculitis complicating ulcerative colitis is presented, and the literature is reviewed. Unexplained pulmonary problems complicating severe ulcerative colitis should prompt a review of rare etiologies to include pulmonary vasculitis, apical pulmonary fibrosis, and salicylazosulfapyridine-induced lung disease. Lung biopsy will establish a diagnosis of pulmonary vasculitis.


[Conservative treatment of severe paralytic ileus. Clinical experiences with Ceruletid]. After the failure of other medicamentous treatment attempts for paralytic ileus, Ceruletid (Takus) was used in 20 surgical patients. Ceruletid was applied as an infusion of 40 microgram in 250 ml or 500 ml physiological saline solution over a period of 2-3 hours. During this time the occurrence of bowel sounds, flatulence and defecation was observed. The most important clinical and serological parameters were measured before and after treatment. Treatment was successful in 17 cases, in 3 cases no success was achieved. Severe side effects did not occur. The use of Ceruletid in the described form of administration can be recommended for the treatment of paralytic ileus.


Polymorphic variants of the third component of complement in Graves' disease. We have examined electrophoretic variants of the third complement component (C3) in 294 controls and in 44 patients suffering from Graves' disease, drawn from the Avalon Peninsula of Newfoundland. Two common C3 variants, S and F, account for 99% of the gene frequencies. The S homozygote phenotype was observed in 170 controls and in 27 patients; 18 controls were found to be homozygous for the F allele (3 patients), and the FS phenotype was observed in 103 controls and 14 patients. The phenotypic frequencies did not differ significantly between controls and patients. It is concluded that C3 variants do not distinguish individuals who have Graves' disease.


Quantitative in vivo measurement of thyroidal iodine content by static x-ray fluorescent technique: some preliminary clinical observations. A static x-ray fluorescent technique utilizing an 241Am source of low activity and a wide view diverging collimator which allows in vivo determination of the concentration and total content of iodine in the thyroid is described. Determinations of normal thyroidal iodine concentration and total iodine content were as follows: 0.40 mg/g and 10.6 mg for 16 men, and 0.67 mg/g and 17.6 mg for 14 women. This fluorescent system has been applied to 70 patients to date. Thyroidal iodine concentrations in patients with Graves' disease were approximately equal to those in healthy suspects, and little change was observed among the concentrations in patients before, during, or after treatment. In most of the patients with chronic or subacute thyroiditis, concentrations levels were lower.


Decisionmaking in regional health planning agencies. Health Systems Agencies (HSAs), the new regional health planning agencies established by the National Health Planning and Resources Development Act of 1974, have as their major goals quality, accessibility, continuity and cost containment. One of the tools for cost containment available to HSAs is their active participation in the statewide certificate-of-need (CON) program. To help anticipate how HSAs may play their CON roles, this article reviews the CON decisionmaking processes of two Comprehensive Health Planning (CHP) agencies, the predecessors of HSAs. While most CHPs lacked specific health plans and powers. the two California agencies examined have had both regional plans and roles in CON programs comparable to the present HSAs'. Our focus is on the decisionmaking process rather than the effectiveness of CON programs. A simple descriptive model is developed based on the assumptions that the planners seek satisfactory, rather than optimal solutions and that the data available are extremely limited. The cases analyzed suggest that, while most projects exceed the bed need standards, institutions were almost always able to demonstrate a need through various special circumstances. Once a need has been shown, the agency was able to deny an application only if a better alternative were available. This study suggests two approaches to improving regional health planning decisionmaking. First, identified needs can be better met either by increasing the agency's ability to generate alternatives or by encouraging health facilities to submit competing applications. Second, a regional health care budget would force the agency to make choices among competing needs.


Deformation of the articular cartilage and joint space of the human knee joint under static load. In order to define the deformation of articular cartilage and the joint space under statically loaded knee joints, we studied serial sections in the frontal plane of knee joints which were frozen under the application of a load. Normal articular cartilage surfaces did not make contact even under loads of 100kg or more, leaving always a space between. The compressive deformation of articular cartilage mainly occurred at the central area near to the intercondylar notch or prominence, but the deformation of cartilage in the area covered by menisci was negligible.


TSH-responsive adenylate cyclase activity in thyroid tissue from patients with Graves' disease. Basal adenylate cyclase activity of thyroid plasma membranes obtained from six patients with Graves' disease was slightly but not significantly lower than normal (83.3 +/- 13.9 pmol cAMP/10 min/mg of protein versus 120.9 +/- 19.5 pmol cAMP/10 min/mg of protein). In five of these patients the adenylate cyclase activity was stimulated by bovine TSH with an apparent Km value similar to that of normal thyroid (3.1 +/- 0.5 X 10-9 M versus 3.4 +/- 0.6 X 10-9 M). The response to prostaglandin E2 was also normal. In the sixth patient adenylate cyclase activity was stimulated by prostaglandin E2 but not by bovine TSH. The distribution of basal adenylate cyclase activity in various gradient layers was studied in two TSH-responsive patients. A relative increase of this activity was found in the denser layer when compared to normal thyroid tissue. This could be the expression of an altered ratio between the protein and lipid components of the plasma membranes in patients with Graves' disease.


The effect of a non-absorbable fat, sucrose polyester, on the metabolism of vitamin A by the rat. Sucrose polyester (SPE) is a fat-like material that is not absorbed. The effect of this material on vitamin A metabolism was determined by measuring the amount of the vitamin that was stored in the liver of rats following the ingestion of a known amount of vitamin A. In one study, the vitamin A was administered as an oral dose in a vehicle consisting of various proportions of cottonseed oil and SPE. Each 1% replacement of cottonseed oil by SPE resulted in a 0.26% decrease in the amount of vitamin A found in the liver. In the second study, the vitamin A was incorporated into diets in which the fat component consisted of various proportions of cottonseed oil and SPE. When these diets were consumed for 1 week, each 1% replacement of cottonseed oil by SPE resulted in a 0.84% decrease in the storage of vitamin A by the liver. It is proposed that in the lumen of the intestine vitamin A distributes between the customary micellar phase and the unhydrolyzed oil phase of SPE. The vitamin A in this latter phase is eliminated in the feces.


Morphologic aspects of bronchopulmonary dysplasia. Some of the morphologic changes of bronchopulmonary dysplasia are frequently found in infants dying of the infantile respiratory distress syndrome, so the frequency of BPD is more frequent as determined morphologically than as determined clinically. Morphologic differences have been described between the lesions of oxygen poisoning and those of BPD, but there are probably no true qualitative differences and such differences as exist are quantitative ones. Clinical and functional studies suggest that lung damage in infancy and early childhood may result in residual functional abnormalities in older childhood, and to a predisposition to chronic airflow obstruction in later life. It is hypothesized that this may be brought about by alteration in postnatal lung growth. Two patients who had an operation for diaphragmatic hernia on the first day of life and who died 8 and 64 months later were used to illustrate this point, since both had obviously abnormal lung structure at the time of death.


Experience in primary mental health care. The author discusses his experience as clinical director of a small mental health unit in a neighborhood health center. Deep-rooted organizational and administrative conflicts resulted in the clinical compromise of this unit's capacity to deliver needed services. Essentially, two recommendations are made to protect and foster the vitality of "primary mental health care." The first is to reduce the organizational complexity that engulfs centers such as the one described. The second is to recognize how vital the community boards of directors are to the quality of care received by patients. Board members must be provided with support and technical assistance by professional advisors and supporting agencies in order to carry out their essential missions.


[Cycloplegia with cyclopentolate for testing-refraction of children (author's transl)]. A comparative study of the cycloplegic effect of 1% cyclopentolate and atropine or homatropine was done by means of Lindner's method of retinoscopy. In 53% of 1.5- to 6-year-old strabismic patients the hypermetropic refraction was higher (average 0.6 dpt) under the use of atropine, and in 27% of 6- to 11-year-old children cyclopentolate was more effective than homatropine (average 0.5 dpt). Therefore, atropine should be used for children with convergent squint up to 6 years, in order to get full correction of hypermetropia. In other cases cyclopentolate is preferable because of its rapid and strong efficiency of brief duration.


[Hyper- and normoprolactinaemia with amenorrhea and galactorrhea-amenorrhea-syndrom (author's transl)]. 10 amenorrhea-patients and 5 galactorrhea-amenorrhea-patients were treated wi2-Br-alpha-ergocryptine (CB 154) as a specific prolactin inhibitor. Side-effects, such as headaches, dizziness, and nausea could be reduced to a minimum by delivering the drug with the meal at night. Before and under the treatment hormone levels were determined in plasma and 24-hour-urine. In the beginning all 15 patients showed a hyperprolactinaemia with a nearly always simultaneously existing hypogonadotropinaemia and the absence of LH-peaks. Also the estrogen- and progesterone-concentrations were on the lower normal level or extremely suppressed. In all patients CB 154 therapy led to a quick decrease of the prolactin levels, to a regaining of typical LH- and FSH-episodes, as well as to a regeneration of ovarian function. 5 women reacted with an ovulation, 3 became pregnant. The galactorrhea diminished significantly and stopped finally after a treatment of one week to 6 months. Discontinuation of CB 154-therapy, however, often provoked the galactorrhea-amenorrhea-syndrome again. For women with normoprolactinaemic amenorrhea a gestagen- and estrogen-test were carried out in order to classify the amenorrhea-type and it was tried to induce an ovulation with Dyneric. For patients with a strong desire for children and without any organic cause for their sterility, in cases of ovarian insufficiency grade I and II a HMG-HCG-treatment was often indicated. In spite of a precise control in order to avoid an overstimulation of the ovaries about 1% of the Dyneric-treated and even 30% of the HMG-HCG-treated patients developed ovarian cysts. In spite of high doses of gonadotropins only 32,5% of our sterility-patients (group I and II) became pregnant, whereas about 60% of the hyperprolactinaemic amenorrhea-patients (group VI) conceived under CB 154 treatment.


Evidence for cerebral involvement in nephropathic cystinosis. Cranial computerized tomography (CCT) of 3 children with nephropathic cystinosis and chronic renal failure (CRF) revealed a hydrocephalus internus and externus. In two boys the findings consisted of bilateral dilatation of the ventricular system and of the subarachnoid space; in one boy the alterations were mainly unilateral. The children had repeated convolsions which could not be explained by deterioration of renal function. Their neurological condition was otherwise normal. In six non-cystinotic patients with chronic renal failure, CCT showed normal anatomical structures. The possibility is discussed that the hitherto unknown pathogenetic mechanism of cystinosis leads to diffuse cerebral atrophy, resulting in internal and external hydrocephalus.


Atypical aspects of hypertensive encephalopathy in childhood. Four patients with hypertensive encephalopathy and misleading focal symptomatology are reported in order to point out the problems of differential diagnosis. The first patient, together with a classical syndrome of hypertensive encephalopathy, had peculiar EEG features consistent with a possible diagnosis of herpes simplex encephalitis. Case 2 presented with a complex clinical syndrome associating bizarre spells suggestive of a psychiatric condition with ocular symptoms pointing to an upper brain stem involvement. The third child was remarkable because of the presence of neuroradiological signs compatible with a space-occupying lesion of the posterior fossa not eventually found after a surgical exploration performed as an emergency procedure. The last patient had central nervous system signs in the context of a Guillain-Barré syndrome: in this case the central symptomatology would not fit the already described pattern of encephalomyelo-radiculo-neuropathy but had to be entirely ascribed to the ill controlled arterial hypertension.


Dissociated motor development--developmental patterns, clinical characteristics, causal factors and outcome, with special reference to late walking children. Dissociated motor development, defined as marked gross motor delay without any abnormal neurological signs and contrasting to a normal fine motor-adaptive performance, was studied prospectively in a consecutive in a consecutive series of 78 children, 48 girls and 30 boys, aged 7-23 months at first examination. When 17 months of age, 10 of them had become normalized, and in further three a disability explaining their gross motor delay had been diagnosed. At an average age of 4.2 years, the remaining 65 late walkers were, regardless of cause and developmental and neurological findings at final follow-up, characterized by a number of deviating clinical features as muscular hypotonia (71%), shuffling (51%) and dissociated or late pattern of learning to sit (79%). In 30 out of 65 late walkers (46%) a defined clinical condition of probable pathogenetic implication was found. In 35 out of 65 late walkers (54%), no explaining clinical condition was found. They have been designed to be idiopathic late walkers. Except for muscular hypotonia, present in 77%, conventional neurology was normal in this group. Minor neurological signs such as a positive Foerster sign, defect balance reactions in standing, or asymmetry in prewalking locomotion were, however, occasionally and temporarily observed. Girls were overrepresented among idiopathic late walkers, 69% compared to 43% among the symptomatic late walkers. Complete normalization was more common in the idiopathic group (66%) than in the symptomatic group (27%). Early differentiation between the late walkers who were normalized and those who developed mild mental retardation or neurological handicaps was difficult but not quite impossible. Heredity for shuffling, a non-revealing pre- and perinatal history, a developmental pattern of late learning to sit, and shuffling favoured a normal outcome. Creepers with a dissociated pattern of learning to sit and crawlers with muscular hypotonia were found to have an increased risk for later handicap.


[A contribution to the psychophysiology of infantile dysmegalopsy (author's transl)]. A 9 year old boy was able to evoke microptic experiences voluntarily. Clinical and historical signs of minimal brain dysfunction were present. An epileptic etiology could neither be proven nor ruled out. Synchronized EEG- and Video recording allowed us to analyze the EEG and the corresponding behavior by using sequential spectral analysis of the EEG data. Coinciding with a progressive increase in rhythmic 6-7 cps. activity we observed a behavior which appeared to correspond to a state of narrowed attention. He signalized the onset of a micropsy a few seconds after the transition from this pattern into one which showed a relative voltage decrease and the reappearance of some alpha-activity. The end was signalized by him coinciding with the recurrence of normal waking activity. Our findings--like those of others--suggest that the gradual development of hypnagogic phenomena is bound to a state of lowered vigilance. The reappearance of alpha activity and the voltage decrease seem to represent an unstable intermediary state with partial arousal preceding the restitution of normal wakefulness. Since the onset of the micropsy was signalized only after manifestation of the intermediary EEG-state, we conclude that partial arousal is a prerequisite for giving an indication of hypnagogic experiences in a quasi retrospective manner.


Neonatal non-ketotic hyperglycinemia: a clinical, biochemical and neuropathological study including electronmicroscopic findings. In a family of four children, three died within 8 days after birth. The fourth child survived after a critical first week with the same symptoms as the siblings. He was at the age of four found to have non-ketotic hyperglycinemia. The histories and neuropathology of the other children were then reexamined. It seems highly probable that all siblings suffered from non-ketotic hyperglycinemia. This report points to the clinical, biochemical and neuropathological diagnostic problems in this disease and also adds new information on the ultrastructural changes, not hitherto visualized.


Nasolacrimal duct obstruction following transantral-ethmoidal orbital decompression. Of 200 patients undergoing bilateral transantral-ethmoidal orbital decompression for Graves' ophthalmopathy, nine suffered symptomatic postoperative obstruction of the lower nasolacrimal excretory system. Five of the nine patients had persistent symptoms of epiphora or repeated episodes of dacryocystitis that necessitated dacryocystorhinostomy. Dacryocystorhinostomy relieved symptoms and objective evidence of obstruction in these five patients. We believe that nasolacrimal duct obstruction occurred in these patients as a complication of nasoantral window construction.


Exposure of the inferior orbit with fornix incision and lateral canthotomy. Exposure of the inferior orbit is necessary for exploration of the orbit for repair of orbital fractures, reconstruction of the orbit to correct enophthalmos with a volume implant, and decompression of the orbit to relieve the symptoms and improve appearance in cases of dysthyroid exophthalmos. The usual approach to the inferior orbit has been through a subciliary skin incision and dissection of a skin flap to the orbital rim. A technique is presented which utilizes an inferior fornix conjunctival incision combined with a lateral canthotomy and outward rotation of the lower lid. The advantages of this technique are that it avoids a lengthy skin incision with dissection which may present skin shrinkage if repeated surgery is necessary, employs a very simple closure, and provides better exposure of the nasal, inferior and lateral orbits while leaving the lower lid structures intact, preserving its integrity.


High-resolution real-time ultrasonography of thyroid nodules. High-resolution real-time ultrasonography was used to evaluate 98 patients with palpable abnormalities of the thyroid and positive isotopic studies. It confirmed 37 of 73 (51%) suspected solitary nodules. Of 25 patients thought to have multinodular goiter, sonography was supportive in 21 (84%). In patients with adenoma or adenomatous nodules, characteristic features included a sonolucent "halo". Colloid nodules tended to be more sonolucent than normal thyroid tissue, whereas Hashimoto thyroiditis was characterized by an enlarged gland and decreased echogenicity.


Herpes zoster and lower motor neurone paresis. Fifteen cases of herpes zoster with lower motor neurone paresis involving the upper and lower limbs are reviewed. Five patients had an underlying disease--three had rheumatoid arthritis, two of whom were on prednisolone; one had chronic lymphatic leukaemia and one lymphosarcoma. Details are given of the time relationship between onset of pain, the appearance of the skin eruption and the later muscle weakness. Electromyographic evidence was available in 12 patients. The difficulty of assessing the muscle power in the presence of severe pain is discussed. Prognosis was generally very good; 11 patients recovered fully, three improved and one was unchanged after 5 months, when he died of lymphosarcoma. One patient was lost to follow-up at 5 months but was improving at the time.


On the vanadium and tin contents of diet and human blood. The vanadium and tin contents of total diet samples collected in five Italian towns are given, and discussed in relation to literature data, their status as essential elements and their levels in human blood. Tin in blood was found to be below 2 ng ml-1 in a group of 14 subjects, and barely detectable even after oral consumption of 60 mg of tin.


The kidney of a teleost, Spinachia spinachia. II. Histochemical identification of sialic acid-containing glycoprotein and fine structure of mucus secreting cells. Kidney cells of the marine stickleback Spinachia have been studied with histochemical methods for the demonstration of glycoconjugates. The fine structure of epithelial cells is described. Mucus threads in the nephronic tubule of sexually mature consist of neutral glycoprotein which corresponds with the secretory granules in proximal tubule segment II cells. Large lysosome-like inclusions, which also react with PAS, are present in many P II cells. All cells of the collecting duct epithelium differentiate into mucous cells in male Spinachia. The nature of their secretory products, which are well preserved by freeze-drying, is discussed. Sialylated glycoprotein is present in mucus granules and sulphated glycoprotein can be demonstrated at the apex of collecting duct cells. Collecting duct cell mucus can be digested with testicular hyaluronidase indicating that proteoglycans may be involved in the structure of macromolecules. The observations are compared with studies of mucus production in the urinary apparatus of several other vertebrates.


[Malignant lymphoma present almost simultaneously in two brothers (author's transl)]. A diagnosis of poorly differentiated, nodular, lymphocytic malignant lymphoma was made in two brothers. One had been operated 10 years earlier for an adenocarcinoma of the descending colon. In addition, another brother had died from a primary tumor of the liver. Although a genetic factor is not proved, the case is suggestive.


[Relationship between vitamin status (A, B1, B2, B6, and C), clinical features and nutritional habits in a population of old people (author's transl)]. 112 patients in a medical ward were examined clinically and biochemically with regard to their vitamin status (plasma vitamin A, plasma vitamin C, blood glutathione reductase, vitamin B1, vitamin B2, N-methyl nicotinic acid amide and pyridoxic acid excretion). The nutritional habits were assessed by means of a questionnaire. The results of these two examinations were correlated with the clinical findings. The assessment of the vitamin B2 status showed a deficiency in 8 cases and a marginal vitamin B2 supply in a further 4 cases. The thiamine intake was insufficient in 43 cases and marginal in 42 cases. The biochemical assessment of vitamins C, B1 and PP indicated a deficiency of these vitamins. Dermatological signs pointed to a deficiency of vitamins A and B2. There was a significant correlation between the plasma vitamin A level and the serum iron level. The importance of milk and vegetables in the diet is stressed and also the association between milk consumption and the serum cholesterol level.


Interindividual and interspecies variation in the metabolism of the hallucinogen 4-methoxyamphetamine. 1. The qualitative and quantitative aspects of the urinary elimination of orally administered 4-methoxy[14C]amphetamine have been examined in the rat and guinea-pig and in three volunteer human subjects, to determine interspecies and interindividual variations in disposition of the drug. 2. Both rat and guinea-pig excreted 70--80% of the administered dose(6 mg/kg) in the urine within 24 h, mainly as metabolites. 3. In the guinea-pig, the drug was metabolized by O-demethylation to give 4-hydroxyamphetamine, which was excreted free (4% dose) and conjugated (73%). No other metabolite was detected. 4. The rat metabolizes the drug both by O-dealkylation and by side-chain oxidation, the products being 4-hydroxyamphetamine (5% of dose free and 60% conjugated) and 1-(4'-methoxyphenyl)propan-2-one oxime (5% dose, free and conjugated). 5. In man the drug (dose 5 mg) is metabolized by O-demethylation and by side-chain oxidation. Marked intersubject variations were observed both in the array and quantitative aspects of metabolite excretion. Two subjects excreted mainly 4-hydroxyamphetamine (free and conjugated) together with smaller amounts of 1-(4'-methoxyphenyl)propan-2-one oxime and 4-hydroxynorephedrine. The third subject, however, who was previously known to exhibit a genetically determined defect in drug oxidation, was defective in O-dealkylation of 4-methoxyamphetamine, and the main excretion products were the unchanged drug together with products of side-chain oxidation, namely, 1-(4'-methoxyphenyl)propan-2-one oxime, 1-(4'-methoxyphenyl)propan-2-one and 4-methoxybenzoic acid. 6. Inter-individual differences in oxidative O-demethylation of the drug are discussed in relation to current theories on the aetiology of schizophrenia and reported fatalities arising from abuse of the drug.


Scintigraphic and clinical evaluation of nontoxic thyroid neoplasms. 256 patients were referred to the endocrinic clinic because of enlarged thyroid gland. All of them except one were subjected to thyroid scintigraphy (TS). The scintiscans were cold in 123 patients. The cold scintiscans were distributed evenly on the various referral diagnoses with half the patients of each group having cold TS. A total of 216 of the referred patients underwent surgery, among them the 123 with cold TS. If the solitary adenomas are left out of account, there was poor agreement between referral diagnosis, primary tentative hospital diagnosis, and surgical findings. Five patients were found to have thyroid cancer (TC), none of whom had been referred with this diagnosis. For the entire material the incidence of TC was 2.3% (95% confidence limits: 0.8--5.7%). Calculated on the basis of those patients who had cold TS, the incidence was 2.4% (95% confidence limits: 0.8--7.1%). It is concluded that the diagnosis of TC is difficult to establish preoperatively, and that TS is of no greater diagnostic value in this connection.


Vascular injury complicating meniscectomy. Report of a case. Severe haemorrhage occurred from the posterior wall of the capsule during meniscectomy in a 17-year-old girl. Arteriography showed an aneurysm originating from a larger branch of the popliteal artery, and the aneurysm was extirpated. Exploration of the blood vessels (or arteriography) is advisable, should severe bleeding occur during meniscectomy or postoperatively.


Glycosaminoglycan metabolism of the medial meniscus, the medial collateral ligament and the hip joint capsule in experimental osteoarthritis caused by immobilization of the rabbit knee. A study was made of glycosaminoglycan metabolism in experimental osteoarthritis caused by immobilization of the rabbit knee in extension. Samples from the medial meniscus, the medial collateral ligament of the knee and the hip joint capsule were obtained and analysed after 2, 6, 10, 17, 30 and 87 days of immobilization, samples from the mobile limb serving as controls. The tissue concentrations of glycosaminoglycans were determined from measurements of hexosamine and uronic acid after prior papain proteolysis and subsequent purification. The uptake of 35S-sulphate (DPM/microgram hexosamine) was used as an indicator of the synthesis rate of sulphated glycosaminoglycans. In both early and advanced immobilization osteoarthritis, the synthesis rate and the content of glycosaminoglycans were increased in all tissues.


Blood flow in proximal femur of the dog determined by the local 133Xe injection method. A new approach for measuring blood flow in bone is presented. It consists of the local injection of 133Xe into the proximal femur of adult beagles and the external measurement of isotope washout curves. The curves were analyzed using a two-compartment exponential model. The half-times for the tracer washout from the fast and slow compartment were 3.34 +/- 0.48 min and 33.6 +/- 11.7 min (mean +/- 1 S.D.) respectively. Blood flow was calculated using a measured blood to bone partition coefficient of 1.55 ml/g. The mean blood perfusion in proximal femur of the dog was 10.8 +/- 4.3 ml/100 g/min (mean +/- 1 S.D.). This value agrees well with most estimates of bone circulation. Due to rapid disappearance of 133Xe the method is easy to repeat and is thus suitable for physiological studies of local blood flow in bones.


[Uptake of retinol-C14 into different tissues of vitamin A deficient albino rats]. Groups of rats were fed a vitamin A free diet for 30, 60 and 90 days. They were then administered orally a single dose of 1,25 microC of retinol-C14. After 3 h, 3, 6 and 12 days from the administration, the incorporation into the different tissues was determined. The results show that the incorporation decreases, on the average, as the experimental period and the intervals after the administration of retinol-C14 grow longer.


[Uptake of retinol-C14 into liver mitochondrial membranes and erythrocyte stroma of albino rats on a vitamin A-free diet]. We have determined the incorporation of retinol-C14 into liver mitochondrial membranes and blood cell stroma in albino male Wistar strain rats, fed with a vitamin A deficient diet for 30, 60 and 90 days. At the end of the vitamin A deficient period, rats were kept fasting for 24 hours and then administered orally retinol-C14 (1,25 microC). They were divided into groups and killed after 3 hours, 3, 6, 12 days from the administration of retinol-C14. The incorporation is very high in one-month deficient rats, it decreases as the experimental period and the intervals after the administration of retinol-C14 grow longer.


Effect of ACP (pyridoxine-2-oxoglutarate) on hepatic failure after diversion of portal blood flow. The protective effect of pyridoxine-2-oxoglutarate (ACP) was studied in end-to-side porto-caval shunted rats. A significant improvement of hepatic conditions was shown in ACP-treated rats, while an increased mortality was observed in pyridoxine and 2-oxoglutarate treated rats. Serum glutamic-oxaloacetic transminase, glutamicpyruvic transaminase and lactic dehydrogenase activities, composition of serum proteins, liver mitochondria oxygen consumption rate, plasma ammonia were tested.


Ascorbic acid therapy for the relief of bone pain in Paget's disease. Sixteen patients with painful Paget's disease of the bone were treated with high doses of ascorbic acid. Of these patients, 8 experienced lessening of pain within a period of 5 to 7 days after commencing the vitamin therapy. In 3 of these patients pain was completely abolished. Subsequent treatment with calcitonin caused improvement in most cases. There was little change in plasma alkaline phosphatase levels but the excretion of hydroxyproline was elevated following administration of the vitamin. The highest excretions were found in those patients who experienced complete relief of pain. In patients treated with calcitonin alone, the excretion of hydroxyproline was reduced and urinary levels of ascorbic acid dropped in parallel. It seems clear that ascorbic acid and calcitonin have different effects upon bone metabolism.


[Vitaminology for practitioners. II. Avitaminoses, risk, latency period, classification]. The concept of risk in the field of avitaminoses is very important and useful for the practitioner, who should consider two aspects: a) risk factors, which could be individual (physiological, pathological and psychological) and extra-individual (alimentary, environmental, etc.); b) subjects with an elevated risk of avitaminosis (childhood, old age, pregnancy, etc.). In these subjects the risk can be a generical one, when there is an elevated requirement for all vitamins (nursing women, sportmen, etc.) or a specific one, when there is a high requirement only for a single vitamin (osteomalacia, some professional diseases, use of oral contraceptives) or a vew of them (alcoholism, diabetes, etc.). On the basis of this kind of knowledge it is easy for the practitioner to estimate which vitamins are necessary for each subject or for a group of subjects in physiological or in pathological conditions. For example, there is an elevated risk of apyridoxinosis in old age (acalciferolosis in aged women), of athiaminosis and apyridoxinosis in diabetes, of apyridoxinosis in oral contraceptives users, of axeroftolosis in hyperthyroidism, of athiaminosis, apyridoxinosis, aniacinosis and anascorbosis in alcoholics. In the second chapter the concept of the latency period in avitaminosis is illustrated. This period corresponds to the interval between the moment when deficiency stimulus starts operating and the moment when its effect, that is the picture of avitaminosis, appears. The latency time is not measurable, on account of the difficulties in establishing the onset of the deficiency stimulus; generally it is very long and is followed by the period of biochemical symptomatology and subsequently by the one of clinical symptomatology. Each of these three phases can be further divided in several steps, which have summarized in a Table. The last chapter is dedicated to the classification of avitaminoses. From the etiopathogenetic point of view avitaminoses can be due to: a) deficiency of introduction (alimentary level)); b) deficiency of absorption (enteric level); c) deficiency of utilization (tissue level). From the clinical point of view avitaminoses can be distinguished in deficiency with: a) a complete clinical symptomatology (scurvy, beriberi, pellagra, rickets, osteomalacia, xerophthalmia, hemeralopia); b) an incomplete clinical symptomatology (mono- or oligo-symptomatic or partial clinical picture); c) a biochemical symptomatology only (subclinic or clinically asymptomatic picture).


beta-Glucuronidase in schistosomal intestinal polypi of the colon. The results of a clinical, histopathological and biochemical study on twenty patients with schistosomal polyposis of the large bowel and ten patients with normal colon as a control are reported. The biopsy showed clearly the absence of any malignant or premalignant changes in all the twenty bilharzial patients. Results of the biochemical study showed that there is a statistically significant increase in beta-glucuronidase activity in schistosomal polypi compared to normal mucosa. This enzymatic activity is absent in schistosoma ova. The causes of the increase in the enzyme activity have been attributed to leucocytic infiltration present in schistosomal granulomata and possible to some degree of liver disfunction. The protein content of the excess mucus present in the colon could also activate the enzyme. Our results also show that the increased enzyme activity does not necessarily have carcinogenic properties. We did not come across a single case of malignancy even in a patient with very high level of enzyme activity (11615 units) or in those patients with a prolonged history of the disease.


The failure of conventional drug therapy in the management of infantile colic. During five years, 97 young infants with colic were studied. One of us (J. C. O'D.) compared homatropine methylbromide plus phenobarbital in a 20% alcohol solution, and all of the individual components of that solution, to see which was most effective in the symptomatic relief of colic. Regardless of the child's age on entry into the study, conditions in no treatment group improved more rapidly than in those treated with a placebo.


Mycotic aneurysms of the hepatic artery. Treatment with arterial embolization. In a 29 year old white man with acute Staphylococcus aureus endocarditis of the aortic valve two mycotic aneurysms of the hepatic artery developed during antibiotic treatment. One aneurysm was treated with surgical ligation and the other with Gelfoam embolization. Successful obliteration of the embolized aneurysm was demonstrated by hepatic arteriography two months later. The pathogenesis, clinical manifestations and management of hepatic mycotic aneurysms is discussed with emphasis on arterial embolization.


[Critical study of the treatment of Grave's disease (author's transl)]. 202 cases of Grave's disease were reviewed; among the 81 patients submitted to medical treatment, 53,1 p. 100 of patients failed to respond; 10 p. 100 relapsed and 35,9 p. 100 are euthyroid. The factors favouring a treatment failure were: age below thirty, severity of thyrotoxicosis, big enlargement of thyroid gland, duration of treatment shorter than 12 months. Relapses are more frequent after two years of medical treatment. Subtotal thyroidectomy was performed in 82 patients: 9,5 p. 100 relapsed, permanent hypothyroidism developed in 30,5 p. 100 and 50 p. 100 were euthyroid. The factors favouring post-operative hypothyroidism are estimated weight of the thyroid remnant, the moderate size of goiter and perhaps a six to twelve months preoperative medical treatment. 39 patients had I 131 therapy: among them, 24 p. 100 relapsed, 25,7 p. 100 had permanent hypothyroidism and 50,3 p. 100 are euthyroid.


Surface carbohydrates of Rhizobium. I. Beta-1, 2-glucans. Because of increased interest in surface carbohydrates of Rhizobium in relation to host specificity, phenol-water extractions were carried out of whole cells of Rhizobium strains of the species R. leguminosarum, R. phaseoli, R. trifolii and R. meliloti. Fractionation of the crude extracts with cetavlon afforded polysaccharide mixtures, which were essentially free of RNA and acidic exopolysaccharide (EPS). They could be separated into a high molecular weight heteropolysaccharide fraction of lipopolysaccharide (LPS) nature and a low molecular weight glucan fraction. Glucan turned out to be the principal polysaccharide component of the cells (up to 10% of the dry cell weight), when cultivated in carbohydrate-rich media, and to be present as firmly attached capsular material. Glucan (mol wt 3000) structure was elucidated by methylation and periodate oxidation techniques. Methylation yielded 3, 4, 6-tri-O-methyl-D-glucose, characterized by GLC-MS, as the only product of hydrolysis of the fully methylated glucan. The glucan consumed 1 mole of periodate per mole anhydroglucose unit and gave sophorose on partial hydrolysis. From these data a linear beta-1,2-linked glucan structure was deduced. The occurrence of beta-1,2-glucan and the implications for the specific binding properties of Rhizobium cells are discussed.


Structural analysis of four strains of Paracoccus denitrificans. Two out of eleven newly isolated strains of Paracoccus denitrificans were investigated by light and electron microscopic methods and compared with two strains of P. denitrificans already kept in culture collections. Samples were taken from different growth phases revealing short rods and nearly spherical cells in the exponential growth phase, and an increasing ratio of nearly spherical cells in the stationary growth phase. Cell division followed the binary fission mode; higher cell aggregates were not observed. Fine structural analysis revealed extracellular surface material stainable with Ruthenium red, a gram-negative cell wall and different storage material inclusions. Structural properties and variations within the four strains under investigation are discussed and compared with those of related bacteria.


Deoxyribonucleic acid base composition and taxonomy in the genus Geotrichum Link. The molar percentage of guanine + cytosine (% GC) in the DNA from 25 yeast-like fungi related to the genus Geotrichum has been measured. This criterion together with the biochemical characteristics allow the division of the species into 3 groups: one group resembling G. candidum (% GC: 31.5--42) and containing 8 imperfect and 6 perfect forms. In this group only G. capitatum has a lower % GC (31.5). A second group of 6 species resembling the genus Trichosporon (57--60%) and a third intermediate category of 4 species (42--53.5%) were observed. The GC-values correlate well with biochemical characters, e.g. the presence of urease, the number of organic substrates assimilated, and also with the presence of characters typical of the Ascomycetes or the Basidiomycetes.


Characterization and classification of fluorescent pseudomonads isolated from tap water and surface water. A total of 665 fluorescent pseudomonads, isolated from surface water and from different types of tap water, were classified into 22 groups defined by the results of the following 5 tests: hydrolysis of casein or gelatin, production of N2 from NO3-, and growth on sucrose, ethanol and D-sorbitol, respectively. Differences in colonial morphology and in the degree of proteolysis revealed that these groups were inhomogeneous. A more detailed subdivision was achieved by adding the following characters: growth on L-arabinose, D-mannitol, mesoinositol, and adonitol, respectively, and hydrolysis of Tween-80. Repeating the tests for hydrolyzing enzymes, denitrification, and growth on the carbohydrates and alcohols with strains stored in the laboratory for 1 to 3 years revealed that most characters, except hydrolysis of Tween-80, denitrification, and growth on sucrose, were very stable. Forty-five biotypes of the fluorescent pseudomonads were defined, based on the results of the repeated tests and the results of tests on nine aromatic compounds. The observed changes of some characters in a number of isolates did not diminish the value of this classification, but indicated that close relationships exist between many biotypes. About half of the biotypes described in this paper are similar to those defined by Stanier, Palleroni and Doudoroff (1966) and by Doudoroff and Palleroni (1974a), confirming the wide-spread occurrence of well-definable biotypes of fluorescent pseudomonads. Representatives of some biotypes were most frequently isolated from surface water and from tap water prepared from surface water. Tap water prepared from anaerobic or aerobic ground water contained representatives of biotypes which were typical of these water types. Some pseudomonads were found to grow especially in filters. The observed relationships between origin of the fluorescent pseudomonads and their classification into biotypes as defined in this paper supported the presented classification.


Thermomucor (Mucorales).

Thermomucor (Mucorales). Thermomucor indicae-seudaticae is described in the order Mucorales. Descriptions and illustrations of both the zygosporic and sporangial states are presented.


A comparison of interfertility and in vitro DNA-DNA reassociation as criteria for speciation in the genus Kluyveromyces. Hybridization studies based on the use of the prototrophic selection technique were undertaken to compare interfertility and DNA-DNA reassociation as criteria for speciation purposes in the yeast genus Kluyveromyces. Degrees of DNA-DNA reassociation greater than 70% between strains, as reported in the literature, were found to correlate with high recombination frequencies. Degrees of DNA-DNA reassociation less than 20% between strains did, however, not invariably coincide with the absence of interfertility between strains. If interfertility is accepted as criterion for conspecificity, the hitherto reported low degrees (less than 20%) of DNA-DNA reassociation in Kluyveromyces cannot confidently be employed for speciation purposes.


Current status of multichannel cochlear protheses. Multichannel cochlear prostheses are being developed and evaluated with emphasis on providing sensory deaf individuals enough information about their acoustic environment to permit communication by ordinary speech. Studies of the safety of the electrode arrays and stimulus values indicate that the remaining nerve fibers will not be damaged at the levels that will be typically used in human prostheses, but that a narrow safety range exists for suprathreshold stimuli. Early multichannel human implants have demonstrated that place pitch can be utilized with scali tympani implants, but this has not been demonstrated with modiolar electrode arrays. With both approaches, information about pitch can be conveyed by the frequency of stimulation. Research questions remain on the long-term viability of the eighth nerve with stimulated implants, on the interactions of closely spaced electrodes, on optimal methods of encoding the acoustic signal for multichannel nerve stimulation and on the ability of deaf individuals to utilize this information.


Comparison of Fusarium acuminatum and Fusarium culmorum isolates by means of tandem-crossed immunoelectrophoresis. F. acuminatum and F. culmorum strains were compared by means of tandem-crossed immunoelectrophoresis in order to estimate the possibilities of serological classification in Fusarium sections "Gibbosum" and "Discolor". On the basis of qualitative similarity the two species could be distinguished well. By the use of anti-F. acuminatum serum a similarity of SSM = 0.52 was found between F. acuminatum and F. culmorum, but the SSM coefficient reached a value of 0.67 when the anti-F. culmorum serum was tested. This asymmetric nature of the qualitative similarity is discussed. In the majority of cases the quantitative differences of the common antigens did not allow differentiation between the species.


[B-immunoblast lymphosarcoma 8 years after a malignant reticulosis]. A girl presented with a malignant reticulosis in the early months of life. For 4 years she was treated with repeated courses of irradiation and chemotherapy, mostly cyclophosphamide. After 6 years of complete remission she developed a rapidly progressive B cell lymphoma. The contribution of the various forms of treatment to the development of the second malignancy are discussed.


[On the synthesis of the cerebrally active compound tinofedrine (author's transl)]. The synthesis of tinofedrine (I), (+)-(R)-alpha-((S)-1-[3,3-di-3-thienylallyl)amino]benzylalcohol, a new cerebrally active drug, and the verification of its structure by spectrometric methods are reported.


A new Ca++ antagonist, Ro 11-1781, and its metabolites. Synthesis and physicochemical properties. The alkylation of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (4) with N-(3-chloropropyl)-3,4-dimethoxy-N-methylphenethylamine (2) leads to N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide (5) (Ro 11-1781). The corresponding hydrochloride (5a), a new Ca++ antagonist, induces in the anaesthetized dog a substantial increase in myocardial flow. The preparation of two metabolites of 5a are described.


[2-(Diethylamino)pyrimidines 2nd Communication: Analgesics (author's transl)]. By condensation of 1,1-diethylguanidine (1) with beta-diketones (2), the 2-(diethylamino)pyrimidines (3) are formed. Aside from beta-diketones substituted by aliphatic (2 a--e), mixed aliphatic-aromatic (2f), and pure aromatic-carbocyclic (2g and h) moieties, also those carrying aromatic-heterocyclic (2i and 4) substitutents are amenable to this reaction.


[Reactivation of phosphorylated acetylcholinesterase. Isomeric bisquaternary salts of pyridine aldoximes]. Mono-quaternary salts Z have been prepared from pyridine-aldoximes and 1,3-dihalogen compounds. These were used to synthesize asymmetrical bis-quaternary pyridine-oximes with three-membered bridge. The effect of reactivation of phosphorylated AChE by these substances is less than that of obidoxim (Toxogonin).


Fluorescent analogue of ampicillin.

Fluorescent analogue of ampicillin. As the outcome of the reaction of ampicillin with 4-phenylspiro[furan-2(3H),1'-phthalane]-3,3'-dione (fluorescamine), the chemical analogue of ampicillin (F-AMPI) has been prepared. This preparation has manifested strong fluorescence in UV light. Some basic chemical and biological properties of this product such as chemical stability electrophoretic mobility, uniformity during thin-layer chromatography and ion-exchange chromatography, and antimicrobial activity were examined. The results were compared with values of the original antibiotic.


[On the surface-anesthetic activity of some ether alcohols (author's transl)]. An account of the preparation and surface anesthetic potency of 12 ether alcohols of the type X-O-Y-OH is given in this paper. The anaesthetic intensity and effective duration of a chloronaphthalene derivative of this type lie within the range of action of cocain.


Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole dihydrochloride (DEPO) on cardiac functions and myocardial metabolism of the dog. Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole (DEPO) on cardiac functions and myocardial metabolism were examined using the heart in vivo and the isolated perfused heart of dogs. In the heart in vivo DEPO i.v. produced dose-dependent decreases in coronary perfusion pressure (PP), heart rate (HR), left ventricular pressure (LVP), dP/dt max of LVP and coronary vascular resistance (VR). DEPO i.c. dose-dependently increased left circumflex coronary flow (LCCF) and decreased PP, LVP and dP/dt max of LVP, but did not change HR. In the isolated perfused heart, DEPO induced a marked increase in coronary blood flow (CBF) and depressed HR and myocardial contractile force. Myocardial oxygen consumption and myocardial redox potential were not significantly changed. DEPO could not modify the effects of isoproterenol, adenosine and reactive hyperaemia on the heart. The results suggest that DEPO may have a coronary vasodilating action and some direct inhibitory actions on the heart.


Effects of a 2',3',5'-substituted adenosine derivative on systemic and coronary hemodynamics and on cardiac metabolism in the anesthetized dog. Hemodynamic and metabolic effects of 2',3'-O-methoxyethylidene-adenosine-5'-(Nethyl-carboxamide) (744-98), an adenosine analogue with long-lasting coronary dilator activity, were studied in the anesthetized, closed-chest dog. The coronary sinus outflow increased 5fold following administration of the compound (5 microgram/kg i.v.) and still remained three thimes higher than the control level after 4 h. Total peripheral resistance decreased markedly, accompanied by a baroreceptor-mediated increase in heart rate, left ventricular dp/dtmax and myocardial oxygen consumption. Blood glucose levels and glucose uptake by the heart increased concomitantly, whereas plasma free fatty acid (FFA) levels decreased markedly, without consistent changes in myocardial FFA balance. These effects are explained by antilipolytic and glucagon-releasing activities of the adenosine analogue. The myocardial oxygen extraction ratio for glucose greatly exceeded the aerobic metabolic requirement, a finding already previously obtained with coronary dilators.


The vascular effects of flunarizine as compared with those of other clinically used vasoactive substances. Flunarizine, a difluoro derivative of cinnarizine, produces a long-lasting inhibition of calcium-induced contractions of isolated vascular preparations of rabbit and rat. In this regard it is slightly more active than cinnarizine and markedly more active than papaverine, naftidrofuryl, bencyclane, cylandelate, dihydroergotoxine, xantinol nicotinate and pentoxifylline; calcium dobesilate does not inhibit the calcium-induced responses. A long-lasting antivasoconstrictor effect was observed also for cinnarizine. This action of flunarizine is selective for calcium channels in vascular tissue, since it has little effect on the calcium-induced response of myocardial preparations of the cat. Flunarizine has no effect on the rhythmic activity of myogenically active blood vessels; it thus shows a further selective activity to calcium channels activated by vasoconstrictor agents and not for those opened by intrinsic changes in membrane permeability. This dual selectivity implies that flunarizine is a useful reference substance in assessing calcium antagonism.


Influence of pentifylline on brain metabolism of normal and anoxic rats. 1-Hexyl-3,7-dimethyl-xanthine (pentifylline) increases significantly (1 h after oral administration of 25 mg/kg) the adenosine triphosphate and the total adenine nucleotide pool in the brain of normal rats and rats subjected to nitrogen breathing for 30 s. An increase in glycogen and in pyridine nucelotides (NAD+ + NADH2) were also noted. The results indicate that pentifylline shows a tendency toward normalizing or "economizing" the brain metabolism.


Potassium-induced release of 14C-dopamine from synaptosomes of corpus striatum of rats: effects of morphine. Synaptosomes of corpus striatum of rats were incubated at 37 degrees C in a medium containing a tracer concentration of 14C-dopamine. The uptake of 14C-dopamine was significantly inhibited by 2,4-dinitrophenol and by lowering the temperature, while morphine (10 mumol/l) was without effect. In another series of experiments, the K+-induced (53 mmol/l) increase in overflow of 14C during superfusion of the synaptosomes previously equilibrated in 14C-dopamine was measured. 10 mumol/l morphine did not affect the overflow of radioactivity, while 50 mumol/l slightly inhibited it. This inhibition, however, was not antagonized by an equimolar concentration of naloxone. In contrast to previous studies in striatal slices, we could not observe any opiate-specific effect on K+-induced release of labelled dopamine in striatal synaptosomes.


Comparative study of two anti-ulcerogenic drugs--glaziovine and sulpiride. The anti-ulcer effect of glaziovine, a major psychotropic alkaloid isolated from Ocotea glaziovii (Laureaceae) and belonging to a new chemical class, has been studied in different types of experimentally induced ulcers in the guinea-pig and the rat. The effect of glaziovine was compared with that of sulpiride.


Antiulcerogenic effect of a pyrido-benzodiazepine derivative (L-S 519) on experimental ulcers. Effects of a tricyclic, pyrido-benzodiazepnie derivative, 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-6][1,4]-benzodiazepin-6-one-dihydrochloride (L-S 519) on experimental ulcers produced by pylorus ligation, cold restraint-stress, and reserpine, and on gastric secretions stimulated by histamine, tetragastrin and carbachol in rats were studied. L-S 519 was half as potent as atropine in preventing these experimental acute ulcers and in decreasing the spontaneous gastric secretion. This compound inhibited to various degrees the gastric secretion stimulated by histamine, tetragastrin and carbachol in acute fistula rats. On the other hand, the antimuscarinic effects of L-S 519 were much weaker than those of atropine in both in vivo and in vitro experiments. Furthermore, the antigastric secretory effect of L-S 519 was observed even in pylorus-ligated, vagotomized rats. By contrast, the effect of L-S 519 was reduced by pretreatment with 6-hydroxydopamine. These results suggest that the adrenergic mechanisms, in addition to a weak antimuscarinic property, are involved in antisecretory and antiulcerogenic effects of L-S 519.


Distribution of 14C-bis-(p-acetoxyphenyl)-cyclohexylidenemethane (F 6066) in mice. The distribution of 14C-bis-(p-acetoxyphenyl)-cyclohexylidenemethane (14C-F 60666, cyclofenil) in mice was studied by means of an autoradiographic technique and organ radioassay. High concentration of radioactivity was found in liver, pancreas, hypophysis, lung, salivary glands, myocardium, blood, skeletal muscles and brain in decreasing order at various times after the administration. The drug penetrated very easily the blood-brain barrier and the highest concentration in the brain was detected in the hypophysis. The radiochemical studies confirm the autoradiographic data. 14C-F 6066 crossed the placental barrier and traces of radioactivity were seen in the foetuses.


A sensitive determination test for beta, beta'-iminodipropionitrile in organ homogenates. A simple method for selective extraction of beta, beta'-iminodipropionitrile (IDPN) from animal tissue and a sensitive method for its detection by dansylation is described. By this method, IDPN could be shown to be present in brain, liver and kidney as well as in blood and urine of rats 30 min after i.p. administration.


Different uptake of two alkylating substances by ascites tumor cells. Considerable quantitative differences have been observed between alkylating agents with respect to their effect on cell multiplication of tumor cells. The ethyleneimine derivative triaziquone is approximately a thousand times more effective than the biologically active conversion products of the nitrogen mustard derivative cyclophosphamide. The main difference may be directly related to the extent to which each of the two substances is able to pass into the cells. After a 60-min incubation period approximately 1% of the cyclophosphamide conversion products have been bound by ascites tumor cells. The uptake of the more lipophilic triaziquone, however, is nearly 50% under identical conditions.


[Renal sites of action of diuretic agents in urine extracts]. In sodium depleted rats, urine extracts of hydrated healthy human volunteers cause a significant increase in water and sodium excretion. Single injection of 100 micrograms/kg bw. of the urine extracts as well as infusion of approximately 100 micrograms/h over several hours induce diuresis and to a lesser degree natriuresis. The sodium and plasma albumin concentrations show similar changes in kidney tissue: in the exterior medulla, the concentrations of sodium and albumin decrease by only 10 and 9%, respectively, whereas in the interior medulla they are decreased by 22 and 23%, respectively. The values obtained for the interior medullary zones are statistically significant. The data show that there is an inhibitory effect of the urine extracts on sodium absorption in the renal medulla. It is assumed that the modulation of sodium excretion occurs in the inner medullary areas.


Binding study of benzamides to serum albumins by fluorescence probe technique. The interaction between human and bovine serum albumins (HSA and BSA) were studied with two derivatives of benzamide, metoclopramide (Primpéran) and sultopride (Barnétil). It was possible to evaluate association constants (K ass.) characterising this interaction by fluorescence probe technique inspite of the very low binding tendency, which can be correlated to pharmacokinetic properties of these drugs.


Neutralising effect of histone fractions from human leukocyte nuclei on heparin. Histone fractions from human leukocyte nuclei can interact with heparin to form complexes measurable by means of laser nephelometry. Histone fractions have not all the same affinity to bound heparin and the lysinrich histone fraction cannot interact with heparin. The formation of histone/heparin complex depends not on the temperature between 20 degrees--37 degrees C or on the pH between 7--8.2. The precision of the method was estimated. The significance of the histones/heparin interactions for an assay method for control to the biological activity of heparin preparations and a possible biological role of these interactions in vivo was briefly discussed.


[Clinical, psychological and neurophysiological results of double-blind study on vincamine-cromesilate in patients with cerebro-vascular insufficiency (author's transl)]. In a long-term double-blind cross-over design 26 patients with amnestic syndrome due to cerebro-vascular insufficiency were submitted to vincamine-cromesilate (Vincaryl) and placebo treatment. The efficiency of vincamine was proved by mildly ameliorated psychometric patterns, biochemically by decreased cholesterol level and ophthalmodynamographically by slight increase of pulsation capacity. By means of EMG, ECG and EEG clinic side effects were excluded.


The variability of the protection factors for sunscreening products. The variation of the preotection factors for a sunscreening product as determined for different test subjects can be described by a logarithmic normal distribution. It is therefore more appropriate to use logarithmically transformed data for statistical analyses. By means of an analysis of variance it was shown that the influence of the subjects is responsible for only 12% of the total variance, whereas the remaining 88% is due to experimental error. Therefore, the difficulties in determining precise protection factors must be ascribed to deficiencies in the method itself. It was further concluded that correcting the protection factors with respect to a simultaneously measured reference preparation is not a means of improving the precision of the data. The reference substance, if it is included in every measuring series may, however, be used to check the long-term constancy of the method and to compare results from different laboratories.


[Partition coefficients and Rm-values of cardenolides (author's transl)]. Partition coefficients (P) of 48 cardenolides were determined in octanol/water. Furthermore Rm-values of most of these substances were measured in different thin-layer chromatography systems (TLC) and related to P. Regression analysis revealed that the best linear fit of the data was obtained when Rm-values from reversed-phase TLC on octanol impregnated silica-gel layer as stationary phase and methanol/water as mobile phase were correlated with log P (r = 0.91). A better correlation between these two sets of data was obtained by restricting the calculations to groups of cardenolides with similar structural features (r = 0.96-0.98). The present results are showing that Rm-values from reversed-phase TLC--a rapid and reproducible method with many advantages over the tedious measurement of P--can be used to predict P.


[Lipophilicity and enteral absorption of cardenolides (author's transl)]. Intestinal absorption of 15 cardenolides has been examined in cats. The 3H-labelled substances were injected intraluminally into ligated duodenal loops of anaesthetized animals. 3H-Concentrations were followed in the portal circulation and in the bile. 1 h after drug administration the duodenal sac was removed, and the residual in the lumen then was washed out and assayed radiochemically. The decrease of radioactivity during 1 h was calculated as extent of absorption (QR). Cardenolide absorption was compared with the corresponding in vitro parameters of lipophilicity like octanol/water partition coefficients and Rm values from reversed phase thin-layer chromatography. The Spearman rank sum correlation test revealed coefficients of 0.95 to 0.97. The result lends support to the use of the easily available Rm values as a good tool to predict intestinal absorption of various cardenolides.


[Lipophilicity-protein binding relationship in cardenolides (author's transl)]. By equilibrium dialysis the binding of 19 cardenolides and cardenolide conjugates to human plasma proteins has been measured. The binding constants were compared with octanol-water partition coefficients described previously. No correlation was found between the two properties. Glycosides and conjugates of a certain genine show the same extent of protein binding, even if some of the derivatives differ in their physicochemical properties more than by three log units. It is concluded that cardenolide protein binding depends solely on hydrophobic property of the genine involved.