[Clinical questions on bioavailability and proff of efficacy (author's transl)]. The problems referring to bioavailability may be considered as follows: up to now extact informations on bioavailability as to the determined substances to meet the requirements of therapy are not obtainable. Obvious is the lack of precise investigations about what kind of bioavailability is desirable in respect to rate of rise of the drug, its course of time and its quantity under consideration for the different groups of disease. For this reason and excluding special cases, only common suggestions can be given at present. Difficulties are also presented by the entitled demand for the proof of efficiency. Test of new substances in man are confined to compromises either on the significance of the tests or the security of the patient.


An overview of the analysis and interpretation of bioavailability studies in man. Bioavailability is defined and types of bioavailability studies are classified. The point is made that the validity or interpretation of comparative bioavailability data does not rest on any correlation between pharmacological or clinical response and blood levels of the drug. Equations used to assess the "first pass" effect, absolute absorption efficiency and relative absorption efficiencies are given. Methods for assessing intrinsic and relative rates of absorption are discussed. Various pitfalls in bioavailability assessment and some of the problems in interpreting bioavailability data are discussed.


[The role of biopharmaceutical parameters in drug development (author's transl)]. The biopharmaceutical factors, which influence the interaction between dosage form and drug activity, extend from the mode of application, through chemical and physical properties of the active constituent, to the final product, including the excipients and manufacturing processes involved. In recent years, important strides have been made in this field, which improve drug safety. This has consequently influenced and enlarged the present scope of pharmaceutical technology drug research.


[Clinical problems of optimum bioavailability, in particular in cytostatic therapy (author's transl)]. The clinical application of cytostatic drugs requires knowledge of their biochemistry, pharmacology, pharmacokinetics as well as their action at the cellular level within the generation cycle. The principles apply to tumor cells as well as to normal, rapidly proliferating tissues. The intensive research on cancer treatment all over the world is leading to a rapid accumulation of experimental data about the action of single cytostatic drugs in tissue culture and on transplantable animal tumor systems, especially in rodents. Clinical chemotherapy in human malignancies today preferentially uses combinations of different cytostatics. Inumerable combinations of drugs are available, especially if variations in respect to drug dose and intervals of drug application are taken into consideration. The experimental basis for such combinations of drugs and drug interactions is scanty. Using the pyrimidine analog cytosine arabinoside and the two antibiotics daunorubicin and doxyrubicin (adriamycin) as examples, it is demonstrated that information on the pharmacolinetic behaviour of cytostatic drugs is a prerequisite for their success in clinical application, but is on its own insufficient to predict the tumor response.


[Therapeutic equivalence and inequivalence of chemically identical substances using cardiac glycosides for an example (author's transpl)]. The problem of therapeutic equivalence or inequivalence cannot be solved by "ignoring facts and proclaiming opinions". The entire problem is multifarious and is not even clearly arranged although heart glycosides have been used for 200 years in the therapy of cardiac insufficiency. It comprises the physico-chemical properties of the drugs, its preparation and its pharmacolinetic behaviour in the organism. Therapeutic equivalence or inequivalence can primarily only be evaluated in connection with the disease and the symptoms of disease, respectively. Thus, manufacturers, pharmacists and physicians likewise are confronted with the problem. The differences in bioavailability of the individual cardiac glycosides show the necessity for: 1. The number of fixed combinations of heart glycosides should be limited in the interest of drug safety. 2. Only such drugs should be approved whose quantitative and qualitative equivalence has been demonstrated with regard to the monoglycoside. 3. When prescribing digoxin derivatives one should not only observe the bioavailability but take also into account the chemical stability and the pharmacolinetic behaviour.


Importance of biopharmaceutics and pharmacokinetics in clinical medicine. Despite the paucity of biopharmaceutic and pharmacokinetic data for many old drugs, these areas of scientific research have demonstrated an immense value in clinical medicine, and can be expected to expand man's knowledge of drug action and the influence of physiological function of drug disposition. Illustrated in this report are four major areas where biopharmaceutics and pharmaco-kinetics have contributed significantly to the field of medicine. Foremost among these contributions are: 1. the assessment of bioavailability and bioequivalence of new drugs and generic marketed drugs, respectively; 2. the pharmacolinetic characterization of new drugs and new drug delivery systems; 3. adjustment of dosing regimen; 4. assessment of kinetic profile of drugs in diseases state and dose adjustment thereof. Patient-drug pharmacokinetic profile designed to avoid toxicity is illustrated.


[Bioavailability, proof of efficacy and their consequences for drug legislation (author's transl)]. Drugs should be effective for the indicatons stated, they should not involve risks which would not be justified in relation to their benefit and they should be of the necessary quality. It is the objective of drug legislation to warrant these requirements in its area of jurisdiction. It has become a necessity to revise current legislation; it is going to be replaced by a new law. A corresponding bill is being considered by Parliament at present. The present and the future legal situation with regards to proof and safeguarding of the bioavailability of pharmacologically active substances and the necessary prerequisites and rules for the procedure of clinical testing of drugs to prove their efficacy and safety is described.


Dry polyacrylamide batch method for determining the binding of various compounds by plasma proteins. A new modification of the gel diffusion method has been developed using dry polyacrylamide gel. The theoretical background is explained and the mathematical formulas are presented. The properties of the gel are studied, concerning the absorbing capacities and changes in ion equilibria. As a model compound the freely diffusible calcium is assayed and the result obtained (52.4 +/- 2.9%) agrees well with the results from previous methods by other authors. The accuracy of the method is discussed and the theoretical explanation to the sensitivity in determinations is calculated.


[The effect of pemolin on the mitotic activity of Vicia faba L (author's transl)]. The effect of diverse concentrations of 5-phenyl-2-imino-4-oxazolidone (PIO, pemolin, Tradon) on the mitotic activity in lateral roots of Vicia faba L. was studied by aerated and non-aerated hydrocultivation with and without mineral nutrition, respectively. With optimal conditions (aerated nutrient solution) weak PIO-concentrations, most significantly 10(-6) g/ml, effected a marked increase of the mitotic index. Contrarily, strong PIO-concentrations (10(-4) and 3 X 10(-4) g/ml = saturated solution) significantly decreased the mitotic index though simultaneously preserving the mitotic activity in long-term experiments, when on account of nutrient deficiency it had already collapsed in weak PIO-concentrations and the controls. The activating effect of weak PIO-concentrations compared with the controls is more significant in stress situations (nutrient deficiency, O2-deficiency) than under optimal conditions. Furthermore a slight acceleration of mid-mitotic phases (metaphase--anaphase) recognized by a marked decrease in percentage of these phases, can be stated with weak PIO-concentrations, again particularly so with 10(-6) g/ml. In total, dependent on concentration, pemolin presumably may either activate or suppress cell metabolism and particularly the mitotic cycle. The exact site of action of the substance is still unknown.


[The effect of pentobarbital sodium on mouse fibroblasts in vitro]. In mouse fibroblasts grown during a period of 48 h in a medium containing between 0.3 and 4.8 mMoles of sodium pentobarbital, there appeared diminished replication, some stathmokinesia, and plain toxicity. In further cells of this kind, taken from fetuses which had been treated with sodium pentobarbital via the dam, cell multiplication, lethality, and mitotic rate did not differ from those of control cells.


[Regulation of lipid and carbohydrate metabolism of the heart by carbocromen (author's transl)]. The influence of 3-(2-diethylaminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen, Intensain) on lipid and carbohydrate metabolism of the heart was investigated. Carbocromen inhibits the incorporation of 14C-palmitate in heart slices of the rat. The degree of inhibition is dose-dependent and can reach a maximum of 30%. However, the relative concentrations of the various lipid components do not vary significantly. In the heart tissue of the mouse carbocromen increases the uptake of 14C-3-O-methyl-D-glucose by about 30% which might be due to an increased influx of glucose into the heart. The metabolic degradation of 14C-palmitate to 14CO2 decreases up to 40% in the presence of carbocromen with a parallel reduction in oxygen consumption.


[Studies on inhibition of platelet aggregation by carbocromen (author's transl)]. 3-(2-Diethylaminoethyl)4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen; Intensaïn) shows dose dependent platelet aggregation inhibitory activity in vitro according to the methods of Born (following ADP, epinephrine and collagen) and of Breddin (platelet agglutination test--PAT--, adhesively). The effect was found to be more pronounced than that of acetylsalicylic acid. Furthermore, in vivo carbocromen inhibited the increased spontaneous platelet aggregation in man.


[The pharmacokinetics of 14C-zolimidine in rats]. The blood levels and urinary and fecal excretion of 14C-zolimidine [2-(p-methylsulfonyl)-imidazo(1,2-a)pyridine-2-14Ci1 were studied following oral and intravenous application. The elimination from the blood after i.v. administration can be described by a 3-compartment model. Male rats eliminate the radioactivity more rapidly than do females. Although radioactivity is detectable for several days in the blood an accumulation of the drug or its metabolites can be excluded on the basis of the calculated values. 14C-Zolimidine is rapidly absorbed in rats after oral administration of 10 mg/kg and reaches peak blood levels within 45 to 60 min. In the first phase the elimination is rapid but trace activity can be measured for several days. Based on the amount of urinary excretion the rate of absorption is estimated to between 80 and 90%. Biliary excretion amounted to about 15% of the i.v. administered dose. It is assumed that the difference of 25% between fecal and biliary excretion is sequestered through the gastrointestinal mucosa.


[Autoradiographic and scintillationspectrographic studies of 14C-zolimidine in rats after i.v. and oral application (author's transl)]. The relative distribution of radioactivity after i.v. (5 mg/kg) and oral (25 mg/kg) application of 14C-Zolimidine [2-(p-methyl-sulfonylphenyl)-imidazo-(1,2-a)-pyridine-2-14C] was examined in male rats by whole-body autoradiography and scintillation fluid spectrometry. 14C-Activity was remarkably concentrated in the stomach of i.v. treated animals, probably as a result of secretion from the pyloric and/or fundic part of the mucous membrane. 14C-Zolimidine also accumulated in the aortic vascular walls, the adrenal gland, and in the excretory organs, liver, kidney, and intestine, after both routes of drug administration. Much less radioactivity could be measured in brain and spinal cord. The estimation of nearly 80% gastrointestinal absorption of 14C-zolimidine and the suggestion of one or more metabolites were in accordance with previously reported results. The elimination of radioactivity from brain occurred more rapidly than from other organs. No striking results were found in the reproductive organs of the rats.


[New findings on the efficacy and mode of action of the horse chestnut saponin escin]. In order to complete previous results of the efficacy of the horse chestnut saponin escin, its activity was tested on two further models of inflammation: the rat serous peritonitis provoked by i.p. injection of formalin solution, and the rat serous pleurisy provoked by intrapleural injection of Evans Blue/carrageenan. The results showed escin to be an anti-exudative substance with regard to its exudation inhibitory effect determined by the reduction of exudative fluid. As to peritonitis the diminution of protein permeation into the abdominal cavity was determined: with increasing doses escin tended to prevent more efficiently the diffusion of small molecules than the permeation of large molecules. The hypothesis that escin has an effect on the vascular walls in the sense of a "sealing" effect on the capillaries was tested on the following model: the permeability of the plasma-lymph barrier of the hind leg of the rabbit was enhanced by injection of bradykinin. Escin antagonised the bradykinin effect dose-dependently determined by the depression of the raised lymph-flow by about 70%.


[The effect of silymarin-N-methylglucamine salt and silybin-dihemisuccinate on (1-14C)-acetate incorporation in rat liver lipids (author's transl)]. 60 min after i.v. application of 140.5 mg silymarin-N-methylglucamine salt/kg body weight dissolved in 4% polyvinylpyrrolidone solution, and 30 min after i.p. administration [1-14C]-acetate, compared to rats treated with solvent only, a statistically significant increase of specific radioactivities in total lipids, triglycerides, total phospholipids as well as in the phosphatidylcholine fraction and a decrease of specific activities in the free cholesterol fraction of the liver can be determined. 70 min after i.p. application of 140.5 mg silybin-dihemisuccinate/kg body weight dissolved in phosphate buffer, and 10 min after i.v. administration of [1-14C]-acetate in comparison with rats treated with solvent only, a statistically significant enhancement of specific activities of total liver lipids, free hepatic cholesterol, liver triglycerides, total liver phospholipids, and the hepatic fraction of phosphatidyl ethanolamine can be measured. Silybin also produces an increased specific radioactivity of the serum triglyceride fraction.


A comparison between the influence of pindolol and propranolol on the response of plasma potassium to catecholamines. The influence of propranolol (0.3 and 1.0 mg/kg) and of D,L-4-(2-hydroxy-3-isopropylamino-propoxy)-indol-hydrochloride (pindolol, LB 46) (0.10, 0.25 and 0.50 mg/kg) on the responses of plasma potassium levels of anaesthetized dogs to slow i.v. infusions of adrenaline, noradrenaline and isoprenaline (5 mug/kg-min-1) was studied. Adrenaline and noradrenaline infusions regularly evoked a dual response (hyperkaliemia followed by hypokaliemia), whereas isoprenaline caused either similar effects or only a decrease of plasma potassium. Propranolol abolished the hypokaliemic phase of the responses to adrenaline, noradrenaline and isoprenaline; the lower dose used had no effect on the primary increase in plasma potassium, but the dose of 1.0 mg/kg modified this part of the response, which was reduced and became less steep. Pindolol antagonized in a dose dependent way the hypokaliemic phase of the responses to adrenaline, noradrenaline and isoprenaline, but did not interfere with the early rise in plasma potassium, thus being more specific than propranolol. It is concluded that the secondary decrease in plasma potassium is due to an activation of beta-receptors, whereas the initial increase is caused by alpha-receptor stimulation. Propranolol shows, in the 1.0 mg/kg dose, some alpha-blocking activity, thus contrasting with pindolol, which is devoid of this effect and therefore appears to be especially suitable for tentative characterization of adrenergic receptors.


Metabolic effects of bunaftine, a new antiarrhythmic agent: comparison with quinidine, ajmaline, procainamide, xylocaine and propranolol. The effects of bunaftine (Meregon), quinidine, ajmaline, procainamide, xylocaine and propranolol have been investigated on glycolysis and oxygen consumption of rabbit heart and on the metabolic rate of trained rats. Quinidine, bunaftine and ajmaline stimulated glycolysis, procainamide was inactive while xylocaine and propranolol inhibited it. Myocardial oxygen consumption was reduced by quinidine and bunaftine only at high concentrations. However quinidine at 1-10(5) g/ml showed stimulating effect. Ajmaline and procainamide were inactive; xylocaine had a weak stimulating effect at 1-10(-6), propranolol had a stimulating effect at 3-10(-5) and 1-10(6) while it had an inhibiting effect at 1-10(-4) and 5-10(-3). With the exception of xylocaine and propranolol, which inhibited metabolic rate of trained animals, all the other drugs were inactive. In view of these findings, the mechanism of action of anti-arrhythmic drugs is discussed and it is suggested that the metabolic changes they induce are to be considered as secondary or toxic effects, the main site of action being the myocardial cell membrane.


[Disaccharidases of the small-intestinal mucosa of the rat under therapy with ifosfamide (author's transl)]. In rats, treatment with 3-(2-chloroethyl)-2-(2-chloroethyl-amino)-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (ifosfamide; Asta Z 4942) results in a decrease of intestinal disaccharidase activities concomitant with morphological alterations of the mucosa. Even after morphological restoration of the tissue, enzyme activities remain reduced for a couple of days. Examinations of patients treated with ifosfamide will show whether there are comparable effects also in man which may lead to malabsorption of disaccharidases.


Magnesium concentrations in plasma and bone following enteral administration of Br-, Cl- and Mg++ in the form of different compounds and combinations. In accordance with the results achieved in previous experiments the intestinal absorption of magnesium and its uptake into bone of rats were significantly improved when MgCl2 or mono-magnesium-mono-aspartate-hydrochloride (Mg asp. HCl) were used instead of mono-magnesium-di-l-aspartate (Mg asp.). Treatment with mono-magnesium-mono-aspartate-hydrobromide (Mg asp. HBr) resulted in remarkably elevated magnesium concentrations in plasma and bone. Since the animals were strongly sedated at the same time, we had to differentiate the influence of anesthesia from unspecific distress and specific actions of bromide and chloride, e.g. on intestinal uptake and/or renal excretion of Mg. Experiments in which the narcotic effect of bromide was reduced to moderate sedation by additional treatment with chloride would appear to suggest that both specific and unspecific mechanisms were involved. In additional experiments it was shown that the effects of Mg asp. plus KBr or Mg asp. plus KCl or CaCl2 were similar to those of the corresponding magnesium aspartate hydrohalogenides.


[Comparative pharmacological effects of dl-amphetaminil and dl-amphetamine in the rat]. The present investigation shows that amphetamine and amphetaminil produce identical pharmacological effects (increase in motility and body temperature, anorexia, stereotypic behaviour). There was neither a qualitative difference under "open field" conditions nor a difference in the capacity of modifying the reserpine induced syndrome. In isomolar doses amphetamine was somewhat more effective. Almost the same amounts of amphetamine were found in blood and brain following amphetamine or amphetaminil administration, with exception of somewhat higher peak levels after amphetamine. These results favor the hypothesis that amphetaminil effects are produced by the amphetamine molecule.


[Preliminary report on an unexpected effect of an extract from Dryopteris filix mas (author's transl)]. In male mice and rats, one drop of an extract from Dryopteris filix mas, administered orally pure or suspended in sunflower-seed oil, caused a spectacular enlargement of the penis. This unexpected effect cannot be explained so far and will have to be elucidated by further experiments.


[Metabolism of methiothepin in the rat, dog and man]. Report is given on a metabolic investigation with non-radioactive and 14C-labelled methiothepin(1-[10',11'-dihydro-8'-(methylthio)-dibenzo mean value of b,f thiepin-10'yl]-4-methyl-piperazine) in rat, dog, and man. After i.p. and oral administration of the drug to the rat, the metabolites of methiothepin were excreted fecally. In the same species, a considerable biliary secretion of the compounds has been demonstrated. In dog and in man, excreted metabolites have been found both in urine and feces after oral application of the drug. The biotransformation of methiothepin within the species investigated proceeds via hydroxylation, sulfoxidation, O-methylation, N-demethylation, N-oxidation and formation of conjugates. The large number of metabolites is due to the various sites of action within the molecule, that are accessible to in vivo oxidation. Of a large number of isolated positionally isomeric compounds, merely the basal structures could be clarified. Possibly the mode of biotransformation to which methiothepin is subjected in the organism, proves determinant for the way of excretion. In the rat, all metabolites are hydroxylated and reach the intestinal tract as conjugates with the bile. In dog and man, however, non-hydroxylated, sulfoxidized metabolites were likewise found, which were excreted mainly renally in both species.


Plasma concentrations during repeated intravenous and oral methyl-proscillaridin application in man. The aim of this study was to establish data on the plasma levels of the glycoside derivative methyl-proscillaridin (MP) following repeated intravenous and oral doses. The study was carried out on healthy male volunteers. Each received 0.5 mg of MP daily at 8 a.m. for 7 days. 6 volunteers received the drug i.v., 6 p.o. as tablets and 5 p.o. as elixir. Plasma glycoside concentrations were measured utilizing a 86Rb-erythrocyte assay. The mean plasma concentrations on the 6th and 7th days of application were: 752.9 (Sx = 303.5) pg/ml for the i.v. route, 432.9 (Sx = 115.5) pg/ml for the tablets and 473.1 (Sx = 321.5) pg/ml for the elixir. The mean ratio between plasma concentrations with tablets and i.v. injection averaged 63%. It is concluded that the therapeutic activity of oral MP is about 60 to 70% that of the i.v. application.


Metabolism, kinetics and metabolic activity of the beta-cytotropic antidiabetic 4-(5-isobutylpyrimidinyl-2)-sulphamylphenylacetic acid-3-chloro-6-methoxyanilide sodium (glydanile sodium) in man after oral and intravenous administration. The metabolism and pharmacokinetics of [3H]-labelled 4-(5-isobutylpyrimidinyl-2)-sulphamylphenylacetic acid-3-chloro-6-methoxyanilide sodium ([3H]-glydanile sodium) were investigated in three diabetics and six healthy volunteers after oral and i.v. administration. In the healthy volunteers the level of compound in plasma was correlated to insulin concentration and free fatty acids in plasma or serum, both after oral and i.v. administration of glydanile sodium. After oral administration of 10 mg I13H]-glydanile sodium, maximum [3H] concentration in plasma is found after 2--4 h. The concentration corresponds to 60-90 mug/100 ml when calculated as mug glydanile sodium in plasma. Glydanile is metabolized rapidly. The four metabolites which have been isolated and identified represent more than 95% of total radioactivity in urine. The main metabolite occurring in plasma and urine is the tertiary isobutyl alcohol of glydanile (metabolite I). This metabolite still possesses about 30% of the hypoglycaemic activity of the original compound. The initial half-life of unchanged glydanile after i.v. injection is about 30-40 min. In human plasma more than 99% of the glydanile present is in the protein-bound form. After oral administration, about 20% of radioactivity is eliminated with urine and about 80% with faeces. After i.v. injection, about 70% of radioactivity is eliminated with urine and about 30% with faeces. After oral administration, only about 30% of the compound given was absorbed under these experimental conditions. It may be possible to improve the poor absorption demonstrated in these trials by making the drug available in another, suitable, oral dosage form. Glydanile is eliminated rapidly via urine and faeces after oral and i.v. administration, which means that no accumulation, involving the danger of hypoglycaemic reactions, need be expected. Plasma insulin is increased by a glydanile concentration of 10-20 mug/100 ml plasma.


Effect of aflatoxin B and rubratoxin B on bacteriophage and rabbit cornea cells. Rabbit cornea cells exhibited a sensitivity to 1 mug aflatoxin B1 and 5 mug rubratoxin B per ml of growth medium. No changes were observed in the bacteriophages tested in the presence of 25 mug aflatoxin B1 or 100 mug rubratoxin B per ml of medium by the plaque-forming unit method or single-step growth curves.


A sensitive assay for proteases using a clot timer apparatus. This report describes the adaptation of milk coagulation by proteases into a quantitative and sensitive assay for these enzymes. The procedure involves the use of a clot timer to determine the precise phase of the coagulation which occurs when buffered milk and a protease interact.


A method for preparing absolute standards for quantitative calibration and measurement of section thickness with X-ray microanalysis of biological ultrathin specimens in EMMA. Specimen thickness is determined using X-ray microanalysis in conjunction with atomic absorption spectrophotometry. Specimens of evaporated metal films and standards comprising fixed concentrations of element (such as potassium) in organic media are used to determine elemental concentrations of endogenous elements in embedding resin, from which section thickness can also be determined. The method finally depends only on the single measurement of X-ray emission of such an element in the specimen. Calibration of the X-ray detector over the energy range with mineral salts enables the standard to be used for the quantitative analysis of any element under investigation.


Hypobaric helium atmospheres for light and electron microscopy of mammalian cells. The development of electron microscope environmental/hydration chambers (EMC's) for the examination of living biological specimens has necessitated a search for a suitable gaseous environment that is compatible with both electron imaging and cell survival. Helium has a lower electron scattering cross section than air. The effects of hydrated helium and hydrated air atmospheres in an EMC at pressures 50-200 Torr were examined with a JEM 200 transmission electron microscope operated at 200 kV and 22 degrees C. Results showed that whereas 200 Torr of air reduced beam transmission by more than 90% under these conditions, 200 Torr of moist helium only reduced beam transmission by 30%. The effects of sub-atmospheric or hypobaric helium atmospheres on human white blood cells attached to glass coverslips were investigated by phase-contrast light microscopy in a simulated EMC or light microscope environmental chamber (LMC) at ...37 degrees C. gross morphological changes were observed in cells held at pressures of 300 Torr of moist helium for exposure times of 15 min. At pressures below 300 Torr, morphological changes occurred more rapidly as the pressure was reduced. At the lowest pressures tested (60 and 80 Torr) 50% of the cell populations died within 6-7 min. The development of morphological changes produced by hypobaric stress followed a characteristic pattern. The filopodia, or microvilli attaching the cells to the substrate, became withdrawn, with only occasional retraction fibers remaining. Blends appeared around the cell surface and increased in size as hypobaric exposures progressed. Vacuoles, or cler spherical regions, appeared within the cytoplasm and the overall shape of the cells became circular. The cells became flatter during circularization, showing an apparent 2-2-5 X increase in size as they respread on the substrate...


A simple method to measure resolution on micrographs. A method for rapid measurement of the resolution of a microscope by finding the smallest distance between pairs of points that appear on two successive micrographs is described. The method based on the visualization of moire pattern gives the same result as other tests with a precision sufficient for routine checks. Neither a special instrument nor time consuming training are required.


A simple electrode for metallic replication. A simple resistive heating electrode has been designed for use in metallic replication procedures. The electrodes are relatively small, reliable, adaptable to most vacuum systems, and are compatible with ultra-high vacuums. They are easily aligned, have good electrical conductivity and ajustable tensions. Using these electrodes with full wave rectified a.c., we found reduced specimen heating, lower background granularity, and improved resolution compared to commercially available designs.


The application of phenoxybenzamine in open heart surgery using cardiopulmonary bypass. The effects of vasodilator therapy upon organ blood flow, beta-glucuronidase activity in plasma and pulmonary surfactant were evaluated before and during cardiopulmonary bypass. Alpha adrenergic blockade with phenoxybenzamine increased the organ blood flow in the heart, brain, stomach, small intestine, large intestine, and liver, whereas it decreased the organ blood flow in the kidney, spleen, and lung. These changes were extremely similar to those observed at hemorrhagic shock. With 2 mg/kg of POB the organ blood flow tended to approach to control levels. The increase of beta-glucuronidase activity at hemorrhagic shock was considerably inhibited after intravenous drip of 2 mg/kg of phenoxybenzamine. We examined the changes of pulmonary surfactant biochemically. Pulmonary surfactant was decreased in endotoxin shock and similar changes were observed in cardiopulmonary bypass when perfusion time was extended to 3 hours. The decrease of pulmonary surfactant after bypass was inhibited by application of POB. From these results, we supposed that the circulatory dynamics during cardiopulmonary bypass might be similar to that of shock and the application of POB in cardiopulmonary bypass might be useful. We applied POB clinically and had good results.


Intrathecal tolerance of metrizamide in chloralose anesthetized cats. The water soluble radiopaque medium, metrizamide (Amipaque) was introduced into the lumbar subarachnoid space in chloralose anesthetized cats at a standard volume of 0.35 cc/kg in concentrations of 300 mgI/cc to 500 mgI/cc during EMG recording. These animals did not differ from controls which received cerebrospinal fluid under otherwise identical conditions; both groups usually showed some mild and occasional muscle fasciculations or mild spasms. Treatment with metrizamide appeared to be a less deleterious procedure than that using hyperosmotic sucrose (1.32 M) as judged from EMG records. In contrast, equivalent amounts of neglumine iothalamate produced frank convulsions in 7 of 15 cases and a range of hyperirritability in the remaining 8.


Mixed venous oxygen tension and hyperlactatemia. Survival in severe cardiopulmonary disease. Mixed venous oxygen tension (PVo2), cardiac output (Q), and arterial oxygen tension (Pao2) were measured in 20 patients with severe cardiac or pulmonary disease or both to determine which of these variables would best predict hyperlactatemia and survival. There was no correlation between Pao2 and either hyperlactatemia or survival, possibly because all oxygen tensions were greater than 40 mm Hg. There was a good correlation between Q and both hyperlactatemia and survival, and a slightly better correlation between PVo2 and both hyperlactatemia and survival. Mixed venous oxygen tension, a reflection of both Pao2 and Q, was a better predictor of hyperlactatemia and death than either arterial Pao2 or Q alone. It is also more easily measured and, therefore, more clinically useful than either Q, as a predictor of anaerobiosis and survival, or blood lactate concentration, as a predictor of survival. A mixed venous oxygen tension below 28 mm Hg was usually associated with hyperlactatemia and was always associated with death.


Adverse drug reactions and death. A review of 827 cases. A study of 827 cases of adverse drug reactions (ADRs) in which autopsies were done was carried out to determine the relative frequency of drugs that caused adverse reactions, their sites of action, and the variety of pathologic processes induced by them. Because a variety of nondrug factors played critical roles in generating many of the ADRs, these 827 cases were divided into seven groups. Only one of these groups (25% of the total) met the criteria of ADRs in the usual definitional sense and were also lethal. The validity of the diagnoses of both the ADRs and the basic diseases being treated was strengthened by the addition of morphologic findings to the data base and by the use of an analytic algorithm that was specifically developed for and directed to the evaluation of ADRs.


The FENa test. Use in the differential diagnosis of acute renal failure. The FENa test, a determination of the excreted fraction of the filtered sodium, was performed in patients in the oliguric phase of acute renal failure. Patients with prerenal azotemia had an FENa of less than 1, and patients with acute tubular necrosis had an FENa of more than 3 (P less than .001). This simple test clearly differentiates between these two conditions and, thus, is of considerable clinical value.


Familial risk and cancer control.

Familial risk and cancer control. An intensive study of the family history of cancer in 4,515 patients screened consecutively by a multiphasic mobile cancer detection unit showed, after age correction, that cancer had developed in 8.9% of the probands when there was one cancer in a single first-degree relative, 16.2% had cancer with two family members affected, and 27.4% had cancer when three or more family members had been affected. This constituted a significant correlation between family and personal histories of cancer in these patients. Extrapolation to the United States population with cancer-control implications are given.


Rubella vaccine in postpubertal women. Experience in Western Washington State. Nearly two thousand nonimmune, postpubertal females given rubella vaccine in western Washington state in 1970 to 1974 were followed up for acute reactions, inadvertent pregnancy onset, and (776 women) seroresponse. Low-level prevaccination immunity appears to explain most of the apparent vaccine failure (11.6%). The 27 vaccine-complicated pregnancies identified resulted in 17 apparently normal infants (nine from nonimmune mothers). The remaining ten were terminated by abortion (four in nonimmune women), but no abortus yielded rubella virus. Frequency of post-vaccination complaints (largely joint-related) varied with age (higher in those over 25 years), with vaccine (higher after HPV-77-DE-5 than after Cendehill strain virus), with stage of menstrual cycle when vaccine was given, and with method of contraception.


The Charlottesville Blood-Pressure Survey. Value of repeated blood-pressure measurements. The population of a community of 29,608 adults was screened door-to-door for elevated blood pressure. Of 12,371 adults screened, 20% were classified as hypertensive. After repeated blood-pressure measurement, however, there were only 9% with sustained hypertension, while 11% had labile hypertension. Sixty percent of the cases of sustained hypertension had been either undiagnosed, untreated, or inadequately treated. Eighty-two percent who initially were unaware of hypertension had labile hypertension after repeated blood-pressure measurement, and 18% were unaware of having, sustained hypertension. Labile hypertension was most prevalent in the young and decreased with age. In contrast, sustained hypertension was least prevalent in the young and increased with age. Labile hypertension was most prevalent in white men, and sustained hypertension was more prevalent in blacks than in whites. Labile hypertension represents a large segment (52%) of the population initially identified as having hypertension in a home blood-pressure survey.


Physical examination. Frequently observed errors. A method allowing for direct observation of intern and resident physicians while interviewing and examining patients has been in use on our medical wards for the last five years. A large number of errors in the performance of the medical examination by young physicians were noted and a classification of these errors into those of technique, omission, detection, interpretation, and recording was made. An approach to detection and correction of each of these kinds of errors is presented, as well as a discussion of possible reasons for the occurrence of these errors in physician performance.


Erythema chronicum migrans in the United States. Four cases of erythema chronicum migrans occurred within a one-month period in southeastern Connecticut. The syndrome may include advancing erythematous rash stemming from an apparent insect bite, hyperesthesias, myalgias, malaise, fever, lymphadenopathy, and, rarely, meningitis. Treatment with penicillin, the tetracycline, or, in our experience, erythromycin usually results in prompt resolution.


Comparison of serum cholesterol in children fed high, moderate, or low cholesterol milk diets during neonatal period. The long-term effects of milk diets in infancy on the blood serum cholesterol concentrations were studied in 97 school children 7-12 yr of age. Detailed histories were available for these children with respect to their diets during infancy. The major criterion for inclusion in the study was milk (human milk, cow's milk, or commercial formula) as the exclusive source of diet  cholesterol during the first 3 mo of life. Fasting blood cholesterol and triglycerides were measured in these 97 school children, and the current diets of 29 of the 97 were evaluated for daily cholesterol intake. A 7-day diet diary was recorded, the food intake was measured and analyzed for nutrients, and validity of the diets was verified by determination of urinary nitrogen excretion. Results of the study showed that the school children fed a low cholesterol formula during infancy had a mean serum cholesterol value 7-12 yr later that was lower than the mean values of the groups fed greater amounts of cholesterol in infancy. Analysis of current diets of 29 of the 97 school children showed that their current dietary intake of cholesterol was low. Dietary intake of cholesterol did not have a noticeable effect on the serum cholesterol levels of the 29 children.


[Bacteriological aspects of preparation, storage and transport of milk formulas (author's transl)]. 1. It was shown that special apparatus for cleaning milkbottles makes additional desinfection unnecessary with regard to bacteriological and hygienic aspects. -- 2. Milk-bottles should be processed centrally for safety reasons. Special basket-containers facilitate a more economic washing process, transport and storage of the bottles. -- 3. Physiologically optimal milk formulas, as available today, should be prepared and filled into bottles in the ward where they are needed, immediately before use, to guarantee bacteriologically optimal conditions. -- 4. With appropriate organization within a clinic it should be possible to store special dietary formulas which have been prepared centrally, not in the wards, over the required time without the risk of bacterial contamination. The need for regular and systemic bacteriological checks is emphasized.


Assessment of fetal pulmonic maturity by measurement of the surface tension of amniotic fluid lipid extract. Fetal pulmonic maturity is currently predicted by the lecithin/sphingomyelin (L/S) ratio which utilizes the changes with increased gestation in the lecithin component of amniotic fluid surfactant. The surface tension lowering property of lipids extracted from the amniotic fluid of 45 patients was measured directly. The surface tension (gamma) of various aliquots of the amniotic fluid lipid extract was measured by a modification of the Wilhelmy plate method. At 80 gamma of the extract, a gamma of 67 dynes/cm or less indicated pulmonic maturity, while a gamma of greater than 67 dynes/cm suggested immaturity, provided that the gamma at 200 gamma was greater than 56 dynes/cm. The fluid was termed transitional if the gamma was greater than 67 dynes/cm at 80 gama, but less than 56 dynes/cm at 200 gamma. A comparison was made with the L/S ratio; there were no false positive values and only 13.6% false negative surface tension values. Addition of blood to amniotic fluid, mature and immature, yielded the same results as with the L/S ratio. Two infants with respiratory distress syndrome had both immature L/S ratios and surface tension results. Results indicate that the surface tension of the amniotic fluid lipid extracts is a reliable and rapid means of antenatally predicting fetal pulmonic maturity.


[Clinical experiences with noxiptilin].

[Clinical experiences with noxiptilin]. Noxiptilin (Elronon) proved to be a good bipolar thymoleptic agent in the clinical test at 3 special clinics. Its stimulating effect on the psychomotor function is more pronounced than its sedative action. Therefore, in cases with the anxious, agitated depressive syndrome the additional therapy with a neuroleptic agent or a sedative tranquilizer may be favourable. N. is well tolerated even at a higher age. The side effects are the same as those of other known thymoleptics.


Differences of the effects of testosterone propionate on the production of LH and FSH. The effects of testosterone propionate (1 mg/day) on the synthesis and circulating levels of FSH and LH were studied in normal adult male rats. The pituitary and serum gonadotrophins were measured by double antibody radioimmunoassay. The de novo synthesis of gonadotrophins was assessed by the rate of in vitro incorporation of [3H]leucine into the immunoprecipitable FSH and LH. After 4 days of treatment with testosterone propionate the circulating LH levels dropped significantly, while FSH remained unchanged. Pituitary LH content and concentration declined significantly after 1 day, and incorporation of [3H]leucine into the immunoprecipitable LH became undetectable 4 days after initiation of treatment. Pituitary FSH content and concentration showed a significant increase after the 4th day of treatment. A slight tendency towards increased incorporation of [3H]leucine into FSH was observed throughout the treatment period, although it was statistically not significant. The data provide direct evidence for a differential effect of TP on FSH and LH production by the pituitary and show that the decrease in the pituitary and plasma levels of LH in testosterone treated rats is due to the decrease in LH synthesis.


Isolation of canine prolactin by polyacrylamide gel electrophoresis. The electrophoretic mobility of prolactin obtained from canine pituitary extract was studied with the aid of polyacrylamide disc electrophoresis. Using a preparative gel electrophoretic system the immunoreactive material was purified on a quantitative scale which was then used to develop a homologous radioimmunoassay for canine prolactin. The radioimmunoassay system was able to detect prolactin in the plasma of dogs after the administration of agents which would be expected to affect prolactin secretion.


Changes in plasma renin activity and plasma aldosterone in the induced paralytic attack of thyrotroxic periodic paralysis. Changes in serum electrolytes, haematocrit, plasma renin activity and plasma aldosterone induced by glucose and insulin (GI) infusion were serially investigated in seven patients with periodic thyrotoxic paralysis. An attack which developed into complete quadriplegia was induced within 90 min after the beginning of the GI infusion in four out of seven patients. Only a slight paralysis of the legs was produced in another two patients and induction of an attack did not materialize in one. In four patients with complete quadriplegia, the mean values of serum sodium and potassium concentrations, haematocrit, plasma renin activity and plasma aldosterone slightly decreased immediately after the beginning of the GI infusion. Induction of a paralytic attack was not accompanied by any significant changes in serum sodium concentration, haematocrit, plasma renin activity and plasma aldosterone either 15 min before or after the onset of attack, while the serum potassium concentration progressively decreased, and an increase in plasma aldosterone associated with an increase of haematocrit and plasma renin activity reached a peak level at the stage of complete quadriplegia. On the other hand, in the three patients in whom an infusion produced slight or no paralysis of the legs, changes in the serum sodium concentration, haematocrit, plasma renin activity and plasma aldosterone were insignificant and the serum potassium concentration was slightly but insignificantly decreased. These results suggest that hyperaldosteronism may not be a trigger for the induced paralytic attack but a phenomenon secondary to volume depletion and a change in potassium homoeostasis induced by GI infusion.


Studies on proteolytic activity and function of the thyroid gland in rats administered excess iodide. Thyroid auto-proteolytic activity in rats increased significantly only after several weeks of treatment with 1 mg iodide per day. Iodide added in vitro did not activate thyroid auto-proteolysis, nor was inhibition observed. Thyroid proteolytic activity was also tested using 131I-labelled heat-inactivated thyroid homogenate from control rats as substrate. Significantly increased proteolytic activity was again demonstrated in thyroid glands from rats on excess iodide for several weeks. The increased proteolytic activity is therefore probably not due to a decreased proteolytic resistance of thyroglobulin in the iodide-treated rats. Increased synthesis or decreased degradation of thyroid proteolytic enzymes is a more likely explanation for this phenomenon. These findings are at variance with those of some previous studies showing decreased proteolytic activity in thyroid glands from rats administered excess iodide. Since the rats remained euthyroid the increased auto-proteolysis, which occurred quite late, was considered an unexpected finding and it is at present not certain whether this is related to the successful adaptation. Treatment with iodide did not alter the thyroid and hypophyseal weight or histology. Serum free thyroxine level and thyrotropin concentration were also unaffected by excess iodide. The adaptation of the imtact rat thyroid to prolonged and excess iodide intake seems to occur without the assistance of an altered thyrotrophin secretion.


The deiodination of thyroxine in hyperthyroid rats as determined by renal clearance of iodide. Other investigators have reported that whole body clearance of thyroxine (T4) is increased in hyperthyroid rats isotopically equilibrated with radioactive T4, using the 24 h post-injection serum T4 concentration in the clearance calculation. Data from this laboratory indicate that serum T4 concentration is lowest at this point yielding falsely high clearance values, particularly when high doses of T4 are injected. To investigate this problem further, two types of experiments were performed. First, rats were equilibrated with [125I]T4, 5 or 20 mug/day, and the urinary clearance of iodide derived from T4 (deiodinative clearance) was measured from 0-7 and 7-24 h after a T4 injection, using the T4 concentration in serum obtained at the midpoint of each urine collection period. Urine was then collected from the ureters for several 1 h periods during the 4th to 8th h following T4 injection, calculating clearances using the midpoint plasma T4 concentration. Second, normal rats were given a single dose of [125I]T4, 5 or 55 mug/rat, and deiodinative clearance was determined during the subsequent 0-7 and 7-24 h periods. The first experiment indicated that deiodinative clearance was significantly enhanced in rats equilibrated with the large dose of T4 under all conditions studied. In contrast, the clearance in normal rats given a single large dose of T4 was not significantly different from that of normal rats given a small dose of T4. These results support the view that T4 clearance is increased in hyperthyroidism, due in part to an increase in the deiodination of T4.


Adrenaline in the human pancreas.

Adrenaline in the human pancreas. The present study describes the results of examinations of the noradrenaline and adrenaline concentrations in the human pancreas as well as in a number of other organs. Tissue specimens were obtained at post-mortem examination. Adrenaline was present in small amounts in the cardiovascular system, the liver and the spleen in comparison with the noradrenaline concentration. The pancreas, especially the body of the pancreas, contained, however, considerable amounts of adrenaline. The average adrenaline concentration was approximately 20 times higher in the pancreas than in the other organs examined. The greatest concentration of adrenaline was found in the posterior and superior parts of the body of the pancreas. There was no relationship between the cause of death in the human subjects and the adrenaline concentration in the pancreas and large amounts of adrenaline were also found in tissue specimens of pancreas obtained from long-term diabetic patients. Adrenaline was present in the pancreas of the rat, dog and rabbit but in small amounts in comparison with the noradrenaline concentration.


Growth hormone, insulin and sugar in the blood plasma of bulls. Interrelated diurnal variations. Plasma growth hormone (GH) of eight young, sexually mature, pedigree bulls, observed at hourly intervals, varied during the day in a manner indicating intermittent secretion in peaks or bursts. The diurnal GH averages were about 10 ng/ml. GH averages for 2-3 h intervals showed minima following or during the periods of morning and afternoon feeding. A third minimum occurred between 10 and 12 p.m. Peak activity, estimated by the frequency of GH values greater than 10 ng/ml was significantly reduced during two of these low-GH-periods (afternoon and late night). The minima in GH followed after (morning) or coincided with (afternoon) maxima in plasma insulin (two materials, GH/insulin, 11 a. m.-10 p.m.: r=-0.31 and -3.34, P less than 0.01). This means that the two hormones behaved after food intake much in the same ways as in man in spite of the fact that plasma sugar decreased after feeding (GH/sugar, 11 a.m.-10 p.m.: r=0.27, two materials combined, P less than 0.001). The possibility of GH involvement in the hour-to-hour metabolic homoeostasis of the animals is discussed.


Growth hormone related to insulin and sugar in nocturnal blood plasma of lactating cows. Nocturnal blood plasma samples from about 190 indoor-fed cows at varying stages of the lactation cycle showed wide variations in the concentrations of sugar (43-88 mg/100 ml) and acetoacetate (0.12-8.7 mg/100 ml). Plasma immunoreactive insulin decreased and acetoacetate increased with decreasing sugar. Plasma growth hormone (GH) was significantly correlated to insulin (r=-0.24, P less than 0.001) and to sugar (r=-0.15, P less than 0.05), but not to acetoacetate (r=+0.13). Since the plasma level of GH in bovines is known to vary widely from hour to hour, individual cows are poorly represented by single determinations of the hormone. However, in accordance with the results from the correlation tests, different GH averages, about 11 and 9 ng/ml, were found for groups of animals with plasma sugar respectively below and above 70 mg/100 ml. By subgrouping according to insulin levels within sugar ranges, categories could be singled out with GH averages as different as 12.7 ng/ml (low sugar-low insulin) and 8.3 ng/ml (high sugar-high insulin). The findings are consistent with the view that GH is involved in the regulation of energy metabolism in bovines. But no support has been provided for the hypothesis of GH hypersecretion as a cause of ketosis in cows.


Effect of an ovulatory dose of luteinizing hormone on the concentration of oestrone, oestradiol and progesterone in the rabbit ovarian follicles. This study was done to determine the effect of an ovulatory dose of LH on the concentration of oestrone, oestradiol and progesterone in the follicular tissue and in follicular fluid of ovaries of sexually mature female rabbits. Eight animals were sacrificed without treatment while others (4 to a group) were sacrificed at 1, 3, 4, 6, 8 and 10 h after administration of LH (50 mug). In each animal follicles from both ovaries were pooled and the follicular tissue was separated from the fluid. Determination of oestrone, oestradiol and progesterone was done by radioimmunoassay separately in the follicular tissue and in fluid. One hour after LH treatment oestrogen levels were found elevated, as compared to the control, in the fluid but not in the tissue. Thereafter oestrogen levels declined and reached levels much below control at times nearing ovulation. On the other hand, progesterone levels were elevated over the control in both the tissue and fluid at 1 and 3 h. The tissue progesterone levels were, however, below control at and after 6 h. The sustained high concentrations of tissue progesterone in the earlier period after LH stimulation could play a role in the chain of events leading to follicular rupture.


Studies of human chorionic gonadotrophin in steroid-primed hypophysectomized rats. The uptake of [125I]HCG was studied in the ovaries of intact and hypophysectomized (Hypox) Sprague-Dawley rats. The [125I]HCG localized specifically in the ovary of the intact rat, and to a lesser extent, in the ovary of the hypox rat. The concentration of HCG in all other tissues and organs of either sex was negligible. However, the localization of [125I]HCG in the hypox rat was enhanced by the presence of exogenous steroids. The greatest increase in HCG uptake was observed in the rats primed with androgen; while a lesser enhancement was demonstrated in the oestrogen treated rats. Comparison of the ovary-to-body weight ratios revealed that a greater amount of HCG localized in the androgen-primed rats than in the oestrogen treated animals even though the ovaries of the former were smaller. These findings suggest that the hypox rat ovary primed with androgen could provide a highly sensitive animal model for further studies of the HCG cell receptor site in animals free of pituitary influence.


Transformation of (1,2-3H)aldosterone in the foetal and placental compartments of the guinea pig. In vivo and in vitro transformation of labelled d-aldosterone (11beta, 21-dihydroxy-3,20-dioxo-4-pregnen-18-al) was studied in the foetal tissues and placenta of guinea pig (35-45 days of gestation). The principal metabolite found in all of these tissues was tetrahydroaldosterone (3alpha, 18,21-trihydroxy-20-oxo-5beta-pregnan-18-al). A large transformation into this metabolite was found in foetal liver (67-68%) and in the placenta (69-82%). Incubation of [3H]- or [14C]aldosterone with the isolated placenta also showed a large conversion to the tetrahydroderivative suggesting that the reductase(s) of ring A of aldosterone is present in this tissue. Most of the unmetabolized aldosterone and tetrahydroaldosterone was found in the unconjugated fraction. Very little of the radioactive material was present in the polar steroids extracted with n-butanol. Aldosterone and tetrahydroaldosterone were liberated from this fraction after enzymatic hydrolysis (beta-glucuronidase and sulphatase) or by solvolysis, suggesting that part of these conjugates is present in the foetal compartment as sulphate esters and glucuronides. Moreover, in this fraction a polar, unconjugated aldosterone metabolite with the characteristics of an acidic compound was detected.


Urinary testosterone glucuronide and sulphate in newborns and young infants. Urinary testosterone glucuronide and sulphate was determined separately by gas chromatography in 39 newborns and young infants (34 males and 5 females). In all cases, testosterone sulphate was higher than glucuronide. Boys excreted more of both conjugates (sulphate 6.7, glucuronide 2.2 mug/24 h) than girls (1.1 and 0.7 mug/24 h, respectively). Boys older than 3 weeks had higher values than boys younger than 2 weeks. The levels correlated positively with chronological age, negatively with the gestational age and not at all with the bilirubin levels. It is concluded that testosterone is excreted preferentially as the sulphate in the newborn period and that the high sulphokinase activity in foetal and neonatal testes is more likely responsible for this phenomenon than an impaired glucuronizing capacity of the liver.


Disappearance of (14,15-3H)d,1-norgestrel from plasma and its distribution in the reproductive tract of women. After an iv injection of [14,15-3H]d,1-norgestrel into 7 women, its disappearance from the plasma and its distribution in the reproductive organs has been investigated. It was found that initially norgestrel disappeared rapidly from the plasma with a half-life of 38.8 min followed by a slower disappearance with a half-life of 45.18 h. The disappearance curve has been analysed on the basis of a biexponential curve representing a two compartmental model. The low metabolic clearance rate of 458.5 1/24 h indicated a more prolonged persistance of norgestrel in the body. Uptake of norgestrel and its metabolites was very high in the endometrium, myometrium, cervix. Fallopian tube, ovary and body fat. Compared to the myometrium, more norgestrel as such was concentrated in the endometrium at 30 min and 12 h after injection of [14,15-3H]d,1-norgestrel. The myometrium on the other hand contained higher amounts of norgestrel at 5 min. The significance and the possible role of localization of norgestrel at multiple sites in the reproductive tract and its contraceptive action are discussed.


Myasthenia gravis. Current concepts.

Myasthenia gravis. Current concepts. The prevalent theory of the past two decades, that the defect in myasthenia gravis (MG) is the packaging of achetylcholine (Ach) into smaller quantal units, has recently been revised. The current theory is based on (1) electron microscopical studies of motor end plates in patients with MG; (2) radioisotope study with alpha-bungarotoxin of postsynaptic membrane Ach receptor (Ach R) sites; (3) sensitization of rabbits with the use of purified Ach R from the electric eel, inducing experimental autoimmune myasthenia gravis (EAMG); (4) detection of antibodies to the Ach R in patients with MG by radioimmunoassay; and (5) apparent induction of MG in mice by passive transfer of immunoglobulin from patients with MG. Thus, the emphasis on pathogenesis of MG is now placed on an autoimmune process involving Ach R in the subsynaptic membrane of neuromuscular junctions.


Changes in hepatic nuclei induced by acetamide and thioacetamide. Rat liver nuclei were examined following intoxication with thioacetamide or acetamide. A prompt increase in nuclear size occurred with the administration of either agent. The acetamide-related change was evanescent and, by 16 hours, the nuclei did not differ from controls. Thioacetamide produced an acute enlargement during the first eight hours and a second, more prolonged increase during the next 24 hours. The enlargement noted by microscopy was also detectable in isolated nuclei by flow spectrometry. Chemical determinations on isolated nuclei appear to sample the same size population seen in situ. An increase in RNA content of thioacetamide-treated nuclei occurred during the late phase. The temporal sequence of physical and chemical change suggests that the initial increase in nuclear volume is not the result of retained macromolecular formation but may involve intracellular water and electrolyte shifts.


Peliosis hepatis in a child.

Peliosis hepatis in a child. Peliosis hepatis, which has previously only been reported in adults, occurred in a chronically ill 11-year-old boy with cystic fibrosis. As in cases in adults, chronic illness, long-term anabolic steroid therapy, and right ventricular congestive failure may well have been the causative factors in this case. Histologically, the phlebectatic and parenchymal types, which were presumed to be separate, were found conjointly in this case. This is compatible with its origin from severe right ventricular congestive failure. The rarity of peliosis, however, indicates that one or more as yet unknown factors might be operative in its development.


Intravascular papillary endothelial hyperplasia. Papillary endothelial hyperplasia is a peculiar benign intravascular process that bears a remarkable resemblance to a hemangiosarcoma. In 44 cases of this lesion studied from the files of the Armed Forces Institute of Pathology, the process manifested as a small tumor-like lesion that occurred most frequently in the subcutis of the fingers (14 cases), the head and neck region (ten), and the trunk (seven). Microscopically, the tuft-like or papillary proliferation of endothelial cells was nearly always intimately associated with a thrombus and seemed to represent a peculiar variant of an organizing process. Features that aided in recognition and differential diagnosis from a hemangio-sarcoma included the intraluminal location of the lesion, the absence of tissue necrosis, and the intimate association of the proliferated tuft-like structures with thrombotic material. Follow-up information obtained in 31 cases indicated a benign clinical course despite the sarcoma-like microscopic appearance of this condition.


Studies on the toxicology of hexachlorobenzene. II. Identification and determination of metabolites. Female rats were dosed intraperitoneally with 14C-hexaxhlorobenzene. The drug was administered on 2 or 3 occasions. The total doses amounted to 260 and 390 mg/kg 14C-hexachlorobenzene, respectively. Urine and feces from the animals were collected over a period of 4 weeks after the first injection. Both excreta and some tissues of the animals were examined for their content of radioactivity and for hexachlorobenzene and its metabolites. Gas chromatography, isotope dilution analysis, and combined gas chromatography-mass spectrometry were used to identify the metabolites of hexachlorobenzene. In urine pentachlorophenol, tetrachlorohydroquinone, and pentachlorothiophenol were present as major metabolites. One of the isomers of tetrachlorothiophenol was present as a minor metabolite. In the feces pentachlorophenol and pentachlorothiophenol only were identified. At the end of the experiment, carbon-14 excreted with urine and feces amounted to 7% and 27%, respectively, of the radioactivity administered. More than 90% of carbon-14 excreted in urine was contained in the major metabolites. In the feces about 30% of the excreted radioactivity was bound to metabolites and about 70% was contained in the unchanged drug, while in the tissues of the animals only pentachlorophenol was detected in measurable amounts, accounting for 10% of label in blood and less than 0.1% of carbon-14 determined in body fat. Total radioactivity contained in the metabolites detected in the animal body and in the excreta at the end of the experiment accounted for about 16% of the administered radioactivity.


Prevention by steroids of cerium hepatotoxicity. In female rats, the lethality and hepatotoxicity of cerous chloride (CeCl3) were significantly altered by pretreatment with steroidal and nonsteroidal compounds (pregnenolone-16alpha-carbonitrile "PCN", dexamethasone, spironolactone, phenobarbital) that stimulate hepatic drug-metabolizine enzyme activity and by estradiol. PCN, estradiol, and dexamethasone considerably decreased hepatic triglycerides, but the latter steroid also greatly sensitized the animals to CeCl3 lethality. Spironolactone and phenobarbital similarly lowered the triglyceride level but not significantly. Light and electron microscopy indicated that the hepatocytic damage elicited by CeCl3 was decreased significantly by PCN, estradiol, and dexamethasone. The steroids may have altered the distribution and binding of the metal to the endoplasmic reticulum (er) thus protecting these membranes against the effect of cerium.


delta-9-Tetrahydrocannabinol: effect on macromolecular synthesis in human and other mammalian cells. The principal psychoactive component of marihuana is delta-9-tetrahydrocannabinol. This compound at 10(-5) molar concentration in the medium of human cell cultures appeared to inhibit DNA, RNA, and protein synthesis by 50, 40, and 30% respectively, as measured by incorporation of radioactive precursors into acid-insoluble cell fractions in human diploid fibroblasts, human neuroblastoma cells, and mouse neuroblastoma cells. While delta-9-tetrahydrocannabinol inhibited semiconservative DNA synthesis, it had no effect on DNA repair synthesis in human cells as assayed by the photolysis of 5-bromodeoxyuridine incorporation into DNA during repair after ultraviolet radiation damage. Delta-9-tetrahydrocannabinol also had no effect on rejoining of DNA single-strand breaks induced by gamma-rays. The nonspecificity of the inhibition of macromolecular synthesis by delta-9-THC suggested a possible interference with uptake of radioactive precursors. However, experimentation has shown that this depression of macromolecular synthesis cannot be accounted for by reduced transport of radioactive precursors into the cell because the rate of transport of these precursors into the cell is essentially the same in the presence or absence of delta-9-THC. Pool sizes of macromolecular precursors as measured radioisotopically (3H-thymidine, 3H-uridine, 14C-leucine) appear to be reduced about 50%, and this reduced pool size could fully account for the reduced macromolecular synthesis seen in the presence of delta-9-THC. We do not know what causes this apparent reduction of pool sizes in the presence of delta-9-THC.


Quinine-N-oxide--a urinary component after the consumption of quinine beverages. After the consumption of quinine-containing beverages, quinine-N-oxide could be identified in the urine mass spectrometrically. Consequently in the analysis of physiological fluids for drugs not only the drugs themselves must be considered but also their metabolites.


[Hexachlorobenzene content in the whole blood of children (author's transl)]. In the spring of 1975, samples of whole blood of 98 male and 96 female children from Upper Bavaria, of 1-18 years of age, were examined for hexachlorbenzene (HCB) by gas chromatographic methods. All blood samples contained HCB ranging in concentration from 2,6 to 77,9 ppb. The HCB concentration shows a positive, hyperbolic correlation with age, tending toward a limiting value of 22 ppb for boys and 17 ppb for girls. The rate of increase in HCB concentration is inversely proportional to the square of the age. The concentration profile suggests that a substantial amount of HCB apparently starts to show up 9-10 months after birth (environmental effects?). No change in HBC concentration could be found in those children with infectious diseases. Furthermore, regional differences could not be detected, although the impression was that the HCB content was higher in children from rural areas than in children from urban areas.


Acute toxicity of bicyclic phosphorus esters. The acute toxicity of 4-ethyl-1-phospha-2,6,7-trioxabicyclo (2.2.2) octane-1-oxide and 4-ethyl-1-phospha-2,6,7-trioxabicyclo (2.2.2) octane has been determined by different routes of application in various species of animals. The compounds stimulate the activity of the central nervous system and are highly toxic. They showed no toxic cumulative effects. The presence of the bicyclic phosphate ester in the combustion products of specific rigid polyurethane foams is discussed. The question is raised whether there may be an additional hazard caused by this combustion product in a real fire situation.


Radioactivity in urine and feces of mink (Mustela vison) treated with [14C] aflatoxin B1. Excretion of radioactivity by mink (Mustela vison) during 7 days after intraperitoneal injection of two different amounts of aflatoxin B1 was studied. Male mink that received a single dose of 25 mug aflatoxin B1/kg body weight excreted an average of 89.5% of administered radioactivity (56.8% via feces, 32.7% via urine); whereas female mink excreted an average of 85% (63.6% via feces, 21.4% via urine) of administered radioactivity during the 7-day period. Male and female mink given 150 mug aflatoxin B1/kg body weight excreted an average of 76.9-80.1% of administered radioactivity during the 7 days that followed treatment with toxin. These mink excreted somewhat more of the administered radioactivity in their urine than did the mink that received the lower dose of aflatoxin (37.2 vs. 32.7% for males and 32.7 vs. 21.4% for females). Regardless of sex and dosage of toxin, most of the radioactivity ultimately excreted either through feces or urine appeared in the first 24 h after toxin was administered to mink.


Subchronic inhalation toxicity of azinphos-methyl in rats. Azinphos-methyl was evaluated for its subchronic inhalation toxicity. The exposure of rats to concentrations of 0.195, 1.24, and 4.72 mg/m3, respectively, for 12 weeks, 6 hrs daily, 5 times weekly, resulted in effects only in those animals which inhaled aerosols of the highest concentration. This group showed a significant depression of the cholinesterase activity in plasma and erythrocytes. The males of this group had a lower body weight gain. The results are in agreement with the established maximum allowable concentration of 0.2 mg/m3.


The subacute and chronic toxicity of cetyltrimethylammonium bromide (CTAB), a cationic surfactant, in the rat. Cetyltrimethylammonium bromide (CTAB), a cationic surfactant, was given to male and female Sprague-Dawley rats in drinking water in dosages of approximately 10, 20, and 45 mg/kg/day for 1 year. The surfactant was well tolerated at the two lowest dose levels. At the highest dose level a reduction in body weight was observed. In males the body weight remained reduced throughout the study, but in females the body weight was reduced only during the first 2 months of the study. It was found that food conversion was less efficient in male rats during the first 7 weeks of the study. No compound-related gross pathologic changes were seen on autopsy and no microscopic alterations were found in the wall of stomach and small intestine of treated animals.


Treatment of experimental imipramine and desipramine poisoning in the rat. The influence of orally administered activated charcoal on organ concentrations of parenteral imipramine and desipramine was investigated. Ancillary distribution experiments indicated that the gastroenteral cycle of these substances might be more important than the enterohepatic cycle. Nevertheless the effectiveness of repeated activated charcoal dosage in lowering antidepressant concentrations of visceral organs is unpredictable. This is interpreted as a consequence of predominant binding of these drugs in the tissues, in contrast to drugs like acetosal and the barbiturates, which are distributed more evenly in the body water. The conclusion is, that activated charcoal has only limited value as an anitdotal adsorbent in imipramine or desipramine poisoning.


Fungal aneurysms of intracranial vessels. Intracranial fungal aneurysms arise from major cerebral arteries. Fungi directly invade vessel walls from the luminal surface (fungal emboli) or from the adventitia (fungal meningitis). The vasa vasorum are free of fungi. Aneurysmal rupture is common with extensive hemorrhagic necrosis of the surrounding brain. Aspergillus is the usual causative agent; its sources are nasal sinusitis or endocarditis.


[On the development of oral preparations of the combination sulfamoxole/trimethoprim (CN 3123) (author's transl)]. Within the broad range of activities in pharmaceutical research, the technological development and analytical evaluation of a new drug formulation represent only one step. The pharmaceutical development of three oral formulations of a combination product containing N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) in a 5:1 ratio (investigational drug CN 3123; Nevin; Supristol), which was based on the physico-chemical characteristics of the 2 active substances, is presented. The various chemical and physical tests conducted with the drug formulations are described. The pharmaceutical or in-vitro availabilities (dissolution rate) of the active ingredients were determined by way of release-rate profiles, both of the active ingredients alone and in their final formulations. Also presented are the results of plasma level determinations following oral administration of film-coated tablets and a suspension. Finally, preliminary results of extensive stability tests with the three drug formulations are discussed.


[Antimicrobial action of the combined preparation sulfamoxole/trimethoprim in vitro (author's transl)]. A number of different methods were used to test the in vitro antimicrobial activity of the combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim). 1. The minimum bacteriostatic inhibitory concentratiions of the sulfamoxole/trimethoprim combination (5 + 1) (CN 3123; Nevin; Supristol) were determined for 131 gram-positive and gram-negative strains of bacteria. More than 88% of the strains tested were found to be highly sensitive to the combination (M1C 0.1-3.75 mug/ml). 2. Comparative studies with the combinations sulfamoxole/trimethoprim and sulfamethoxazole/trimethoprim revealed no relevant differences of the M1C-values. 3. The synergistic effects of sulfamoxole and trimethoprim can be demonstrated with the aid of the agar dilution and agar diffusion tests using various types of bacteria and different ratios of sulfamoxole and trimethoprim. 4. Results obtained by studies on growth kinetics also demonstrate the synergistic and potentiating effect of combining sulfamoxole with trimethoprim and bactericidal properties are achieved.


[Experimental studies on the effect of the combination sulfamoxole/trimethoprim on the Toxoplasma infection of the mouse (author's transl)]. Albino mice infected with Toxoplasma gondii (virulent strain BK) were treated for 20 days with a combination of N1-[4,5-dimethyl-2-oxazolyl]-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) in the ratio of 5:1 (trial preparation CN 3123; Nevin, Supristol). By the suitable dosage the mortality rate could be reduced considerably. In contrast to the untreated controls no antibodies were formed. No cysts could be detected in the brains of treated animals. Compared with the combination of trimethoprim/sulfamethoxazole the combination of trimethoprim/sulfamoxole showed a slightly better effect.


[Pharmacological investigations with the combination sulfamoxole/trimethoprim, a new broadspectrum chemotherapeutic agent (author's transl)]. Investigations were conducted with the combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) in a dose ratio of 5:1, with respect to pharmacological activity and possible side effects. The effects obtained with the combination CN 3123 were compared with those of the single substances. In a dose range comparable to that as used in clinical treatment, there were no effects on cardiovascular or respiratory functions, on functions of autonomic and central nervous system, on contractility of smooth muscles and on data of clinical chemistry such as urine and electrolyte excretion, blood sugar, blood coagulation and liver function tests. Doses which are 5 to 10 times higher than the initial dose or 10 to 20 times higher than the maintenance dose used in man caused an increase of urine and sodium excretion without influencing potassium and chloride output. There were no signs of sedation as alteration of motility or EEG patterns, but in mice and rats there was an increase in both duration and depth of anaesthesia caused by barbiturates or ether. Only in a dose range 30 to 40 times higher than the initial dose for man there were some slight alterations with respect to cardiovascular system and liver function tests. In vitro, with high concentrations of CN 3123 there was a weak, unspecific spasmolytic effect on the isolated ureter and an increase in the refractory period of the guinea pig atrium. There were no hints that the side effects seen with separate administration of high or very high doses of sulfamoxole or trimethoprim were increased or poteniated by their simultaneous administration. Slight side effects in animals were only observed with doses exceeding the tenfold of the doses for therapeutic use in men. Therefore, the therapeutic range of CN 3123 seems to be more than adequate.


[Toxicological investigations of the combination sulfamoxole/trimethoprim, a new broad-spectrum chemotherapeutic (author's transl)]. The chemotherapeutically effective 5:1 combination N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) was investigated to determine any evidence of toxicological potentiation or new toxic signs. It was found that CN 3123 had a very low acute toxicity when administered orally to mice, rats and dogs (oral LD50: mouse greater than 12 000 mg/kg; rat greater than 14 000 mg/kg; dog greater than 1000 mg/kg body weight). The combination was also tolerated by rats and dogs in repeated doses administered over a period of 4 or 26 weeks, that greatly exceeded the therapeutic dose. The only change observed occurred in the thyroid, which in all doses administered exhibited a dose-related increase in weight accompanied by histological changes indicating an activation of thyroid function and a hypersecretion of basophilic thyrotropic cells in the anterior lobe of the pituitary. Six weeks after discontinuation of treatment this condition showed a tendency to reversibility or had already returned to normal. In dogs there was a dose-related increase in iodine uptake by the thyroid and a decrease in serum thyroxine over a period of 6 months under the highest dosage of CN 3123 administered. Whereas the thyroid changes observed under the combination could be reproduced with sulfamoxole, no effect on thyroid weight was observed in rats and dogs in the subacute toxicity phase of a comparative investigation with trimethoprim. Moreover, trimethoprim did not increase the effect of sulfamoxole on the thyroid gland. The effect of sulfamoxole on the thyroid is discussed in detail with a review of the literature. It can be characterized as species-specific for sulfonamides in mice, rats, rabbits and dogs but not in monkeys or in man and appears to be caused by the inhibition of the organic binding of iodine in the thyroid, whereby the predisposing factors must vary considerably from species to species. The thyroid hypertrophy observed is due to the activation of the regulatory cycle via the anterior lobe of the pituitary. The following systemic changes occurred after 600 mg CN 3123/kg, a lethal-toxic dosage and the highest administered in the study: reduced body weight, decreased food consumption leading to cachexia, slightly increased SGPT and alkaline phosphatase, slight thrombocyte depression, enlargement and increased fatty degeneration of the liver, occurrence of necrotic areas in the liver, hemosiderin accumulation in Kupffer's cells, and an increase of reticular cells in the spleen. The acute toxicity of CN 3123 and all major functional and histological changes under repeated administration were due exclusively to sulfamoxole. The combination sulfamoxole/trimethoprim gives no indication of toxicological potentiation or new toxic signs.


[Investigations on the effect of the combination sulfamoxole/trimethoprim on fertility and fetal development in rats and rabbits (author's tranls)]. The chemotherapeutically active combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) in a dose ratio of 5:1 (CN 3123, Nevin, Supristol) was investigated, with respect to teratogenicity, effects on fertility and reproduction and influence on peri- and post-natal development. Experiments with the combination and partly with the single substances were done on Sprague-Dawly and Wistar rats and on rabbits (New Zealand White). With regard to the known effects of trimethoprim in this field--fetal malformations typical of those caused by folic acid antagonists--it was to clarify whether or not potentiation phenomena or new toxic effects occur with the combination. The results were as follows: 1. CN 3123 is teratogenically and fetotoxically active when given in very high doses to pregnant rats and rabbits during the critical phase of organogenesis (day 8-15 of pregnancy in rats, day 8-14 in rabbits). There were malformations, decrease in the number of pups and an increase in the number of absorption sites. Litter size and litter weight were reduced. The malformations observed were cleft palates, rarely cleft lips, micrognathies and shortening of limbs. Doses up to 180 mg/kg CN 3123, corresponding to more than tenfold the daily maintenance dose in man, were without any effects on all parameters observed. Toxic effects were observed in Sprague-Dawley rats at a dose level of 420 mg/kg and in Wistar rats with 600 mg/kg, corresponding to the effects seen following 100 mg/kg of trimethoprim alone. Sulfamoxole in the corresponding dose of 500 mg/kg caused no embryotoxic effects in the rat. In rabbits 600 mg/kg CN 3123 induced no malformations but increased fetal loss. Therefore it can be concluded, that the teratogenic and fetotoxic effects seen with high doses of CN 3123 are due to the amount of trimethoprim in the combination. The observed effects with the combination are quantitatively related to those seen with trimethoprim. 2. CN 3123 in high doses which are teratogenic also provoked a reduction of growth of the animals. Food consumption and weight gain were reduced in dams with 420 and 600 mg/kg CN 3123. In this dose range the pup weights and the weight gain of the offspring of dams with continued dosing during lactation were also reduced. Variation rate including retardations was increased. The depressing effect of CN 3123 in high doses on food consumption and weight gain is known from long-term toxicological studies previously described [7]. 3. CN 3123 even with high doses has no effects on the fertility of male and female rats. The number of corpora lutea and implantations and also the pregnancy rate were unaffected when either the female or the male rats used for mating had been treated. There was also no influence on mating activity of the male animals treated. 4. According to the results of the fertility study with treatment of the male rats for a period of ten weeks or more there were no signs of mutagenic effects due to CN 3123.


[Pharmacokinetic studies with the combination sulfamoxole/trimethoprim in animals and men (author's transl)]. The pharmacokinetics of the 5:1 combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (thrimethoprim) (CN 3123, Nevin, Supristol) corresponds to the well known data of the single substances. Investigations on blood level, concentration in plasma water and excretion via urine and bile were done on experimental animals and with therapeutic dosage (single and repeated administration) on men. There were no alterations of the kinetics of the single substances due to drug interaction during simultaneous administration, neither qualitatively nor quantitatively. The dosage schedule elaborated is as follows: dosage interval=12 h, ratio initial dose: maintenance dose=2:1. For adults this regimen with a maintenance dose of 400 mg sulfamoxole and 80 mg trimethoprim results in a steady state of the minimal concentrations immediately before the following dose. These minimal concentrations in plasma water exceed the minimal inhibitory concentrations determined in vitro for most pathogens by several times.


[Studies on the antibacterial activity of the combination sulfamoxole/trimethoprim (CN 3123) (author's transl)]. After giving a survey on the situation of antibiotic resistance in the region of Northern Bavaria during 1973/74 and comparing the activity of a sulfamethoxazole (SMZ) trimethoprim (TMP) combination to other commonly used antibiotics and chemotherapeutic agents, the results of tests with the new combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide) (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) at a ratio of 5:1 (CN 3123; Nevin, Supristol) are compared to those of tests with TMP/SMZ. This was done by correlating the inhibition zone diameters and, on the other hand, by referring to a great number of sensitivity evaluations in routine diagnostic tests. According to the size of the inhibition zone, CN 3123 showed a somewhat greater activity on Enterococcus (fecal streptococci), Escherichia coli, and Klebsiella aerogenes, whereas the TPM/SMZ combination had apparently a stronger antibacterial effect in vitro against Proteus mirabilis, Staphylococcus aureus, and the Achromobacter-group. Analysis of sensitivity readings from routine diagnosis demonstrated accordance of CN 3123 with TMP/SMZ in 92.6% (first series) and 94.2% (second series), respectively. These results should be considered critically in view of the manifold factors which influence sensitivity tests in the agar diffusion method.


[Clinical trial of the antibacterial combination sulfamoxole/trimethoprim (CN 3123). 2. Results of a multicenter clinical trial of CN 3123 in infections of the kidneys and urinary tract]. During the clinical trial of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) results from 925 treated cases of bacterial infections of the urinary organs were documented. The analysis revealed the following conclusions: 1. On the basis of all the assessable cases, there was no clinical effect in less than 10% of patients and no bacteriological effect in only 13% of patients. The therapeutic response was clinically good in 76% and bacteriologically good in 68% of the patients. The rest of the patients showed a fair clinical response, that is to say they showed a definite improvement in the clinical picture, or some bacteriological response, i.e. a definite reduction in the organism counts or, in mixed infections, not all the strains of pathogen were eradicated. 2. There was a higher success rate in acute urinary tract infections which had not previously been treated than in chronic or previously treated cases. 3. The therapeutic results in the principal indications were as follows: Pyelonephritis: 73.9% good and 16.5% fair effect clinically; 63.6% good and 21.6% some effect bacteriologically. Pyelitis: 81.1% good and 18.9% fair effect clinically; 70.4% good and 25.9% some effect bacteriologically. Cystitis: 81.3% good and 8.6% fair effect clinically; 68.9% good and 17.6% some effect bacteriologically. Postoperative urinary tract infections: 98% good effect clinically and bacteriologically. Infections of the urinary organs (not specified in more detail): 71.8% good and 16.1% fair effect clinically; 65.0% good and 18.8% some effect bacteriologically.


Observations on autoregulation in skeletal muscle: the effects of arterial hypoxia. Autoregulation of blood flow in skeletal muscle, as manifested by steady-state resistance changes, has been shown to be present in the low range of perfusion pressure but has been demonstrated by some observers to be lacking at higher perfusion pressures. Transient responses have often been neglected or observed only qualitatively in analyses of autoregulation. The present study was undertaken (1) to determine the relative importance of steady-state and transient responses in flow in demonstrating autoregulation of blood flow over a broad range of perfusion pressures, (2) to establish a means of quantitating autoregulation, and (3) to observe the effect of hypoxia on autoregulation. In isolated, perfused canine gracilis muscle, perfusion pressure was increased and subsequently returned to baseline (9.7 +/- 0.13 kPa [73 +/- 1 mmHg]) during perfusion with normally oxygenated blood (PO2 = 9.3-13.3 kPa [70-100 mmHg]), and mildly (PO2 = 6.1-9.2 kPa [46-69 mmHg]), moderately (PO2 = 4.5-6.0 kPa [34-45 mmHg]), or severely (PO2 = 2.7-4.4kPa [20-33 mmHg]) hypoxic blood. Consistent with other studies canine gracilis muscle was often found to possess passive vascular responses when only steady-state parameters were considered. However, quantitation of the transient response in flow with step increases in perfusion pressure demonstrated substantial transient responses under conditions of normal oxygenation, and progressive attenuation of flow transients with increasing hypoxia.


Effects of dichloroacetate on myocardial substrate extraction, epicardial ST-segment elevation, and ventricular blood flow following coronary occlusion in dogs. Glucose metabolism in the healthy heart is stimulated by dichloroacetate (DCA). The possibility has been examined in dogs that DCA, by increasing glucose utilization, might limit the severity of acute myocardial ischaemic injury. Intravenous administration of DCA reduced the degree of epicardial ST-segment elevation induced by subsequent coronary occlusion, both under basal conditions and during isoprenaline infusion. A similar result was obtained when DCA was given during an established coronary occlusion. This effect could not be explained by changes in mean aortic blood pressure, heart rate, or regional myocardial blood flow as measured by radioactive microspheres. Measurements in arterial and coronary sinus blood demonstrated an increase in the extraction of glucose and a decrease in that of FFA by the heart. Glucose extraction also tended to be increased in the ischaemic zone, as shown by the differences in the concentrations of these substrates between arterial blood and blood obtained from the local vein draining that zone. Lactate release by the ischaemic zone was markedly reduced.


Effects of hypertension on the static mechanical properties and chemical composition of the rat aorta. The contributions of the relative radius, relative wall thickness, incremental strain, incremental elastic modulus, and medial scleroprotein content to the static elastic properties of the rat aortic wall have been examined in three groups of rats. Controls, rats made hypertensive at four weeks of age, and rats whose blood pressure was lowered after 6 weeks hypertension, were studied. The results show evidence of adaptive changes in the aorta of hypertensive animals, and that irreversible alterations in the mechanical properties of the wall may be induced by a brief period of hypertension. A direct relationship between aortic medial scleroprotein content and the elastic properties of the wall is demonstrated.


Time course of changes in ventricular fibrillation threshold in myocardial infarction: characteristics of acute and slow occlusion with respect to the collateral vessels of the heart. The time course of the changes in ventricular fibrillation threshold (VFT) was determined in 28 dogs by means of electrical stimulation, triggered from the R wave, with DC square wave pulse series (of 140 ms duration) inserted into the vulnerable period of the cardiac cycle. After acute coronary occlusion there was a sudden decrease in the VFT followed by a slow increase such that 30 min after the ligation pre-occlusion values of VFT were reached. The magnitude of the decrease in VFT depended upon the collateral blood supply. There were no other changes in VFT during the remaining course of the experiment. Following slow coronary occlusion the first arrhythmic phase was not detectable. Any decreases in VFT that occurred were smaller and of shorter duration than those occurring after acute occlusion and were independent of the extent of the collateral blood supply.


Alterations of the Frank orthogonal scalar leads induced by anaphylactic shock in the rabbit. The anaphylactic shock of the rabbit is characterized by an acute right ventricular overload, accompanied by severe alterations of cardiac electrogenesis. During shock, the mean QRS vector, as measured from the algebraic sum of the Q, R, and S deflections on the three leads, shifts to the right, inferiorly and anteriorly. An injury current quickly appears. The TQ vector points away from the right ventricle. A progressive depolarization on the right ventricular wall is displayed by suction electrodes and the suppression of right ventricular hypertension by a cross circulation produces an almost immediate disappearance of the injury current. The geneses of these electrical alterations are briefly discussed. The possibility of an anaphylactic reaction at the level of the coronary arterial wall, previously mentioned in the literature, seems unlikely. The role of the haemodynamic changes and of the increased right ventricular blood pool is thought to be predominant.


Influence of myocardial mechanical activity and coronary blood flow on myocardial digoxin uptake. The myocardial content of digoxin 60 min after intravenous administration in open-chest dogs correlated with heart rate controlled in individual dogs between 64 and 215 beats/min. In other dogs, increasing right ventricular mechanical work by constriction of the pulmonary artery resulted in greater right ventricular digoxin uptake. Increase in myocardial blood flow per se could not explain these findings since, in further dogs, increasing regional myocardial blood flow by adenosine infusion did not much affect digoxin uptake. Active uptake of cardiac glycosides is probably influenced by myocardial mechanical and metabolic activity.


Simultaneous measurement of cardiac output and its distribution with microspheres in the rat. The radioactive microsphere method was used to estimate simultaneoulsy the cardiac output and its distribution in the same rat by the use of an arterial reference sample obtained during microsphere distribution. Sufficient microspheres were injected so that all counted samples contained more than 400 spheres. No haemodynamic changes occurred during microsphere injection. The results for cardiac output of 253 +/- 11 ml/min per kg body weight agree with published estimates utilizing other techniques. The distribution of cardiac output also agrees with most published reports. This method should allow the rat to be conveniently used for certain haemodynamic studies when cardiac output and organ blood flow are necessary.


Measurement of regional myocardial blood flow in dogs using a catheter semiconductor radiation detector. Simultaneous total left coronary and regional myocardial blood flow were measured by injecting 85Kr into the left coronary artery and recording its clearance using a precordial gamma detector and a catheter tip beta detector (CASRAD) placed directly on selected regions of the myocardium. There were no significant differences between total left coronary (175 ml-100 g-1/min) measured by the precordial gamma detection and regional myocardial blood flow (183 ml-100 g-1/min) determined in the area of the left anterior descending coronary artery (LAD) by the beta detector in five open chest dogs. After ligation of the LAD regional clearance of 85Kr ceased in the area of myocardium distal to the ligation while total coronary blood flow decreased only slightly from 152 to 126 ml-100 g-1/min. Measurement of regional myocardial blood flow by CASRAD may be of value in determining the extent of myocardial ischaemia in experimental animals and assessing the effect of therapeutic interventions.


[Education in health sciences and medical care: analysis of their interrelations]. The article analyzes the systems of training and using manpower. It also points up the varied and complicated aspects of the interaction of the two systems. The author claims that the data he provides make it possible to analyze them in depth and to map out operational approaches and feasible action lines. He makes interesting suggestions about the points to be taken into account in designing a strategy for health manpower planning.


[Method for analyzing and estimating human resources for maternal and child care programs]. This report described the version of the Human Resources Analysis and Estimation Method (MAERH) that was specially devised for analyzing maternal and child health and family planning personnel (the MAERH/AMI/1 version). The general features of the method are presented and its ability to analyze health programs and to estimate the human resources needed is emphasized. In addition, the operation and use of the method, its advantages and short-comings, as well as its development and possible adaptation to wider-ranging or more specific problems are described. Finally, the results obtained in the maternal and child health area of the State of Pernambuco, Brazil, are presented to exemplify the use of the method.


[Distribution of physicians in Costa Rica]. This article provides detailed information on the location of medical practitioners of Costa Rica by rural and urban area and by province, further broken down by medical specialty and place of practice. The data were obtained from a survey made from 1967 through 1975. The authors emphasize the apparent close correlation between the development of health institutions, the characteristics of the health care given the population, and the level of economic development of a country.