Childhood pheochromocytoma: treatment with alpha methyl tyrosine for resistant hypertension. A 12-year-old boy with a norepinephrine-secreting pheochromocytoma that caused hypertension resistant to oral alpha adrenergic blockade is reported. Resistance to alpha adrenergic blocking agents developed when the patient's daily propranolol dosage was lowered from 10 to 1 mg/kg. Subsequently, alpha methyl tyrosine, an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, controlled the patient's blood pressure and was associated with reduction in total urinary catecholamine excretion. Norepinephrine content of the tumor and uninvolved adrenal gland removal at surgery was reduced. These findings confirm that alpha methyl tyrosine inhibited in vivo synthesis of catecholamines.


A syndrome of childhood polyarteritis.

A syndrome of childhood polyarteritis. In this report the clinical, laboratory, and histopathologic findings of nine children with polyarteritis are reviewed. All have had evidence of systemic involvement. Eight presented with fever, calf pain, erythematous painful nodules, and elevation of the acute-phase reactants. All were treated with prednisone at a dosage of 2 mg/kg/day. All of the children are alive but have had relapses at least once during the course of tapering the dosage of corticosteroids. Serious complications of disease have included myocardial infarction, hypertension, and impaired renal function.


Necrotizing arteritis in acute poststreptococcal glomerulonephritis: report of a recovered case. A patient with biopsy documented acute poststreptococcal glomerulonephritis and arteritis recovered completely with supportive therapy. Illness was preceded by group A streptococcal pharyngitis. At the time of presentation, serum creatinine concentration was 11.5 mg/dl. Serum cryoglobulins containing IgG and C3 were present. The first biopsy, performed during the acute illness, contained glomeruli with typical features of acute PSGN. Medium-sized arteries had extensive necrosis and leukocytic infiltration, and contained IgG, C3, and fibrin. Glomerular filtration rate returned to normal within three weeks; proteinuria cleared by three months, and microscopic hematuria by 11 months. Renal biopsy one year later showed minimal mesangial hypercellularity and no arteritis.


Studies in acid-base balance. I. Effect of alkali therapy in newborn dogs with mechanically fixed ventilation. The effect of rapid or slow infusion of hypertonic sodium bicarbonate on acid-base balance and serum osmolality was studied in 36 acidotic newborn dogs. Respiratory acidosis and hypoxia were produced by mechanically fixed hypoventilation. One group of animals breathed 100% O2 to prevent hypoxemia. Rapid infusion of HCO3- in acidotic and hypoxic animals resulted in only a transient (1 minute) and small (0.05 pH units) elevation of arterial pH followed by a continuous fall, resulting in a lower pH and a worsened metabolic condition than in the nontreated controls. In nonhypoxic acidotic animals, rapid infusion of HCO3- had little effect on arterial pH. PaCO2 increased suddenly by 17 Torr in hypoxic and, by 13 Torr, in nonhypoxic animals. There was a concomitant fall in PaO2 (15 Torr). Serum osmolality rose rapidly after rapid infusion of HCO3-. Rapid infusion of hypertonic bicarbonate into an animal or infant whose ventilation is fixed thus results in a less than predicted elevation of arterial pH. PaCO2 rises, PaO2 falls, and serum osmolality rises. The net result may be a worsening rather than an improvement in the animals' metabolic state.


Mullerian inhibiting substance in human testes after birth. Tiny testicular biopsies from humans were assayed for Mullerian inhibiting Substances using a graded organ culture technique. Mullerian Inhibiting Substance activity was high during the first year of life, declined during the second year of life, and then disappeared. Mullerian Inhibiting Substance activity is lower in boys with undescended testis than in children with normal or intersex testes at comparable ages under two years. It is possible that Mullerian Inhibiting Substance affects testicular descent as well as causing Mullerian duct regression.


Pharmaceutical suspensions: relation between zeta potential, sedimentation volume and suspension stability. The effect of added surface-active agents of various ionic types on the sedimentation volume of drug suspensions of betamethasone, griseofulvin, nalidixic acid and thiabendazole has been investigated, and the results correlated with previously measured zeta potentials. Study of the zeta potential/sedimentation volumes versus concentration plots showed that apparently only coagulated, deflocculated or sterically stabilized systems were formed. In most cases the sterically stabilized systems were produced from mixtures of ionic/non-ionic surfactants. These are examples of controlled coagulation, although non-ionic surfactant alone conferred stability against caking. Secondary minimum flocculation was not apparent but this may have been due to the method of examination of suspensions. The work confirmed that the DLVO theory of colloid stability and its modification to include a steric term can be applied to coarse suspension systems.


The in vitro bioavailability of various drugs formulated as hard gelatin capsules. A factorially designed experiment has been carried out to study the influence of various additives on the in vitro release of drug from hard gelatin capsules. Analysis of variance confirms previous findings that, although the main factors of diluent type, diluent concentration, the absence and presence of both magnesium stearate and sodium lauryl sulphate, were highly significant, the existence of interactions between the factors prevented exact quantitative prediction of the influence of each factor. There appears however, to be a strong indication that the in vitro drug release of capsule formulations (y), expressed as the % of the drug content of the capsule which dissolves, can be related to the solubility of the drug (cs) by the expression y = 21-2 log cs + 31.2.


Extraocular muscle transplantation.

Extraocular muscle transplantation. 1. The transplantation of extraocular homografts in dogs and humans has been described. 2. The extraocular muscle tissue transplanted remains viable, but loses its characteristics of muscle tissue during the period of the normal healing process following extraocular muscle surgery. 3. Autogenous homograft of extraocular muscle has an advantage over artificial synthetic material with the absence of extrusion and less reaction. 4. This is a clinically usable procedure today, especially in the amblyopic ehe with high deviation to accomplish an additional lengthening of one extraocular muscle, particularly if extraocular muscle surgery has previously been performed.


Phase equilibria and stability characteristics of chlorpropamide-urea solid dispersions. Physical mixtures and melts of various compositions of chlorpropamide and urea have been prepared. The phase diagrams and the effects of ageing of the systems have been measured by differential scanning calorimetry. The eutectic composition was found to contain 89% w/w chlorpropamide. Greater concentrations of chlorpropamide produced solid solutions of urea in chlorpropamide, whereas solid solution formation did not occur at compositions less than 89%. Melts in the range 50-100% chlorpropamide, which included the eutectic, existed as glass solids. The effect of ageing produced generally an increase in the liquidus peak temperature which was considered to be due to a gradual increase in crystal size.


Derivatization to stabilize some aliphatic primary hydroxylamines for g.l.c. analysis. By appropriate choice of trimethylsilylating and trifluoroacetylating reagents and organic solvents for extraction, stable derivative of aliphatic primary hydroxylamines metabolites, N-hydroxyphentermine, N-hydroxychlorphentermine, N-hydroxymexiletene, N-hydroxyphenethylamine, N-hydroxyamphetamine, and N-hydroxy-3,4-dimethoxyamphetamine, were obtained and examined by g.l.c. analysis without decomposition and without interference from the parent drug or other metabolic products.


Carrageenan and thrombin trigger prostaglandin synthetase-independent aggregation of rabbit platelets: inhibition by phospholipase A2 inhibitors. Acetylsalicylic acid, salicylic acid and indomethacin were equally effective in inhibiting aggregation of plasma-free rabbit platelets induced by carrageenan and by thrombin. In contrast, only acetylsalicylic acid and indomethacin suppressed the accompanying formation of prostaglandin-like activities. Blockade of aggregation required the presence of the inhibitors in the platelet preparation, whereas blockade of prostaglandin synthetase remained even when the inhibitors were washed out. Prostaglandin synthetase-derived  products appear not to be involved in the development of aggregation by carrageenan or by thrombin. Such aggregation was inhibited by two phospholipase A2 inhibitors, bromophenacyl bromide and mepacrine. It is suggested that carrageenan and thrombin-induced aggregation are mediated by non-prostaglandin, phospholipase A2-derived products.


The interaction between clonidine and various neuroleptic agents and some benzodiazepine tranquillizers. The central hypotensive action of clonidine, infused into the vertebral artery of chloralose-anaesthetized cats was antagonized by several phenothiazine-neuroleptics (chlorpromazine, promazine, promethazine, thiethylperazine, thioridazine), by chlorprothixene and to a limited extent by haloperidol administered via the same route. Pimozide and some benzodiazepines (chlordiazepoxide, diazepam and flurazepam) hardly influenced the central hypotensive response to clonidine. The antagonism between clonidine and the psychotropic drugs is probably associated with central alpha-adrenoceptors, clonidine being the agonist and the neuroleptic agents the antagonists at these receptors. Virtually the same type of antagonism was observed in conscious, spontaneously hypertensive rats where both clonidine and the neuroleptic drugs were injected intravenously. The phenothiazines and also piperoxane effectively diminished the centrally induced hypotensive response to clonidine, whereas the initial pressor effect to clonidine was not reduced.


The enkephalins and opiates: structure-activity relations. The X-ray structures of 9 "opiate" drugs which exhibit a range of pharmacological activity have been examined in detail leading to the theory that one of the reasons why the enkephalins and related peptides possess morphine-like activity is because they have a tyrosine, and hence a "tyramine", residue at the amino terminal position. This residue or a conformationally similar moiety, can be shown to be present in many opiates and analogues.


Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats. The elimination, distribution and anticoagulant activity of S(-)-, R(+)-, and R,S(+/-)- phenoprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0.6 mg kg-1. From the plasma concentrations which elicited the same anticoagulant effect, S(-)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocouman. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(-)-enantiomer was shorter (12-5 h) than that of R(+)-phenprocoumon (17-8 h). No differences were observed in the apparent volume of distribution. However, the mean liver:plasma concentration ratio was higher for the S(-)-(6-9) than for the R(+)-enantiomer (5-2). At a total concentration of 16-8 microgram ml-1 the percentage of unbound drug in rat serum was significantly higher for the S(-)- (1-13%) than that for the R(+)-enantiomer (0.76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(-)- over the R(+)-enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.


The effects of etilefrine on blood vessels in the rat tail. Etilefrine was found to constrict blood vessels in the rat tail through a mechanism which was partly dependent on the sympathetic nerves present in these vessels. The response to the drug was enhanced by pretreagment with noradrenaline and cocaine, and totally abolished by the alpha-receptor antagonist phentolamine. When compared with several other sympathomimetic agents which were tested on the vessel, etilefrine appeared to have a low order of vasoconstrictor activity. These findings would seem to have considerable relevance to the clinical situation where an attempt has been made to use etilefrine in the treatment of patients with orthostatic hypotension.


The effects of prostaglandins E1, E2, F1alpha and  F2alpha on guinea-pig ileal and colonic peristalis. Prostaglandins (PGE1, E2, F1alpha and F2alpha) have been tested on the peristaltic reflex in isolated segments of guinea-pig ileum and colon using simultaneous recordings of fluid propulsion and longitudinal and circular muscle activity. Propulsion and circular muscle peristaltic activity were increased by serosally applied PGF compounds in the ileum and PGE or PGF compounds in the colon following initial contraction of the longitudinal muscle. This is consistent with a role for prostaglandins in peristalsis. Mucosally applied PGF compounds has no significant effect.


The identification and analysis of mexiletine and its metabolic products in man. Sensitive and specific gas-liquid chromatographic methods were developed for the analysis of mexiletine and its metabolites in urine of man. The identity of the g.l.c. peaks was established by mass-spectrometry. The hydroxylamine (Va) was qualitatively identified and determined quantitatively after conversion to the more stable oxime (Vb). Selective extraction procedures, t.l.c. and derivatization with hexamethyldisilazane (HMDS) and trifluoroacetic anhydride (TFA) were used in the qualitative identification of the major metabolites (VI-IX), particularly in distinguishing the basic products VI and VII from their corresponding alcoholic products VIII and IX. The limit of detection of the g.l.c. method was 6 to 12 ng ml-1 for compounds I-IV, and 40 to 50 ng ml-1 for compounds Vb-IX.


The decomposition of acidic and neutral cannabinoids in organic solvents. High-pressure liquid chromatography was used to study (a) the relative efficiencies of methanol, chloroform, light petroleum (B.P. 40-60 degrees) and methanol-chloroform (9:1) for extracting neutral and acidic cannabinoids from cannabis resin; (b) the decomposition patterns of the resulting solutions under various storage conditions, and (c) the cannabinoid profile of a cross section through a block of cannabis resin. The results show that (a) methanol is the most effective extracting solvent of those tested; (b) acidic cannabinoids in solution decompose in darkness by varying amounts depending on the temperature, solvent, storage time and particular cannabinoid; (c) neutral cannabinoids in solution are relatively stable in darkness; (d) daylight causes appreciable decomposition of both acidic and neutral cannabinoids in solution, (e) the cannabinoid profile of a resin is complex with lower levels of acidic material in the outer layers.


Application of orthogonal functions to the spectrophotometric determination of phenytoin in pharmaceutical preparations. A simple ultraviolet spectrophotometric method for the determination of phenytoin in pharmaceutical preparations has been developed. The mean was 100.9% (6 determinations) and the coefficient of variation was 1.2%. The method was applied successfully to the determination of phenytoin in capsules and suspensions.


The influence of additives on the presentation of a drug in hard gelatin capsules. The influence of the concentration of lactose, magnesium stearate and sodium lauryl sulphate in the in vitro dissolution and the drug content of hard gelatin capsules filled under conditions which result in  a maximum tapped bulk density, has been evaluated by a factorially-designed experiment. The 3 factors have a significant effect on both drug release and capsule filling. Interactions between the 3 factors, however, limit the exact quantification of the magnitude of their influence by a simple linear model. A quadratic relation, when only 2 factors are considered, can be used to provide a prediction of the influence of these factors. The relations between 2 factors are demonstrated as contours of equal in vitro drug release and equal drug content of capsule, at constant concentrations of the third factor. The contours show the important influence of lactose concentration  drug release and capsule filling, and the large changes in response which can occur by the addition of a third factor. They also provide a clear guide to the formulation of hard gelatin capsules.


The distribution of components in the different size fractions of granules prepared from binary mixtures. Boric acid, sulphanilamide and citric acid have been mixed separately with lactose and then granulated by massing and screening. The granules have been fractionated by sieving and each fraction has been analysed for lactose content. The effect of premixing time, massing time, binder volume and ratio of components on the distribution of lactose between size fractions of granules prepared from lactose: boric acid mixtures has been investigated. Uneven distribution of lactose has been found for all blends examined. There is a premixing time and massing time that gives the optimum distribution of lactose for any given blend and binder volume. Increased binder volume in some cases improves granule uniformity. The proportion of lactose in the blend has a major effect on the distribution of this component in the granules, as does the particle size of the lactose. Granules prepared from blends of lactose with sulphanilamide and with citric acid were also examined for lactose distribution.


Desensitization to portrayals of real-life aggression as a function of exposure to television violence. In two separate experiments, the hypothesis that exposure to violence in the context of television drama decreases subjects' emotional responsivity to portrayals of real-life aggression was tested. Subjects were shown either an excerpt from a violent police drama or a segment of an exciting but nonviolent volley-ball game before watching a videotaped scene of real aggression. Emotionality was measured by changes in skin resistance which was measured continuously throughout the session. In Experiment 1, subjects were 8- to 10-year-old children and the real aggression was a film of an argument and fight between two preschoolers. In Experiment 2, college students participated and reactions to real aggression were measured while subjects watched scenes from news films of the riots at the 1968 Democratic National Convention. With the exception of adult females, subjects who previously had viewed the aggression drama were less aroused by the scenes of real aggression than were subjects who had seen the control film. Further support for the hypothesis was provided by the finding that for most groups of subjects, the amount of television violence normally viewed was negatively related to responsivity while viewing aggression.


Determination of aqueous solubility and pKa values of estrogens. Reported estrone pKa and solubility data show wide variation. Improved experimental procedures were designed and used to obtain reproducible results. The pKa values for several estrogens and related compounds also were determined to assess the effects of structural differences on ionization. No evidence was obtained for long-range D to A ring electronic transmission affecting pKa. Significant differences in pKa values resulted only when conjugated unsaturation was added into the B ring of estrone or estradiol. The aqueous solubilities of estrone and 17alpha-estradiol were 0.8 and 3.9 microgram/ml, respectively, at 25degrees.


Acetylacroninium salts as soluble prodrugs of the antineoplastic agent acronine. The low aqueous solubility of acronine (approximately 2 mg/liter) has been overcome by identification of quaternary prodrug salts exhibiting apparent molar solubilities two to five orders of magnitude greater than acronine. The synthesis and kinetics of hydrolysis of the various prodrug acetylacroninium salts were studied, and the half-life for hydrolysis under conditions approximating the in vivo situation was estimated to be about 5 min. Such rapid reversion, together with the greatly increased solubility, appears to qualify the prodrug for intravenous use.


Microencapsulation of phenobarbital by spray polycondensation. A new method for the microencapsulation of solids is described. It is based on the polycondensation of amphiphilic and, thus, tensioactive precondensates on a melamine-formaldehyde base on the surface of suspended particles during spray drying. A film-forming agent, preferably one that reacts chemically with the resin, is indispensable for spray drying and also for the formation of an efficient membrane around the drug particles. The resulting microcapsules are essentially spherical and have, after appropriate curing, a sustained-release effect in vitro. The factors that most influence the formation and properties of the microcapsules are the composition (qualitative and quantitative), pH, and viscosity of the suspension.


Quantitative analysis of degradation products in pilocarpine hydrochloride ophthalmic formulations. The presence of isopilocarpine, an epimer of pilocarpine, and of pilocarpinic acid, a hydrolytic degradation product of pilocarpine, was established and all three substances were assayed in various commercial ophthalmic formulations of pilocarpine hydrochloride by 13C-Fourier transform spectroscopy. Assay was based upon integrated intensities of selected resonances from any formulation calibrated against the intensity of tetramethylammonium bromide, used as a common external reference. The normalized intensities were then related to those of a reference solution of pilocarpine hydrochloride, thereby eliminating any factor arising from variability of 13C-relaxation times. The 13C-resonance for the N-methyl group, being common to all products, provides a convenient basis for the assay of the total alkaloid content whereas the C-8 resonances are best suited for assaying residual pilocarpine and its degradation products. This procedure, estimated as accurate to +/- 5%, constitutes the first comprehensive analytical method to differentiate between pilocarpine and its degradation products.


Determination of meclizine hydrochloride by ion-pair extraction with methyl orange. A method, based on ion-pair extraction, is described for the quantification of meclizine hydrochloride in various pharmaceutical dosage forms, for content uniformity determination, and for concentration monitoring in dissolution and bioavailability studies. Methyl orange, dissolved in pH 2.8 MacIlvaine buffer, gave excellent recovery of meclizine after its isolation from aqueous solutions of gelatin, urine, and blood serum. The chloroform-extracted molecular species appeared to be a 1:1  ion-pair. Beer's law was obeyed for a wide concentration range. Because the extracted species seemed well defined and stable and since a surface or an interphase adsorption phenomenon was not a problem, the reported method is considered sensitive, accurate, precise, rapid, and simple.


Recording pH method of characterizing composition and monitoring dissolution profile of an anhydride-acid copolymer and its salt derivatives. A sensitive potentiometric monitoring method was developed that permits the continuous measurement of the disolution profiles of methyl vinyl ether-maleic anhydride-acid copolymers and salt derivatives. Three distinct rate periods were observed in the dissolution rate of the anhydride copolymer, expressed as percent anhydride dissolved, was independent of sample weight over the weight range studied. The acid form of the copolymer showed only one dissolution rate period, with dissolution being very rapid. The rapid initial pH decrease observed during the first stage of dissolution for a series of anhydride-acid copolymer powder samples correlated closely with the anhydride-acid ratio, permitting chemical characterization of the copolymer functionality simultaneously with the analysis of dissolution profiles. Similarly, the extent of copolymer alkaline salt conversion was inversely proportional to the initial maximum pH increase observed during the first stage of dissolution of these salts. Mechanisms of dissolution of copolymer powder materials are discussed and compared to the dissolution of compressed disks and films reported previously.


Systems approach to vaginal delivery of drugs IV: methodology for determination of membrane surface pH. A physical model including a diffusional layer in series with the membrane was developed for studying the possible differences between the pH at the membrane surface and that in the bulk solution. Both the membrane-secreted substances (acids and bases) and buffer constituents in the bulk solutions are assumed to contribute to the surface pH. Equations derived for this situation, together with experimental determinations of the acidic dissociation constant of the secreted material, the total secretion flux, the flux of total secreted acidic species, and the diffusion layer thickness, allow estimates to be made of the pH at the membrane surface. With the rabbit vagina, the membrane surface pH was close to that of the bulk solution in most cases. These results were supported by the fact that the absorption of 1-alkanoic acids in pH 2.2 phosphate buffers was relatively constant over the buffer concentration range of 0.003-0.1 M phosphate.


Systems approach to vaginal delivery of drugs V: in situ vaginal absorption of 1-alkanoic acids. The vaginal absorption of a homologous series of ionizable compounds, the 1-alkanoic acids, was studied using a perfusion method with a rib-cage cell surgically implanted in the rabbit vagina. The absorption rates of these compounds followed first-order kinetics. The physical model previously used for the 1-alkanols, but accounting for the pKa and pH effects in the present case was employed in the analysis of the carboxylic acid data. The aqueous diffusion layer thickness was 0.031 cm. The permeability coefficient for the lipoidal pathway increased 3.5-fold per methylene group. Both values agree reasonably well with those obtained in the alcohol study.


Kinetics and mechanisms of hydrolysis of 1,4-benzodiazepines III: nitrazepam. The hydrolysis of nitrazepam involves a two-step sequential mechanism. The intermediate is the ring-opened compound resulting from scission of the azomethine bond. The final products are glycine and 2-amino-5-ni-robenzophenone. Recyclization of the intermediate to nitrazepam occurs at pH values above the pKa of the intermediate, in the pH region where the amino group of the intermediate is not protonated. As opposed to chlordiazepoxide and oxazepam, the initial hydrolysis step occurs at the 4,5-bond, not at the 1,2-amide linkage. This difference is attributed to a preferential activation for hydrolysis of the azomethine linkage by the nitro group. The hydrolysis involves an uncatalyzed reaction, specific acid-base catalysis, and general acid-base catalysis for acetate and phosphate buffers.


UV spectrophotometric determination of aminophylline, amobarbital, and ephedrine hydrochloride in an antiasthma capsule preparation. A simple and rapid procedure for the determination of aminophylline, amobarbital, and ephedrine hydrochloride in a capsule preparation is described. Aminophylline and amobarbital are determined simultaneously using differential UV spectrophotometry; ephedrine hydrochloride is determined separately after elution from an alginic acid column with 0.1 N hydrochloric acid.


Stability of aqueous solutions of pirbuterol. The hydrolytic degradation of pirbuterol was investigated under saturated oxygen conditions over a wide range of pH values and at different temperatures. Two of the five observed breakdown products were positively identified. The first-order decomposition rate appeared to depend on the rate constants of the four dissociated ionic species. The most stable region for the drug was pH 1-2, where the diprotonated molecule predominated; appropriate thermodynamic parameters were calculated.


Micellar distribution equilibria: ultracentrifugal study of apparent partition coefficients. Ultracentrifugation was used for the partial isolation of polysorbate 80 micelles in aqueous media to determine the apparent partition coefficients of various drug species between water and the micellar pseudophase. The ratio of solute concentration in the micelles to that in water was measured for procaine, salicylic acid, sulfapyridine, sulfisoxazole, and sodium 2-naphthalensulfonate over ranges of pH, surfactant concentration, drug concentration, and micelle sedimentation. Apparent partition coefficients for the systems investigated were independent of both drug concentration and surfactant concentration, indicating that the mode(s) of surfactant-drug interaction are essentially invariant over the ranges of systematic variables studied. The method provides a relatively simple and rapid means of quantitatively evaluating drug-surfactant interactions above the CMC, when surfactant and solute can be assayed in mixtures without interference.


Physicochemical properties of beta-lactam antibacterials: deuterium solvent isotope effect on penicillin G degradation rate. To obtain kinetic evidence on the degradation mechanism of penicillin in aqueous solution, degradation rates of penicillin G in water and deuterium oxide were measured in the pH (pD) range of 4-10. The solvent isotope effect (kH2O/kD2O) of 1.53 below pH (pD) 6 supports the mechanism of water-catalyzed rearrangement of undissociated penicillin G to benzylpenicillenic acid. The spontaneous degradation at neutral pH (pD) and the hydroxide-ion-catalyzed degradation in the alkaline pH (pD) range progress with a deuterium solvent isotope effect (kH2O/kD2O) of 4.5 and 0.59, respectively. This finding indicates the mechanisms of general base-catalyzed hydrolysis by water in the neutral pH range and of nucleophilic attack of the hydroxide ion on the beta-lactam in the alkaline pH range. No significant side-chain dependency was observed in the reaction of penicillins with bases. The solvent isotope studies led to the conclusion that penicillin degradation is catalyzed by a series of bases via general base-catalyzed and nucleophilic mechanisms, depending on their basicity.


GI pharmacology of polyethyleneimine II: motor activity in anesthetized dogs. The effects of orally and intravenously administered doses of polyethyleneimine were observed in 18 chloralose-urethan-anesthetized dogs. Polyethyleneimine produced an initial augmentation of rhythmic segmenting gastric antral contractions, a copious flow of gastric mucus, increased segmenting and propulsive activities of the small and large intestines, and occasional micturition and defecation. The gastric corpus and fundic regions became relaxed and enlarged. These events were associated with the prompt appearance of retching. The retching response to oral administration could only be abolished by bilateral vagotomy or bilateral sympathectomy. The skeletal muscle component of retching was blocked by tubocurarine. Intravenous administration of chlorpromazine blocked the retching response and gastric corporal atonia to either intravenous or oral doses of polyethyleneimine. Either oral or intravenous administration of polyethyleneimine produced no detectable changes in the lead II ECG but was associated with marked transient reductions in both mean and pulsatile arterial blood pressures. These depressor effects showed clear tachyphylaxis. In all cases where GI effects were noted, respiration was augmented and erratic in a manner associated with the retching responses.


Association of in vivo and in vitro propranolol levels in canine Purkinje fibers with antiarrhythmic effects. This study has determined the propranolol content of Purkinje fibers associated with antiarrhythmic and electrophysiological actions of the drug both in vivo and in vitro. The minimum effective tissue content of propranolol that consistently reversed a sustained ouabain-induced ventrivular tachycardia in vivo after i.v. propranolol was between 6.7 and 11.1 micron g/g of tissue. Propranolol doses producing Purkinje fiber contents of less than 6.7 micron g/g failed to revert the arrhythmia but did ponotropic responses to 0.5 micron g/kg of isoproterenol. The in vivo minimum effective tissue content was produced in isolated Purkinje fibers perfused with Tyrode's solution containing 1.7 X 10(-6) M propranolol. In Purkinje fibers this concentration of propranolol depressed the rate of phase 4 depolarization previously enhanced by ouabain 2.1 X 10(-7) M. Propranolol, 1.7 X 10(-6) M, did not alter membrane responsiveness and only slightly accelerated repolarization at 5 minutes. Propranolol, 0.85 X 10(-6) M, did not significantly depress the ouabain-enhanced rate of phase 4 depolarization but did attenuate the response to epinephrine through beta blockade. This study indicated that the initial direct action of propranolol in reverting a ouabain-induced ventricular tachycardia to a sinus rhythm in the dog is depression of automaticity.


Detection of light-induced changes of intracellular ionized calcium concentration in Limulus ventral photoreceptors using arsenazo III. 1. The metallochromic indicator dye, arsenazo III, was injected intracellularly into Limulus ventral photoreceptor cells to concentrations greater than 1 mM.2. The absorption spectrum (450-750 nm) of the dye in single dark-adapted cells was measured by a scanning microspectrophotometer. When a cell was light-adapted, the absorption of the dye changed; the difference spectrum had two maxima at about 610 and 660 nm, a broad minimum at about 540 nm and an isosbestic point at about 585 nm.3. When intracellular calcium concentration was raised in dark-adapted cells previously injected with arsenazo III, the difference spectum had two maxima at about 610 and 660 nm, a broad minimum at about 530 nm and an isosbestic point at about 585 nm. The injection of Mg(2+) into dark-adapted cells previously injected with the dye induced a difference spectrum that had a single maximum at about 620 nm. Also, decreasing the intracellular pH of cells previously injected with the dye induced a difference spectrum that had a minimum at about 620 nm. The evidence suggests that there is a rise of intracellular ionized calcium when a Limulus ventral photoreceptor is light-adapted.4. The intracellular calcium concentration, [Ca(2+)](1), in light-adapted photoreceptors was estimated to reach at least 10(-4)M by compaing the light-induced difference spectra measured in ventral photoreceptors with a standard curve determined in microcuvettes containing 2mM arsenazo III in 400 mM-KCl, 1 mM-MgCl(2) and 25 mM MOPS at pH 7.0.5. In cells injected to less than 3 mM arsenazo III, light induced a transient decrease in optical transmission at 660 nm (T(660)). This decrease in T(660) indicates that illumination of a ventral photoreceptor normally causes a transient increase of [Ca(2+)](1).6. Arsenazo III was found to be sensitive, selective and rapid enough to measure light-induced changes of intracellular ionized calcium in Limulus ventral photoreceptor cells.


Regulation of cerebrospinal fluid bicarbonate by the cat choroid plexus. 1. The regulation of cerebrospinal fluid (c.s.f.) bicarbonate concentration was studied using the cat choroid plexus isolated in a chamber in situ. 2. Decreases in plasma bicarbonate concentration caused relatively small changes in the c.s.f. bicarbonate concentration. 3. Alterations in c.s.f. bicarbonate concentration (c.s.f. HCO3-=9 or 28 m-equiv/l.) were countered by changes in the bicarbonate concentration of the fluid produced by the plexus or in the rate of bicarbonate transport which returned c.s.f. bicarbonate towards normal. 4. There was significant regulation of pH in the choroid plexus fluid during hypocapnia and hypercapnia. 5. Alterations of plasma acid-base status did not significantly alter the potential difference across the choroid plexus. However, the potential difference increased when c.s.f. bicarbonate was increased and decreased when c.s.f. bicarbonate was decreased. 6. The data indicate that the bicarbonate concentration in the c.s.f. is actively regulated by the choroid plexus during acid-base disturbances occurring either systemically or in the c.s.f.


Surface potential reflected in both gating and permeation mechanisms of sodium and calcium channels of the tunicate egg cell membrane. 1. Threshold changes of Na and Ca currents due to various polyvalent cations (stabilizing cations) or H(+) ions were studied in the egg cell membrane of a tunicate, Halocynthia roretzi, by using the voltage-clamp technique.2. With an increase in [Ca](o) or a decrease in pH in the external solution, the current-voltage (I-V) relations for the peak of the Na and Ca currents shifted along the voltage axis in the positive direction. These voltage shifts in the I-V relations, measured at a potential of V((1/2)) where inward current attains its half-maximum, were shown to be identical to shifts in voltage-dependence of the time courses of Na and Ca currents, and also identical to shifts in the inactivation curves of Na current along the voltage axis.3. The shifts in V((1/2)) produced by various polyvalent cations or H(+) ions were analysed by the Gouy-Chapman equation for the diffuse double layer, by assuming that a change in V((1/2)) directly corresponds to a change in the surface double layer potential.4. The V((1/2))-divalent cation concentration relations of Na current were exactly described by the predictions of the theory with a constant value of the surface charge density of 1e(-)/(9 A)(2). The weak stabilizing effects of Mg(2+), Sr(2+) and Ba(2+) were quite similar to each other and were explained in terms of a ;screening' effect. Other divalent cations, such as Ca(2+), Mn(2+) and Ni(2+), showed various different stabilizing effects which were explained in terms of a ;binding' effect. The binding constants (K(1)'s) for Ca(2+), Mn(2+) and Ni(2+) were 0.21, 0.45 and 0.94 M(-1), respectively.5. H(+) ions showed a powerful stabilizing effect upon the Na current with a K(H) of 6 x 10(4)M(-1). This value indicates that the acidic sites around Na channels have a pK(a) of 4.78. La(3+) ions also acted as a strong stabilizer upon the Na current with a K(La) of 15 M(-1). For both H(+) and La(3+), the V((1/2))-concentration relations were also exactly described by the Gouy-Chapman equation with the same charge density of 1e(-)/(9 A)(2) as estimated by varying divalent cations.6. The stabilizing effect of permeant cations such as Ca(2+), Sr(2+) and Ba(2+) on Ca channel currents was analysed. The effect of lowering pH was also studied. It was found that the surface charge density of 1e(-)/(9 A)(2) estimated by Na current is also applicable to the explanation for the V((1/2))-divalent cation concentration or - pH relationships. The estimated binding constants for H(+), Ca(2+) and Sr(2+) were 1.2x10(5), 0.58 and 0.035 M(-1), respectively. Ba(2+) does not bind to charged sites near to the Ca channels.7. It was noticed that a considerable reduction in the conductances of Na and Ca currents occurred in parallel with a stabilizing effect. This reduction was ascribed to a decrease in the concentration of permeant cations at the external surface of the cell membrane, as predicted by the theory of the diffuse double layer. The Goldman, Hodgkin-Katz equation for ionic currents was applied to explain the conductance suppression.8. The conductance suppressions of Na and Ca channel currents due to Ca(2+), Sr(2+) and Ba(2+) were found to be apparent ones, only reflecting decreases in the surface concentration of permeant cations without any changes in the permeability. After correction for the apparent suppression, the real permeability ratio among Ca(2+), Sr(2+) and Ba(2+) for Ca channels was determined as 1.00, 0.56 and 0.21 respectively.9. The conductance suppression of Na current by lowering pH was explained in terms of a real suppression or blocking which is superimposed on the apparent suppression. Considering the surface [Na](o), the plot of P(Na) against the surface pH yielded a blocking curve of Na channel by H(+) ions, which implies that two H(+) ions are necessary to block each Na channel. For Ca channels no real blockage was observed in acidic pH.10. It was concluded from the present experiment that there exists a surface potential capable of affecting both gating and permeation mechanisms of ionic channels in this tunicate egg cell membrane.


Effects of prostaglandin antagonism on sodium arachidonate fever in rabbits. 1. Sodium arachidonate, the prostaglandin precursor substance, when injected intraventricularly into rabbits, results in dose-dependent hyperthermia, which is rapid in onset and of several hours duration. 2. Arachidonate fever was inhibited by intraventricular injection of indomethacin, but not by the simultaneous intraventricular injection of either of the two prostaglandin antagonists SC 19220 or HR 546. 3. Both antagonists effectively inhibited the fever induced by the intraventricular injection of an equipotent dose of PGE1. 4. Our results show that a derivative of arachidonic acid other than prostaglandin is pyrogenic.


Kinetics of luminal acidification in cortical tubules of the rat kidney. 1. Some kinetic aspects of renal tubular acidification were studied in proximal and distal tubules of the rat kidney by combining stationary microperfusion methods and continuous measurements of luminal pH changes of phosphate or bicarbonate buffers by means of antimony electrodes. The analysis included the measurement of steady-state pH, steady-state buffer concentrations and acidification half-times. From these data, net rates of tubular bicarbonate reabsorption and of H ion secretion were obtained since it was shown that the rate of phosphate  acidification provides a realistic estimate of H ion secretion. 2. Experiments were performed in control rats, in animals undergoing metabolic acidosis or alkalosis and in control and acidotic rats receiving the carbonic anydrase inhibitor Diamox. 3. In all experiments, the rates of tubular bicarbonate reabsorption and of phosphate acidification (H ion secretion) were proportional to luminal buffer levels. The changes of luminal acid concentrations followed first-order kinetics. 4. Steady-state transepithelial pH differences were reduced in metabolic alkalosis and after diamox but augmented during metabolic acidosis. 5. Acidification half-times were prolonged in metabolic acidosis and after Diamox but remained similar to control levels in metabolic alkalosis. 6. From the observation that both bicarbonate reabsorption and phosphate acidification are similarly affected by these experimental manoeuvres, it is concluded that H ion secretion plays a key role in both transport processes.


Mechansims and components of renal tubular acidification. 1. Renal cortical tubules of control and acetazolamide infused rats were perfused with 100 mM phosphate buffer at pH 5-5. The rate of alkalinization was measured by means of antimony micro-electrodes and was used to compute passive H ion fluxes from lumen to blood across the proximal and distal tubular epithelium. 2. The importance of other ionic movements that might contribute to pH changes of luminal buffers (chloride inflow into the lumen and bicarbonate diffusion across the epithelium) was assessed but found to be minor. H ion movements accounted for the majority of the observed pH changes. 3. H ion permeability of the tubular wall was calculated from the measured H fluxes and transepithelial concentration differences. It was 1-10 cm/sec, several orders of magnitude larger than those for other ions. However, such values are compatible with the mobility of protons in a medium of structure water within the limiting membrane. 4. A kinetic analysis of the mechanism of movement of H ions across the renal tubule is presented on the basis of experiments in which acidification and alkalinization of luminal buffers was followed in stationary microperfusions. The data are compatible with a pump-leak system in the proximal tubule, and with a model with low H ion permeability and a gradient dependent pump in the distal tubule.


A mathematical model for counter-current multiplications in the swim-bladder. 1. A computer model for swim-bladder gas filling has been developed. Phenomenological descriptions of the Root effect (pH-dependent O2 capacity of fish haemoglobin), of the lactic acid production in the gas gland and of the geometry of the rete mirabile are incorporated in the general counter-current equations to give a comprehensive model of gas filling. 2. It is known that pH along the rete is not constant, as supposed in an earlier gas-filling model. It is also known that the Root shift reaction has a different half-time model. It is also known that the Root shift reaction has a different half-time depending on whether the haemoglobin absorbs or releases O2. These particular effects are accounted for in the present model. 3. The model gives gas filling rate and maximum swim-bladder pressure for CO2, O2 and N2. The partial pressure of these gases as well as the concentration of lactic acid and the pH along the rete are also calculated. 4. The model reproduces quite accurately experimental values for gas-filling rate in eel, together with lactic acid, CO2 and O2 concentrations measured at the rete end-points. There is also good correlation between maximum predicted stable swim-bladder pressure and maximum recorded depth for four fishes investigated (r=0-937; P=0-06). 5. The model predicts an enhancement of O2 filling rate and maximum swim-bladder pressure of at least 4 when the reaction rates of the Root shift in eel haemoglobin are 0-2 sec (Root-off) and 10 sec (Root-on), as compared to an instantaneous Root shift. 6. With a swim-bladder pressure of 1 atm and Root-shift reaction rates of equal magnitude, the po2-profile along the rete is nearly linear. When the reaction rates are such as found experimentally in eel haemoglobin, the po2 along the rete is non-linear, with a maximum of approximately 2 atm near the bladder pole of the rete. An experimental verification of this maximum will constitute a crucial test of the model. 7. The calculations show that blood flow through rete can regulate both gas-filling rate and stable swim-bladder pressure. At high pressure, the main factor limiting gas filling is loss of gas through back diffusion along the rete. 8. Maximum po2 in the swim-bladder is highly dependent upon the Root effect. If the Root effect persists up to about 100 atm, as seems to be the case blue hake, maximum po2 is more than 200 atm. When the Root effect is abolished at 10 atm, as is expected in eel, the maximum po2 drops to about 30 atm. 9. The pN2 in the bladder can reach 10-15 atm depending on blood flow, whereas PCO2 will not exceed 1 atm.


Contraction and recovery of living muscles studies by 31P nuclear magnetic resonance. 1. Phosphorus nuclear magnetic resonance ((31)P NMR) can be used to measure the concentrations of phosphorus-containing metabolites within living tissue. We have developed methods for maintaining muscles in physiological condition, stimulating them and recording tension while at the same time accumulating their (31)P NMR spectra. Experiments were performed on frog sartorii and frog and toad gastrocnemii at 4 degrees C.2. The NMR signals from (31)P (the naturally occurring phosphorus) is weak, and signal averaging is required. In order to follow the time course of reactions it is necessary to maintain the muscles in a steady state for many hours while they are undergoing repeated contractions. Signals were accumulated in separate computer bins according to time after initiation of contraction. By these means spectra were obtained which corresponded to the different intervals during the contraction and recovery cycle.3. In the absence of stimulation, the spectra of frog sartorius muscles and of their extracts indicated concentrations of adenosine triphosphate (ATP), phosphoryl creatine (PCr), inorganic orthophosphate (P(i)) and sugar phosphates (sugar P) which are in reasonable agreement with the values obtained by chemical analysis.4. We have confirmed that unidentified resonances representing unknown compounds appear in the spectra of both frog and toad muscle; one of these is much larger in spectra from toad than from frog. We have found an additional small, unidentified resonance which appears to be specific to toad muscle.5. Spectra accumulated during actual contractions (1 s tetani every 2 min) did not differ dramatically from those accumulated throughout the 2 min cycle of contraction and partial recovery.6. Following 25 s tetanii, approximately 20% of the PCr had been hydrolysed; it was then rebuilt exponentially with a half-time of about 10 min. The increase in [P(i)] immediately after contraction and the time course of its disappearance corresponded to the changes in [PCr]. During the later half of the recovery period the concentration of P(i) was reduced to below that in resting muscle. The [sugar P] remained very high ( approximately 4 mmol kg(-1)) throughout the 56 min interval between contractions.7. When frog sartorii were tetanized for 1 s every 2 min, the changes in [PCr] and [P(i)] between contractions could not be observed because too little signal was obtained from these small muscles. However, when toad gastrocnemii were similarly stimulated, the changes in these compounds could be readily detected and were even greater than expected.8. The position of the P(i) resonance can be used to monitor intracellular pH and changes in pH. Under the conditions of our experiments the average intracellular pH in unstimulated frog sartorius muscles was 7.5. After a 25 s tetanus this was observed to move in the acid direction by a few tenths of a pH unit and to return to its pre-stimulation value before the end of the recovery period. After a 1 s contraction of toad gastrocnemius the environment of P(i) became slightly more alkaline for the first few seconds.


Micro-electrode measurement of the intracellular pH and buffering power of mouse soleus muscle fibres. 1. The intracellular pH (pHi) of surface fibres of the mouse soleus muscle has been measured in vitro using recessed-tip pH-sensitive microelectrodes. 2. In 5% CO2 and pH 7-40, the mean pHi was 7-07 +/- 0-007 (S.E. of mean) at 37 degrees C and 7-23 +/- 0-01 at 28 degrees C. The difference between these tow values is the same as the change in neutral pH between 37 and 28 degrees C. 3. Alteration of the CO2 level at constant external pH caused a biphasic change in pHi with a rapid displacement followed by a slower partial recovery. Because the recovery was incomplete, different stable pHi values were recorded at different CO2 levels, the higher the CO2 the lower the pHi. The differences in pHi were highly significant both at 37 and 28 degrees C. 4. Alteration of the CO2 level at constant external pH also changed the membrane potential (Em), an increase in CO2 leading to an increased Em. The dependence of Em on the CO2 level was much smaller in the fast-twitch muscle, extensor digitorum longus, than in soleus. 5. Changing external pH, either by alteration of the bicarbonate or CO2 level of the Ringer solution, caused pHi to change by a mean 38-7% of the external pH change. The change in pHi was accomplished about 10 times more rapidly, and in the same direction, by altering CO2 than by altering the bicarbonate. 6. Application of external NH3 and NH+4 caused a rapid intracellular alkalinization followed by a slower acidification. On removal of external NH3 and NH+4, there was a large and rapid acdification, followed by a fairly rapid recovery in pHi. 7. The size of the pHi changes occurring on alteration of the CO2 level at both constant external pH and constant external bicarbonate, and on removal of external NH3 and NH+4, suggests a non-CO2 buffering power of 45m-equiv H+ ions/pH unit per litre and a constant-CO2 buffering power of 58 m-equiv H+ ions/pH unit per litre. The buffering power was apparently unaffected by a change in temperature between 37 and 28 degrees C. 8. It was concluded that H+ ions are not passively distributed across the muscle cell membrane, and that the pHi is closely controlled by the active transport of H+, OH- or HCO-3 ions.


The effect of temperature on the potential difference and input resistance of rat seminiferous tubules. 1. The p.d. of rat seminiferous tubules was 5.86 +/- 0.15 mV, lumen negative, at 33 degrees C and varied linearly with temperature between 24 and 37 degrees C, exhibiting an apparent Q(10) (25-35 degrees C) of 2.0 with a slope of 0.43 mV/ degrees C. Exposing testes to a temperature of 37-43 degrees C resulted in an initial hyperpolarization followed by depolarization of the tubules. These changes were more rapid in testes exposed to 41-43 degrees C than in testes exposed to 37-39 degrees C.2. The R(in) of seminiferous tubules was 198 +/- 7.8 kOmega at a testis temperature of 33 degrees C. The R(in) decreased when testes were maintained at 37 and 41 degrees C, the rate of decrease being similar to the rate of depolarization.3. Exposing testes to deep body temperature by unilateral surgical cryptorchidism caused a reduction of 30 and 64% in tubular p.d. and R(in) respectively when measured 24 hr after surgery. Exposure to deep body temperature for up to 4 days did not cause any further change in either parameter.4. There was no evidence that lanthanum penetrated through the Sertoli cell tight junctions after exposing testes to 41 degrees C for up to 30 min.5. The results indicate that the seminiferous tubule p.d. is maintained by a temperature-sensitive, cellular mechanism. Exposing testes to deep body temperature or above depolarized the tubules and increased their permeability.


Hyperpolarizing effects of dopamine on chemoreceptor nerve endings from cat and rabbit carotid bodies in vitro. 1. The effects of dopamine on DC potential changes recorded from the carotid sinus nerve were studied in vitro using carotid bodies and associated sinus nerves removed from anaesthetized cats and rabbits.2. The carotid body was placed in one compartment of a superfusion chamber and was superfused with buffered salt solution. The carotid sinus nerve was led into an adjoining compartment, containing lightweight mineral oil, for recording DC potential changes with chlorided silver electrodes.3. Dopamine injected into the superfusing solution in amounts of 50-250 mug caused hyperpolarization of the DC potential. This effect occurred repeatedly in each preparation, the maximum number of tests in any one preparation being twenty-seven.4. In the same preparations, acetylcholine (50-100 mug) and NaCN (10-20 mug) caused depolarizations of the DC potential, effects that have been described by others.5. The hyperpolarizing effects of dopamine were reduced or abolished by the alpha-adrenergic antagonists, dihydroergotamine (10-100 mug/ml.) and phenoxybenzamine (5 mug/ml.) and the dopamine antagonist droperidol (10-25 mug/ml.).6. The results indicate that the inhibitory effects of dopamine on the frequency of carotid body chemosensory discharges in cats and rabbits are due to hyperpolarization of chemoreceptor afferent nerve endings and not necessarily to local vascular effects in the carotid body.


Interacting effects of temperature and extracellular calcium on the spontaneous release of transmitter at the frog neuromuscular junction. 1. Temperature has a characteristic effect on the frequency of m.e.p.p.s at the frog neuromuscular junction; the spontaneous release of transmitter is not affected by temperature changes below 10 degrees C whereas the system is highly temperature-sensitive above 20 degrees C.2. A very similar result is obtained when the experiment is repeated in saline containing Ca(2+) buffered at 5 x 10(-7)M, suggesting that it is unlikely that the major action of temperature is to cause an increase in Ca(2+) influx.3. It is suggested that the main effect of temperature at the presynaptic terminals is a modification of [Ca(2+)](i) by an action on intracellular Ca(2+) stores.4. The interacting effects of theophylline and the divalent cation ionophore A23187 on m.e.p.p. frequency suggest that intracellular Ca(2+) stores, in addition to the mitochondria, may well be of importance in controlling [Ca(2+)](i).5. Changes in [Ca(2+)](o) produce a modification of m.e.p.p. frequency, but the details of the response are dependent on temperature. The spontaneous release of transmitter is most sensitive to an increase in [Ca(2+)](o) at 23 degrees C, whereas the greater effect is found at 13 degrees C when [Ca(2+)](o) is lowered.6. It is suggested (i) that m.e.p.p. frequency is primarily determined by [Ca(2+)](i) at the presynaptic terminals, (ii) that the presynaptic terminals are normally able to maintain [Ca(2+)](i) almost constant in spite of increases in Ca influx associated with ionophore treatment or with a rise in [Ca(2+)](o). However, if the steady-state position of [Ca(2+)](i) is previously raised by an increased efflux from intracellular stores (produced by elevated temperature or theophylline pre-treatment), increased influx causes a rise in both [Ca(2+)](i) and in m.e.p.p. frequency.


The effects on breathing of alternate breaths of air and a carbon dioxide rich gas mixture in anaesthetized cats. 1. An in vivo pH electrode was used to assess the effect in anaesthetized cats of the administration of 5% CO(2) (21% O(2), balance N(2)) and air as alternate inspirates upon the time course of the carotid arterial pH, and by inference, the P(CO2).2. This method of administration of CO(2) and air resulted in a lowering of the recorded pH with the production of oscillations of twice the duration seen on air alone. These larger oscillations had a period of two respiratory cycles and their amplitude was approximately twice that of normal oscillations.3. The respiratory response consisted in all cases of an increase in mean tidal volume and ventilation, and in 50-60% of recorded runs, of a highly specific sequence of tidal volume changes. The specific sequence was composed of alternately larger and smaller breaths which persisted while the larger oscillations continued.4. The use of the in vivo pH electrode made it possible to determine whether or not the tidal volume alternation was a result of sensitivity to carotid arterial P(CO2) oscillations. By diverting the carotid arterial blood through a mixing chamber the amplitude of the double (respiratory) period oscillations was, in some cases, reduced but not eliminated. In these cases the specific pattern of tidal volume changes was still present in 60% of trials. In the cases where the pH fluctuations were completely eliminated the specific respiratory pattern was never present.5. Average breath to breath differences in tidal volume seen during control runs with large oscillations present ranged in size from 3.6 to 8.6% of the mean tidal volume. When the oscillations were completely eliminated by means of the mixing chamber the breath by breath differences only ranged from 0.2 to 2.7% of mean tidal volume. The change was highly significant.6. Mean tidal volume and ventilation were not altered by eliminating the large (double period) oscillations.7. It has been shown that the tidal volume is made to change from breath to breath in a persistent manner when there are recurrent changes in carotid arterial blood chemistry. The effects on respiration involve vascular receptors above the mid carotid arterial region. It is argued that the effects involve the sensitivity of the carotid bodies to rapid (within breath) changes in P(a, CO2). There appears to be no significant effect on mean ventilation of the dynamic component of the arterial P(CO2) changes produced in these experiments.


Further observations on an ether-O-oxidase, formerly called alkyl etherase, from liver tissue. 1. The microsomal enzyme from liver previously called an "etherase" is now described more accurately as an ether-O-oxidase. It has been investigated further to free it from the membranes in aqueous solution and to try to define its physiological substrate. 2. After a variety of attempts with detergents, etc., the enzyme was obtained in impure solution from precipitation with 35-45% (NH4)2SO4 solution after a short digestion at room temperature. 3. When a suitably reinforced the enzyme in solution forms citrate from added ethyl ether, as it does in membranous form. This indicates the intermediary formation of acetyl CoA. 4. The enzyme in solution is unstable, though some activity remains after standing at 0degrees C for 2-3 days. Activity is lost rapidly by deep freezing, exposure to 2M-NaCl and at a pH more acid than pH 5-0. 5. The enzyme does not appear to be a known oxidase obtainable from liver microsomes; it is not for instance part of the inducible mixed oxygenase system, nor a peroxidase or catalase. 6. Since there were some similarities in stability with enzymes dealing with protozoal plasmalogens, or with lanosterol or cholesterol, we were led to explore these substrates in detail, with negative results. But a specimen of cholesterol oxidase from the branching bacterium Nocardia gave O-oxidation with diethylether. 7. The enzyme is present in the livers of all four animals examined, namely the rat, pig, guinea-pig and pigeon, but not in kidney or brain. 8. The enzyme takes up O2 with some compounds containing O-me groups. 9. The hypothesis is advanced that this normal oxidase in liver membranes exists to deal with some substances from plant sources which might prove toxic upon entering the circulation.


5-Aryl-1,5-dihydro-2H-1,4-benzodiazepin-2-one derivatives as antianxiety agents. A new series of 7-chloro- and 7-nitro-5-methoxy-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-ones (7a, c--e) was synthesized and found to have potent antipentylenetetrazole activity. These compounds were also employed as intermediates in the synthesis of 3-substituted 1,3-dihydro-1,4-benzodiazepin-2-ones (8f--v).


3,4-Methylenedioxyphenyl-, isopropylidenedioxyphenyl-, and benzyl-substituted chiral 2-aminosuccinimides and 3-aminopyrrolidines. Stereoselective investigations of potential anti-parkinsonian, antipsychotic, and anticonvulsant activities. The chiral title compounds 2--11 were assessed for their potential anti-Parkinsonian, antipsychotic, and anticonvulsant properties. The most striking differences in the biological activity of enantiomeric pairs were noted for D-(R)-2-amino-N-(3,4-methylenedioxyphenyl)succinimide hydrochloride (2) vs. L-(S)-3 and D-(R)-2-amino-N-(3,4-isopropylidenedioxyphenyl)succinimide (4) vs. L-(S)-5. D-(R)-2-partially attenuated amphetamine-induced stereotyped behavior, whereas D-(R)-4 antagonized oxotremorine-induced tremors. Their respective enantiomorphs were inactive in these tests. No differences in anticonvulsant potency of enantiomeric pairs were observed. The stereoselective actions of D-(R)-2 and 4 were rationalized on the basis of the presence or absence of gem-dimethyl functions in isopropylidenedioxy vs. methylenedioxy groups; the data seem to indicate that these methyl groups influence selective receptor site interaction in the D-(R) series.


A comparison of the antiserotonin, antihistamine, and anticholinergic activity of cyproheptadine with analogues having furan nuclei fused to the 10,11-vinylene bridge. A series of cyproheptadine derivatives having furan nuclei fused to the 10,11-vinylene bridge has been prepared. None of the compounds retain the potent antiserotonin and antihistaminic actions of cyproheptadine. 1-methyl-4-(1-methyl-8H-dibenzo[a,e]furo[3,4-c]cyclohepten-8-ylidene)piperidine (7), 1-methyl-4-(1,3-dihydro-1-oxo-8H-[3,4:6,7]cycloheptal[1,2-c]furan-8-ylidene)piperidine (10), and its reduction product 11 retained the peripheral anticholinergic activity of cyproheptadine.


Absolute configuration of glycerol derivatives. 4. Synthesis and pharmacological activity of chiral 2-alkylaminomethylbenzodioxans, competitive alpha-adrenergic antagonists. The optical isomers of alpha-adrenergic receptor antagonists prosympal (2), piperoxan (3), and dibozane (4) were prepared by methods establishing the absolute configuration of each. (2S)-3(2'-Hydroxyphenoxy)-1,2-propanediol ditosylate (10) was prepared from (2R)-3-tosyloxy-1,2-propanediol acetonide (6). Intramolecular displacement afforded (2S)-tosyloxymethylbenzodioxan [(2R)-11]. Reaction of (2R)-11 with the appropriate amine (diethylamine, piperidine, or piperazine) afforded the 2S isomers of 2, 3, and 12, respectively. Reaction of (2S)-12 with (2R)-11 afforded the SS isomer of 4. Reaction of (2S)-3-benzyloxy-1,2-propanediol ditosylate (14) with catechol (NaOMe) afforded (2R)-benzyloxymethylbenzodioxan (15). Subjecting 15 to hydrogenolysis, tosylation, and displacement with the appropriate amine afforded 2R isomers of 2, 3, and 12. Reaction of (2R)-12 with (2S)-11 afforded (RR)-4. Reaction of (2R)-12 with (2R)-11 afforded meso-4. The S isomers were more effective antagonists to the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips by twofold in 2 and 18-19-fold in 3 and 4. meso-4 was as effective as the SS isomer of 4. The results are interpreted in terms of a similar conformational distribution of aminoalkyl, oxygen, and aromatic functional groups of the (S)-benzodioxans and (R)-epinephrine.


Synthesis and biological evaluation of a tetrahydroisoquinoline derivative possessing selective beta2-adrenergic agonist activity. This paper reports the synthesis of 4-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (2) and 2-(3,4-dihydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)propylamine (3). The biological activity of these agents relative to that of trimetoquinol (1) in guinea pig atria and guinea pig trachea is reported. The relative activities in relaxation of guinea pig trachea is 1 greater than 2 greater than 3 while in the chronotropic response in guinea pig atria the relative order of activity is 1 greater than 3 greater than 2.


Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. In the histamine H2-receptor antagonist metiamide (2a) isosteric replacement of thione sulfur (=S) by carbonyl oxygen (=O) or imino nitrogen (=NH) affords the urea 2c and guanidine 2d which are antagonists of decreased potency. The guanidine is very basic and at physiological pH is completely protonated. However, introduction of strongly electronegative substituents into the guanidine group reduces basicity and gives potent H2-receptor antagonists, viz. the cyanoguanidine 2b (cimetidine, "Tagamet") and nitroguanidine 2e. A correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4. The close correspondence between cyanoguanidine and thiourea in many physicochemical properties and the pharmacological equivalence of these groups in H2-receptor antagonists leads to the description of cyanoguanidine and thiourea as bioisosteres. Acid hydrolysis of the cyanoguanidine 2b yields the carbamoylguanidine 2f at ambient temperatures and the guanidine 2d at elevated temperatures. Cimetidine is slightly more active than metiamide in vivo as an inhibitor of histamine-stimulated gastric acid secretion and has clinical use in the treatment of peptic ulcer and associated gastrointestinal disorders.


beta-Adrenoceptor blocking activity of halogenated thienylethanolamine derivatives. The synthesis of a number of ring-halogenated N-isopropyl- and N-tert-butyl-2-amino-1-(2-thienyl)ethanols has been carried out in order to ascertain the influence of chloro or bromo substitution at the thiophene moiety on their blocking beta-adrenoceptor activity. It was found that chloro- and bromo-substituted compounds exhibited a similar activity. Monohalo substitution at positions C4 or C5 of the thiophene ring resulted in comparable blocking potency, whereas C3 halo-substituted compounds were practically devoid of activity. The highest activity in these series was observed with compounds dihalogenated at C4 and C5, their effect on myocardial beta-receptors being comparable to that of propranolol.


B/C-cis- and -trans-1,3,4,9,10,10a-Hexahydro-2H-10,4a-methanoiminoethanophenanthrene (homo- and homoisomorphinan) derivatives as analgesics. N-Alkyl derivatives of B/C-cis- and B/C-trans-6-hydroxy-1,3,4,9,10,10a-hexahydro-2H-10,4a-methanoimino-ethanophenanthrene have been prepared. The analgesic potency and physical dependence capacity of these compounds were determined. The N-methyl derivatives were analgesically equipotent with morphine. None of these compounds except the N-methyl-B/C-trans isomer 2b suppressed or precipitated the abstinence syndrome. Compound 2b was a narcotic agonist. The N-methyl-B/C-cis compound 2a appears to warrant further examination for its potential as a potent analgesic having no physical dependence liability.


Retro-umbilical ectopic testicle: report of a case. A case of a retro-umbilical ectopic testicle in a 13-year-old cryptorchid boy is reported. To our knowledge this has not been reported previously. There is no definite explanation for this highly aberrant ectopia. During the neonatal period the boy had an umbilical suppuration that required drainage. This may offer a possible explanation since the consequent healing process could have pulled the peritoneum upwards, dragging the testicle with it. Despite the high position of this testicle (and previous operation on the other side) it was easy to cross over both testes successfully to the heterolateral scrotum.


Complications of autonomic dysreflexia.

Complications of autonomic dysreflexia. Autonomic dysreflexia can be a life-threatening problem if not promptly recognized and treated. Since the most common cause is bladder distension it is essential that the urologist be familiar with this syndrome. Several patients with serious complications owing to autonomic dysreflexia, including 1 mortality, are presented. The complications of autonomic dysreflexia result from a sudden marked rise in blood pressure, which may be severe enough to rupture single or multiple cerebral blood vessels or lead to a considerable increase in intracranial pressure. The neurophysiology, clinical features and therapeutic measures are discussed.


High-flow total body perfusion with severe hemodilution and normothermia in infants weighing less than 10 kg--safe limits of hemodilution in cardiopulmonary bypass in infants. Cardiopulmonary bypass with 17 to 57 per cent dilution of hemoglobin for repair of ventricular septal defect (VSD) was applied to 26 infants weighing less than 10 kg at normal temperature. The higher flow rate was required to compensate the reduced oxygen carrying capacity and to maintain an adequate arterial pressure in proportion to a decrease of hemoglobin value. Perfusion index resulted in 3.0 to 6.5 L/m2/min in this series. When the dilution ratio of hemoglobin became more than 50 per cent and high flow rate was required, however, oxygen transfer ratio decreased remarkably on account of inadequate oxygen delivery and imparied venous return. In these cases, it was difficult to remove the diluent immediately after the operation in spite of powerful diuretic therapy. The results of the present study indicate that the safe limits of hemodilution is 50 per cent in cardiopulmonary bypass at normal temperature in infants.


Potassium and intracellular pH.

Potassium and intracellular pH. Recent work has clarified some of the complex interrelationships between cell pH and potassium. These studies have been limited by the techniques available for accurately measuring cell pH. At present it is obvious that intracellular pH is a major regulator of the cellular potassium concentration, but the precise relationship between these two is still uncertain. It has become increasingly clear, however, that no simple relationship exists between the intracellular to extracellular hydrogen ion and potassium ion ratios. Many experiments do demonstrate that the extracellular metabolic alkalosis of potassium depletion is accompanied by a decrease in skeletal muscle pH in rat, rabbit, and probably dog. The response of cardiac and renal tubular cell pH to potassium depletion is less clear, although most evidence indicates that there is also a reduction in the pH of these tissues. This effect on cell pH appears to be independent of chloride. By contrast, hyperkalemia seems to raise muscle cell pH at the same time it induces an extracellular metabolic acidosis. The metabolic and physiologic consequences of potassium-induced alterations in cell pH have yet to be fully elucidated.


Relationship of renal ammonia production and potassium homeostasis. Renal ammonia production appears to be intimately related to potassium homeostasis, and the two may comprise the components of a closed loop regulatory system. Studies with both intact organisms and in vitro systems indicate that potassium depletion stimulates and chronic potassium-loading suppresses renal ammonia production. An increase in ammoniagenesis has been shown to decrease potassium excretion. These observations suggest that changes in potassium modulate ammonia production, which in turn maintains hydrogen ion homeostasis and influences potassium excretion. Potassium depletion increases rat renal cortical ammonia production by altering metabolism in fashion identical to metabolic acidosis, but there is no convincing evidence that both processes are mediated by similar changes in either cellular hydrogen ion or potassium concentration. By contrast, potassium-loading, which depresses ammonia production, appears to affect primarily the outer medulla, a region that is not influenced by potassium depletion. Thus, potassium-loading apparently affects different portions of the renal tubule than depletion does, but the specific mechanism and physiologic significance of the different sites of action is unknown.


Side effects and contraindications of beta-receptor blocking agents. Unwanted effects of beta-receptor blocking agents can be divided into three categories: 1. Those arising specifically from the pharmacologic, i.e., beta-blocking action. 2. Side effects not directly (or not with certainty) related to beta-blockade. 3. Adverse and potentially specific reactions to individual beta-blocking agents. Category 1 covers the majority of adverse effects (heart failure, severe bradycardia and hypotension, arterial insufficiency, increased airways resistance, gastrointestinal symptoms, hypoglycemia). These can largely be avoided by proper selection and preparation of patients. Category 2 covers cutaneous reactions (rashes, alopecia, pruritus), purpura (thrombocytopenic and nonthrombocytopenic) etc. as well as side effects attributable to the central nervous system (antianxiety effects, nightmares etc.). In the third category the "oculo-cutaneous syndrome" associated with practolol is discussed.


[Psychopharmacology in aviation and astronautics]. Flights aboard modern vehicles are associated with high nervous-emotional and physical stresses. This may induce depletion of reserve capabilities, development of fatigue and, consequently, reduction of work capacity of crewmembers. The paper discusses approaches and results of the use of drugs by pilots and cosmonauts in order to alleviate their fatigue and emotional stress. It gives indications and contraindications for the adminstration of stimulants and tranquilizers. On the basis of a comprehensive analysis of the literature data and their own findings, the authors draw the conclusion that the use of stimulants and anxiolytics may increase the level of reliability and performance of air- and spacecraft pilots during programmed and, particularly, contigent situations of the flight.


[Psychoneurological requirements in evaluating the functional state of cosmonauts in flight]. Selection and training of experts-psychoneurologists to be included into a team of operational medical monitoring are described. In regards to the capacity for synonymic paraphrasing, the conditions required for stability of individual opinions and their coincidence in different people are discussed. The capacity refers to the choice of the most suitable word among a number of synonyms. On this basis it is recommended to use similarity problems in appraising the function of an expert who involves verbal description of various events.


[Dynamic control of the atmospheric parameters of spacecraft]. On the basis of experimental data a mathematical model of relationships between physiological parameters, oxygen content in the atmosphere and exercises has been developed. Using the model, it has been demonstrated that circulation and respiration reactions to exercises can be optimized by increasing the partial pressure of oxygen as related to the exercise level. A probable law of the dynamic and physiologically  optimal control of the oxygen content in the space cabin atmosphere has been advanced. In cases of an uncontrolled decrease of PO2 the oxygen supply of crewmembers can be optimized by the dynamic control of the ambient CO2 content.


[Electrolyte content in the blood of animals and potassium ion transport in the erythrocytes under the action of a constant magnetic field]. The content of potassium and sodium ions in the blood and plasma of rats exposed to constant magnetic fileds (CMF) of 1000 and 4500 oersted for varying time was studied. The transport of potassium ions through membranes of red blood cells was examined in in bitro experiments using a CMF of 4500 oersted. An exposure of animals to a CMF of 1000 oersted for 1 and 24 hours did not produce significant changes in the potassium and sodium content in blood. An exposure of animals to a CMF of 4500 oersted induced certain changes in the electrolyte composition of the blood. During an hour exposure the most distinct changes were an increase in the potassium concentration in plasma and its decrease in blood. During a 3-hour exposure the most marked change was a decrease in the sodium content in blood. Repeated and prolonged chronic exposure did not bring about summation of the effects. The exposure did not influence the transport of potassium ions. The exposure did not affect the pH and hematokrit values of the blood.


[Study of the nature of the associated microflora in the prolonged substrateless cultivation of beet plants]. The purpose of the present investigation was to study variations in the population density of microorganisms, their qualitative and quantitative composition during substrate-free cultivation of beats. The results obtained show that the microbial number in the nutrient solution increased by the time of intensive growth of beats and decreased by the time of harvesting. The number of root microorganisms was much greater than the total number of microorganisms in the nutrient solution. Oligonitrophils and nitrogen fixing bacteria were found in the solution. This may be associated with a transient decrease of nitrogen in the solution. The number of ammonifiers and denitrifiers in the solution increased significantly by the end  of plant vegetation; the amount of denitrifiers inhabiting the roots decreased during vegetation and that of ammonifiers increased. In the middle of vegetation cellulose decomposing aerobes appeared; this might occur since root hairs began to die off. By the end of vegetation an insignificant amount of fungi was also found. Nitrifying and spore-forming microorganisms were not detected. The identification of predominant microbial species showed them to be bacteria of the genera Pseudomonas and Mycobacterium. Besides, microorganisms of the genera Bacterium, Micrococcus, Mycococcus, Chromobacterium and Pseudobacterium also occurred.


[The use of Goetze cerclage in the treatment of tibial fractures]. On the basis of the authors' experiences and the data of the available literature Goetze's cerclage in the treatment of tibia fractures is discussed--as far as the authors know, this is the first report of this method in the Hungarian literature. On the basis of the authors' material, the method is very useful for the treatment of the long, spiral and oblique fractures of the leg.


[Diabetic osteoarthropathy of rare localization]. The typical location of diabetic osteoarthropathy is the foot. Involvement of other joints is rare. In the case treated by the author, the osteoarthropathy of the ankle and knee joints presented at the same time. The process healed in the ankle joint by grave deformity and arthrosis deformans resulted in the knee joint. If arthrosis appears in an unusual location, it is worth while to look for diabetes.


[Thoracic injury and fat embolism].

[Thoracic injury and fat embolism]. The authors state that fat embolism occurs rather frequently following thoracic injuries. It is difficult to make a diagnosis because of the complexity of the symptoms. The correct evaluation of the characteristic clinical and laboratory signs arising after a period free of symptoms is essential. The authors outline the brief case history of a successfully treated patient, who recovered, owing to the use of the respirator in the intensive care unit.


[Vascular injury associated with shoulder luxation]. The author reports on the rupture of subscapular artery that followed the reduction of an anterior dislocation of the shoulder joint. On this occasion, vascular injuries associated with shoulder joint dislocation, their diagnosis and treatment is discussed in the article. The aim of the author was to remind the reader to a complication of our everyday activity. He wants to call attention to the importance of gentle manipulation and the careful observation of the circulation after reduction.


[15 years of anesthesia in hand surgery]. The authors give an account on their experiences in the anaesthesy on the hand area. Methods used during a 15 year period are reported, different sorts of narcosis and the intravenous regional anaesthesy is discussed. Advantages and disadvantages of the particular methods are outlined.


[Early surgery of the soft tissues in congenital clubfoot]. The role and position of early complete operative procedures on the soft tissues in the treatment of the congenital club foot is discussed in the article. The authors report on the operative indications in principles and in their own practice. Closed and operative treatment are not contradictory but complementary terms. The aim of the operative treatment is to bring all residual contractures following conservative treatment to an end. It must be done by relatively minimal intervention on the soft tissues and as early as possible. Thus the proper development of the foot and the prevention of bone deformation can be attained.


[Management of mass injuries in railway accidents]. Authors write up the experiences they gained at repeated train accidents on the same section of railway line. The circumstances of the two accidents are evaluated and analysed. The experiences they obtained at the first accident were put to use the second time. The authors stress that the growing number of mass accidents makes it necessary to prepare an alarm and provision plan for every institution.


[Surgical management of thoracic and thoraco-abdominal injuries]. From 1970 to 1974 407 patients with thoracic injuries have been treated by the authors in the 2nd Surgical and Thoracic Surgical Department of the "János" Hospital, Budapest--out of them 190 patients were classified as severely injured. The material and the operative technique in isolated thoracal and combined thoracal-abdominal injuries are discussed. The importance of the operative stabilization of the thoracic wall is emphasized and fixation of the thoracic wall by means of pericostal sutures is advocated, if because of the intrathoracal injury--just the same--thoracotomy is to be performed. On the basis of their experiences and because of the risk of late complications and of residues impairing the function in certain types of the thoracal injuries surgical treatment is advocated by the authors.


[Fracture-dislocation of the hip joint. II. Central luxation]. 64 cases of central luxation are analysed by the authors. 4--10 years after the injury 31 patients appeared at the check-inspection. It has been stated by the authors that because of the severity of the injury and the age of the injured patients surgical intervention may be performed even in case of greater dislocation but rarely. The result of the conservative treatment is in the case of congruency of the loading surface satisfactory, but it is even in the case of incongruency generally better than it may be supposed on the basis of the roentgenogram. For the prevention of later occurring severe arthrosis the importance of the rehabilitation is emphasized by the authors.


[Pathological sagittal shifting of vertebral bodies]. The results of the lumbar spine examinations performed in one year and a half are evaluated by the authors. The types of the sagittal positional changes of the vertebral bodies are discussed in detail. The importance of the functionally centrated and lateral telephotographs in the diagnosis of the antepositional olisthesis and the retropositional retrolisthesis is pointed out, and the indication and the differential diagnostical value of the oblique roentgenograms are dealt with.


Drug utilization review in an HMO. I. Introduction and examples of methodology. An experimental drug utilization review program was developed for a health maintenance organization (HMO). The objectives of the program were to develop and implement an ongoing mechanism for reviewing drug use using criteria based on the scientific literature, and to evaluate the effect of the drug use review program on physician precribing patterns. Seven therapeutic categories of drugs, accounting for over 65 per cent of prescribing, were selected and criteria developed for their use. The drug use review prcedure is described briefly. The evaluation of the drug use review program is based on a comparison of rates of prescription use for specific therapeutic categories before and after the criteria were ceveloped and approved. As an example, data for the antihistamine therapeutic category are presented. Criteria for prescribing antihistamines suggested restricting use of combination cold preparations and refraiming from antihistamine use in viral upper respiratory tract infections. After the criteria were adopted, prescribing of antihistamines for viral URIs declined, particularly in pediatrics. In general, prescribing of combination antihistamine preparations did not change; where one combination preparation was deleted from the formulary, prescribers appeared to substitute another combination preparation.


[Effects and side effects of oral drugs used in common cold (author's transl)]. A report about effects and side effects of common cold remedies that are taken orally is presented. There are advantages and disadvantages in the use of either locally administered nose drops or orally taken cold remedies, which are compared to each other from the pharmacological point of view. Based on the experience of a great toxicological center and a pediatric clinic, the clinical symptoms of poisoning as a result of accidental ingestion are described and contraindications are pointed out. It is concluded that, especially in children, the dosage of both oral and local drugs should not exceed the recommended amount.


Alkaline ribonuclease inhibitor in human thyroid. Thyroids of goitrogen-treated rats contain increased amounts of a protein inhibitor of ribonuclease activity at pH greater than 7 (alkaline ribonuclease inhibitor, ARI). We report here that thyroids from hyperthyroid patients contain more ARI than normal human thyroids. This increase parallels RNA concentration. The inhibitor is heat labile, inactivated by sulfhydryl blocking agents, and has a molecular weight near 50, 000 daltons. ARI is quantitated by its activity against bovine pancreatic RNase, but it also inhibits human thyroid RNase. Analyses of a solitary toxic nodule and its surrounding suppressed tissue confirm in tissues from a single patient our results in tissue from numbers of thyrotoxic and euthyroid individuals and decrease the likelihood that changes are induced by antithyroid medication. A possible regulatory role for ARI is suggested.


Alcohol: its effect on the kidney.

Alcohol: its effect on the kidney. The effect of ethanol feeding on renal function, gross and microscopic morphology, and constituent content was determined in alcohol-fed rats and compared to similar studies in isocalorically fed animals ingesting the same diet except that dextrimaltose was isocalorically substituted for ethanol. Alcohol-fed animals have significantly reduced renal function and interstitial edema compared to their isocaloric controls. When renal mass and renal constituent analysis were normalized for body weight, alcohol-fed animals were found to have renal hypertrophy characterized by significantly increased absolute amounts of protein (p less than 0.01), fat (p less than 0.01), and water (p less than 0.01). All of these constituents increased in proportion to their percentage of total renal mass in control animals. In contrast, DNA content per kidney was similar for alcohol and isocalorically fed animals.


Lophyrotomin, a new toxic octapeptide from the larvae of sawfly, Lophyrotoma interrupta. Lophyrotomin, a new toxic octapeptide, has been isolated from sawfly (Lophyrotoma interrupta) larvae using solvent extraction, dialysis, adsorption on polyamide, ion exchange chromatography on DEAE cellulose and silica gel G chromatography. On the basis of evidence from chemical methods, pmr and mass spectrometry, a partial structure is proposed. Lophyrotomin has an approximate intraperitoneal LD50 of 2 mg/kg for mice.


Heterogeneity of staphylococcal enterotoxin A on isoelectric focusing and disc electrophoresis. Heterogeneity of purified staphylococcal enterotoxin A, obtained from a culture supernatant of Staphylococcus aureus, strain 13N-2909, was demonstrated by isoelectric focusing. The toxin was composed of three immunologically identical fractions with isoelectric points of 6.5, 7.0 and approximately 8.0. Heterogeneity of the toxin was also shown by disc electrophoresis. At pH 8.0 and 9.4 two major bands and a faint minor band were observed, while at pH 4.3 only one band was observed. The faster-moving band for the anode in disc electrophoresis at pH 9.4 was found to correspond with the pI 6.5 component from isoelectric focusing, while the slower-moving band corresponded with the pI 7.0 component. From the results of the electrophoretic migration tests of the toxin, the components corresponding to the two major bands found in disc electrophoresis at pH 9.4 were considered to be charge isomers.


An analysis of factors influencing the isolation rate of herpes simplex virus. Attempts were made to improve the rate of isolation of herpes simplex virus (HSV) from clinical specimens by minimizing loss of virus infectivity during transportation and employing the most sensitive cells for isolation. Basical analyses using standard strains of type 1 and type 2 HSV indicated that virus titer decrease was marked even at low temperatures in environments free of proteinous stabilizer such as normal serum or tissue extract, negating the generally held concept that HSV is stable in distilled water. YLE (Earle-lactalbumin HYDROLYSATE-YEAST EXTRACT) medium containing 20% inactivated calf serum was determined to be a transport medium of choice, because degradation of suspended virus during storage and freeze-thawing was negligible and loss of virus during Millipore filtration was minimal. Special coating of the membrane could also be obviated by the use of this solution. In a cell susceptibility test using clinical specimens, secondary rabbit kidney (SRK) cells were the most sensitive, showing a quick development of cytopathic effect. Vero and RK-13 cells were the second best, whereas monkey kidney, HeLa and L cells were far less sensitive. A total of 136 specimens from suspected cases, sent by dermatologists, were tested using SRK cells, and 99 strains of type 1 and 15 strains of type 2 HSV were isolated. Excluding one case from which vaccinia virus was isolated, the isolation rate of HSV was 84.4%.


Human infection caused by penicillin-insensitive pneumococci. Three cases of infection, including two fatal ones, caused by pneumococci relatively resistant to penicillin are reported. The patients were a 19-year-old New Guinean with fatal multisegmental pneumonia, a 10-week-old Caucasian infant who died suddenly from purulent meningitis, and an Australian Aboriginal child aged two years with bronchiectasis complicated by pneumococcal bacteraemia. The pneumococci isolated (serotypes 6, 16 and 19) showed minimal inhibitory concentrations of penicillin G ranging from 0-1 microgram/ml to 1-0 microgram/ml (resistance ratios five to 50) and were also relatively resistant to penicillin V, methicillin, cloxacillin and cephalosporins.


[Bromureide intoxication with acute renal failure and bilateral deep vein thrombosis (author's transl)]. A case of bromureide intoxication with 8 gm. of carbromal is described, in which an acute renal failure and bilateral deep vein thromboses occurred. After treatment with heparin and peritoneal dialysis the symptoms regressed completely.


In vivo and in vitro studies of nitrate reductase regulation in Asperillus nidulans. Induced wildtype cells of A. nidulans rapidly lost NADPH--linked nitrate reductase activity when subjected to carbon and or nitrogen starvation. A constitutive mutant at the regulatory gene for nitrate reductase, nir Ac 1, rapidly lost nitrate reductase activity upon carbon starvation. This loss of activity is thought to be due to a decrease in the NADPH concentration in the cells. Cell free extracts from wildtype cells grown in the presence of nitrate, rapidly lost their nitrate reductase activity when incubated at 25 degrees C. NADPH prevented this loss of activity. Wildtype cells grown in the presence of nitrate and urea have a higher initial NADPH:NADP+ ratio and cell free extracts from such cells lost their nitrate reductase activity slower than extracts of cells grown with nitrate alone. The Pentose Phosphate Pathway mutant, pppB-1, had a lower NADPH concentration compared with the wildtype grown under the same conditions and cell free extracts lost their nitrate reductase activity more rapidly than the wildtype. Cell free extracts of nirAc-1 and a non-inducible mutant for nitrate reductase, nirA- -14, upon incubation lost little of their nitrate reductase activity.


Mutagenicity of 22 N-nitrosamides and related compounds for Salmonella typhimurium TA1535. Twenty-two N-nitrosamides and related compounds, including 14 nitrosoureas, 5 nitrosocarbamates, and one nitrosocyanamide, were tested at various concentrations for mutagenic activity towards Salmonella typhimurium TA1535 without the use of microsomes. The ether-water partition coefficient, solubility in water, and half-life in aqueous solution were also measured. Twenty compounds were mutagenic, with "standard mutagenic concentrations" (i.e. those producing 100 mutants/dish) of 0.0024--6500 micron. Standard mutagenic concentration was negatively correlated with the partition coefficient. Three compounds (ethyl 2-acetoxyethylnitrosocarbamate, nitrosocarbaryl, and methylnitrosobenzamide) were more active than the classic mutagen methylnitrosonitroguanidine. Nitrosocarbamates were at least 50 times more mutagenic than the corresponding nitrosoureas. Nitrosodihydrouracil and propylene-nitrosourea were more active than related compounds. Ethylnitrosocyanamide was 730 times more mutagenic than ethylnitrosourea. Fifteen of the test compounds (of which 14 were mutagenic) had previously been assayed in rats for carcinogenicity, all with positive results.


Nitrosation in vitro and in vivo by sodium nitrite, and mutagenicity of nitrogenous pesticides. 37 nitrogenous pesticides, belonging to the chemical groups of amides, carbamates and ureas, were nitrosated with sodium nitrite in vitro. The nitrosated compounds were tested for mutagenic activity in the bacterial spot test with Salmonella typhimurium his G 46. Those pesticides reacting positively in this test after nitrosation were then fed to mice in combination with sodium nitrite in order to assess the formation and mutagenicity of these nitroso compounds in vivo. With the already known exception of ethylenethiourea (ETU), no pesticide produced enhanced numbers of micronuclei in mouse bone-marrow erythrocytes when fed together with nitrite. Dose-response experiments with intraperitoneal injection of N-nitroso-ETU revealed an apparent no-effect level of about 15--18 mg/kg. The findings are correlated with the pesticide residues actually present in the environment.


Detection of gastroesophageal reflux in the pediatric-age patient by esophageal intraluminal pH probe measurement (Tuttle test). The esophageal intraluminal pH probe test (Tuttle test) was used in 24 pediatric-age patients who had symptoms of gastroesophageal (GE) reflux to determine its sensitivity in detecting gastric acid reflux and to document its usefulness as a prognostic indicator. Eight children had a positive Tuttle test. Six of these patients failed a trial of medical management and required surgery to control their symptoms. None of these patients had GE reflux on esophagrams. Only one of 16 children with a negative test required surgery. This patient also did not have GE reflux on esophagram. The Tuttle test should be included in the diagnostic evaluation of pediatric patients with the clinical presentation of GE reflux.