[Metabolism and pharmacokinetics of piprozoline in the rat, dog and man. 1. Studies with the radioactively-labeled substance]. The new choleretic ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Probilin) is absorbed well and rapidly in rats, dogs and humans. Maximum 14C plasma concentrations are found 1-2 h after oral administration of the labelled substance to fasting animals and human volunteers. When administered to test persons after breakfast, the absorption is delayed but the absorbed amount is unaffected. Elimination of the radioactivity from the plasma occurs in two phases; 24 h after administration the radioactivity concentration has dropped to 5-8% of the maximum levels. Piprozoline is almost completely metabolized during absorption. The primary metabolic step is the enzymatic hydrolysis of the ester bond to the corresponding acid (metabolite I). At the time of maximum plasma concentration most of the plasma radioactivity corresponds to metabolite I, which also possesses choleretic activity. Approx. 65% of the radioactive dose is eliminated renally in all three species, approx. 60% being excreted within the first 24 h. Approx. 40-60% of the urinary radioactivity can be ascribed to metabolite I, both in its free form and conjugated with glucuronic acid. No unchanged substance is found in the urine. A comparison of the pharmacokinetic and metabolic behaviour of piprozoline in rats, dogs and humans showed that it was similar in all three species.


[Metabolism and pharmacokinetics of piprozoline in rat, dog and man. 2nd Communication: Determination of metabolic profiles with the aid of an HPLC-radioactivity detection system following direct injection of urine and bile onto a reversed-phase column (author's transl)]. This paper describes the determination of metabolic profiles of 14C marked ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Probilin) in rat, dog and human urine and rat bile with the aid of an HPLC-radioactivity detector system following the direct injection of large quantities onto an analytical C-18 column. Metabolite 1 and two glucuronic acid conjugates of metabolite I were determined quantitatively, isolated and identified. Following HPLC separation, the specific detection of radioactivity permits the determination of metabolic profiles without prior clean-up so that unstable metabolites can also be analyzed.


[Metabolism and pharmacokinetics of piprozoline in rat, dog and man. 3rd communication: Determination of piprozoline and metabolite I in plasma and urine (author's transl)]. The new choleretic ethyl (Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Probilin), a monosubstance of the substituted methylthiazolidones, was investigated by thin-layer chromatography with regard to pharmacokinetics in the rat (100 mg/kg i.v.; 20 mg/kg i.v.), dog (100 mg/kg i.g.; 20 mg/kg i.v.) and man (200 mg orally in sugar coated tablets). The substance was absorbed quickly in all species. Because of its rapid metabolisation, unchanged substance could be detected only in the dog after oral administration. In this case and after intravenous administration of piprozoline, the plasma level of the unchanged substance cold be described by two-compartment models with first-order kinetics. After intravenous administration, piprozoline was also rapidly transformed into metabolite I, as metabolite I existed in higher concentrations than the unchanged substance already after 6 min. In all cases, metabolite I was eliminated from the plasma with a half-life of approx. 2 h; 15-30% of the given dose appeared as metabolite I in urine, piprozoline itself could not be detected. After correction to uniform doses of 100 mg/kg, in all species the area under the plasma level curve of the metabolite amounted to approx. 12 mg/ml X h and the apparent volume of distribution to approx. 1-1.5 1/kg body weight. This indicates good availability in animal and man, regardless of the galenic formulation.


[Studies on the influence of piprozoline on the microsomal enzyme system of the rat liver (author's transl)]. Studies of hexobarbital sleeping time in rats showed that only a very high dosage of ethyl(Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Problin) (500 mg/kg) produced a weak interaction with the metabolism of hexobarbital; no signs of any induction of the oxidative enzyme system were observed until 4 days after pre-treatment with 3 X 250 mg/kg. Determinations of the in vitro activity of hepatic microsomal enzymes after several days pre-treatment of male Wistar rats with 2 X 250 mg piprozoline/kg per day showed that piprozoline has only a slight inductive effect on some of the enzymes of the oxidative system. Some of the glucuronidation reactions tested showed marked increases.


[On the efficiency of new antiinflammatory agents. A comparative study (author's transl)]. In a comparative study new antiinflammatory agents, like sodium-(3-[(2,6-dichlorephenyl)-amino5-phenyl)-acetate (diclofenac); d,l-2-(3-phen0xy-phenyl) propionic acid (fenoprofen); 2-(3-benzoxyl-phenly-propionic acid (ketoprofen); cis-5-fluoro-2-methyl-1-(p-methylsulfinyl) benzylideryl-3-indenyl-acetic acid (MK 231, sulindac); 2-(6-methoxy-2-naphthyl)-propionic acid (naproxen/, showed nearly the same antiiflammatory effectiveness as 5-methoxy-2-methyl-1-(4-chlorobenzoyl)-indolyl-(3)-acetic acid (indometacin). In homogenates of inflamed rat paws an antiproteolytic activity of the new antiinflammatory agents was lacking.


[Contribution to the course of enzymatic processes in inflamed tissue of rat paw (author's transl)]. With the method of gel filtration we found fraction in rat paw homogenates which was smaller in inflamed tissue than in normal tissue. Our data suggest a substrate degradation by inflammation. The enzymatic processes were also seen invivo and inhibited by sodium salicylate.


[Investigation of some basic propyl(alkyl)-phenyl ketones with local-anesthetic activity (author's transl)]. We synthetised several ketone analogues of procain (II) with different lipophilic substituents (XVI). In order to investigate structure-activity relationship, the Rm values (measure for the partition coefficient), the -CO- wave frequency (expression of electron density) and the local anesthetic activity (rabbit cornea) were determined. The studied lipophilic substituents do not influence the inductive or mesomeric effect on the carbonyl oxygen and so do not increase its electron density. On the other hand, they do increase the partition coefficient, therefore the hydrophobic binding effect of the substituents is improved. The lower efficacy of the carbonyl group in ketones against the acrboxyl group can be compenstaed for by introduction of groups with higher liposolubility, so that even in ketones it is possible to prepare substances with high local-anesthetic activity.


Semimicro-titrimetric method for the determination of activity-concentration of heparin. A semimicro-titrimetric method for the determination of heparin is developed. The method depends upon the determination of the sulphate content of the acid drolysate of heparin by adding an excess of barium chloride and back titration with standard sulphuric acid, using sodium rhodizonate as indicator. The method measures the biological activity of 10-50 mg of heparin, with a mean accuracy (p = 0.05) 99.73 +/-0.81%. Application of the proposed method for the determination of heparin in some pharmaceutical preparations is carried out by precipitation of the intact heparin molecule with cetyltrimethylammonium bromide, ashing of the precipitate and determination of its sulphate content; alkaline and acid degradation products do not interfere with the proposed procedure.


Pharmacokinetics as an aid in the interpretation of toxicity tests. A method is described which makes the detection of alterations in the pharmacokinetic profile possible when substances are administered during long-term toxicity tests. By superposition of a radioactive dose at the end of the toxicity study a blood level can be obtained which--on the assumption of first-order kinetics--is comparable to that after a single radioactive dose in controls. Differences between blood levels of pretreated and control animals may indicate enzyme induction or damage of the elimination organs, etc., even when morphological changes are evident.


[Modification of toxicity of the calcium antagonist verapamil by depletion of catecholamines (author's transl)]. The acute toxicity of verapamil in mice was nearly doubled by a partial depletion of catecholamines with reserpine 2 mg/kg s.c. 40 and 24 h prior to the experiments. These experiments are in favour of the view that a regulatory effect of the sympathetic nervous systme plays an important role in the treatment with organic calcium antagonists.


[Diuretic and saluretic effects of bemetizide and triamterene compared to those of their combination (author's transl)]. The diuretic and saluretic effect of the benzothiadiazine derivative 3-(a-methylbenzyl)-6-chlore-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-diozide (bemetizide) and the pteridine derivative 2,4,7-triamino-6-phenylpteridine (triamterene) were compared with those of their combination in the animal experiment on rats. Dose-effect relationships at a ratio of 1:2. The combination displayed marked advantages over the individual substances. The mixing proportion of 1:2 may be considered suitable.


Pharmacokinetics, enterohepatic circulation and biotransformation of [2-3H]-9,9-Dimethylacridane-10-carboxylic acid S-(2-dimethylamino) thiolethyl ester in the rat and dog. Dogs receiving a 7.5 mg/kg oral or i.v. dose of tritium labelled 9,9-dimethylacridane-10-carboxylic acid S-(2-dimethylamino)thiolethyl ester (DMA) as the methane sulfonate salt (DMA-MS) excreted 86-95% of the radioactivity within 6 days. A similar recovery was obtained for rats receiving 300 mg/kg orally of 15 mg/kg i.v. In both species, approximately 66% of the dose was excreted in the feces as metabolites. Absorption of the oral dose was shown to be 80% and 100% for the rat and dog, respectively. Up to 47% of an i.v. dose was excreted in the bile of rats and an efficient enterohepatic circulation process insues. The parent drug is rapidly metabolized in the tissues yielding at least 6 polar metabolites which contribute to relatively long plasma half-lives in the order of 40 h for dogs and 58-90 h for rats. An atypical increase in plasma radioactivity following an i.v. dose could be rationalized in view of these results. Metabolite profiles were examined in plasma, urine, bile and feces and found to be qualitatively similar. Des-methyl-DMA and DMA-N-oxide were identified as two minor metabolites.


[Studies on antiarrhythmic effects and toxicity of quinidine and dihydroquinidine as well as defined mixtures of both in rats (author's transl)]. The antiarrhythmic and acute toxic actions of quinidine (Q) and dihydroquinidine (DHQ) were investigated in experiments in rats. 1. No significant difference was found between Q and DHQ with regard to the doses necessary to suppress electrically induced ventricular fibrillation in the heart (p greater than 0.05). 2. On oral administration, pure DHQ was slightly less toxic than pure Q. This difference is significant (p less than 0.05). It may be explained by a lower absorption rate of DHQ in the rat. Addition of 15 or 30% DHQ to Q did not produce any significant difference in the acute toxic doses (LD50) in comparison with pure Q (p greater than 0.05). 4. The results of a published clinical study showed that the antiarrhythmic actions of pure Q and "commercial" Q are the same with regard to quality, potency and duration. The frequency of side-effects after adminstration of the two alkaloids also did not differ. 5. Limitation or reduction of the DHQ content of pharmaceutical quality quinidine below a technically practicable level does not seem to be justified from a medical point of view from the results of the animal experiments presented and from the clinical study mentioned.


The disposition of radioactivity after administration of the anthelminthic methyl-14C-5-cyclopropylcarbonyl-2-benzimidazole carbamate (ciclobendazole) to rats and dogs. 1. The disposition of radioactivity has been studied in rats and dogs after administration of a new anthelminthic agent, 14C-labelled methyl-5-cyclopropylcarbonyl-2-benzimidazole carbamate (14C-ciclobendazole). 2. An oral dose of 14C-ciclobendazole (4 mg/kg) to rats was rapidly absorbed and about 70% and 20% of the dose was excreted in the faeces and urine, respectively, during 2 days. Bile duct cannulated rats excreted about 80% of the dose in 48-h bile, about 2% in the faeces and about 10% in the urine showing that an oral dose was well-absorbed and that some enterohepatic circulation probably occurred. The excretion of radioactivity in the bile was less after i.v. administration. 3. An oral dose of 14C-ciclobendazole (4 mg/kg) to dogs was mainly eliminated during 2 days with about 80% of the dose in the faeces and only about 10% in the urine. Anaesthetised bile duct-cannulated dogs, excreted between 26% and 35% of an oral dose in the bile during 24 h and up to 58% of an oral dose was absorbed at this time. 4. The tissue distribution of radioactivity in rats and dogs after single or multiple oral doses of 14C-ciclobendazole (4 mg/kg) showed that there was no unusual accumulation or localisation of radioactivity in the measured tissues. Highest concentrations were present in the intestinal tract, liver and kidneys, organs associated with biotransformation and excretion and also in the lungs and adrenals. 5. After oral administration of 14C-ciclobendazole to rate at three different dose levels (4, 40 and 400 mg/kg), peak plasma levels occurred at 15-30 min and declined with similar half-lives (about 20 h). A comparison of peak concentrations and areas under the plasma concentration-time relationships showed that the absorption of ciclobendazole was probably dose-dependent, a lower proportion probably being absorbed at higher doses. After repeated daily oral dosing with 14C-ciclobendazole (4 mg/kg), there were no significant changes in either the daily plasma concentrations or the biological half-life measured after the last dose, indicating that ciclobendazole probably did not induce or inhibit its own metabolism when dosed repeatedly at 4 mg/kg. 6. A comparison of the areas under the plasma concentration-time relationships after oral, i.p. and i.v. administration of 14C-ciclobendazole to rates indicated that there was no signigicant uptake by the liver during first pass and that an oral dose was well absorbed by rats. 7. The peak plasma concentration in the dog, after an oral dose of 14C-ciclobendazole (4 mg/kg) was reached at about 30 min and declined with a half-life  of about 3 h. 8. Ciclobendazole was probably well-absorbed by rats and dogs and excreted more rapidly by the latter species than by the former Relatively higher plasma concentrations of drug and/or metabolites were thus achieved in rats than in dogs.


Gastrointestinal prokinetic and antiemetic effects of a new substituted pyrimidinO 6553 (2-methylamino-4-N-methylpiperazino-5-thiomethyl-6-chloropyrimidine hydrochloride). 2-Methylamino-4-N-methylpiperazino-5-methylthio-6-chloropyrimidine hydrochloride (O 6553) is a new molecule showing an original pharmacological profile in the laboratory tests. It possesses at the same time potent gastro-intestinal prokinetic and central antiemetic properties, demonstrated on the one hand by the gastro-duodenal transit of barium meal in rats, and on the other hand by apomorphine-induced vomiting in dogs. The drug also has interesting anxiolytic and antiserotonin properties and, at doses which change gastro-intestinal behaviour, it is devoid of any untoward side effect. The acute and subacute toxicities of O 6553 show that the drug has a very good safety margin.


[Effect of a benzopyrone compound on liver function. Short communication (author's transl)]. The results of the presented double-blind trial proved that the benzopyrone compound Venalot, a combination of coumarin and troxerutin used in the treatment of local inflammatory oedemas of traumetic, phlebopathic and lymphostatic origin, can be administered unhestitatingly in case of severe parenchymatous liver damages even in a dosage which was chosed higher than that recommended and usually given (2 depot tablets b.d.).


[Test of combination of the agents coumarin and troxerutin for embryotoxic and teratogenic side-effects in Göttingen miniature pigs (author's transl)]. Göttingen miniature pigs were used to test a combination of the active principles coumarin and troxerutin (Venalot) for teratogenic and embryotoxiic side-effects. The experimental group consisted of 17 mother pigs with 95 fetuses, the control group of 6 untreated sows with 45 fetuses. The combination of coumarin and troxerutin was administered orally at a level of the 100-fold therapeutic dose (i.e. 25 mg coumarin + 150 mg troxertutin/kg/day) from day 6 to day 30 of gestation. The pathological and histological examinations of the uteri and fetuses revealed no indications of any embryotoxic or teratogenic damage caused by the tested combinations. Morphological and clinico-chemical investigations did also not result in any findings definitely attributable to the medication.


[Different enzyme liberation in the liver of rats and mice by a combination of coumarin and rutin sulphate sodium salt (author's transl)]. In Wistar rats, combined treatment with ethanol or carbon tetrachloride and a mixture of coumarin and sodium salt of rutin sulphate (Venalot injectable solution) causes slight increases of some liver-specific enzymes in plasma. This effect was not observed in DBA/2 4-mice whose metabolism of coumarin is widely analogous to that of man. The LD50 for coumarin in those mice was twice that in rats. These results are discussed in the light of different metabolic pathways of coumartin in both species.


The effect of two inhibitors of histidine decarboxylase on gastric secretion in the rat. The effects of the hydrazino-analogue of histidine (HH) and DL-gamma-N(1,2,3,4-tetrahydroisoquinolyl)-alpha-hydrazino-butyric acid (AIS 48), two inhibitors of histidine decarboxylase, and atropine on gastric secretion stimulated by histamine and pentagastrin were studied in the perfused rat stomach. The results confirm that the mechanism of action of the physiological polypeptide is mediated, and that the inhibition of histidine decarboxylase can be useful means to control gastric secretion.


[Behaviour of intestinal goblet cells following application of oxidated water soluble terpenes. A pilot study (author's transl)]. 1 and 3 h after i.p. application of Ozothin, an oxidation product of Bordeaux terpin oil, in rats there is a significant increase in goblet cells both totally and in the tightly filled ones (respectively in the villi of the small intestine). Double i.v. injection of therapeutic doses of Ozothin (first 14 h and booster 2 h preoperatively) induces a significant decrease in the number of the tightly filled goblet cells. These contradictory results may partly be explained as an initially timed ischesis of mucigenous glands by Ozothin. Statistically significant differences among the different series of tests could be found only in the epithelium of the villi. In the crypts there were similar results lacking statistical significance.


[The efficacy of established, systemically active trichomonacidal agents in the infection model tri-chomonas vaginalis/rat (author's transl)]. Experimental chemotherapeutical studies were carried out with metronidazole, tinidazole, nitrimidazine and ornidazole in rats infected with Trichomonas vaginalis intravaginally. All compounds tested showed a systemic trichomonacidal activity within rather a narrow dosage range after three oral doses and also after a single dose, i.e., 1.4-3.0 mg/kg and 7.7-15.9 mg/kg body weight (DC50), respectively.


Studies on the lissamine green distribution in three model rat tumors. In order to gain knowledge on the extent of distribution of chemotherapeutical agents through the blood systems of various tumors, we studied as an indicator the lissamine green concentrations in various tumor segments after different exposure times. As model tumors we used the autochthonic benzpyrene fibrosarcoma and the transplantable tumors Walker and Yoshida in Sprague-Dawley rats. Remarkable differences in the providing blood vessel were observed.


[Inhibition by "essential" phospholipids of the bactericidal effect of cetylpyridinium chloride on common bacteria. Short communication]. The authors examined the conditions under which the bactericidal action of the disinfectant cetylpyridinium chloride (CPC) is neutralized by a dispersion of "essential" phospholipids (EPL). Both gram-positive and gram-negative  strains of bacteria were exposed to various concentrations of the quarternary ammonium over different periods of time. Three cultures were prepared for each contact model to check on the effect of either pre-treatment and after-treatment with phospholipids or of CPC-exposure without the addition of phospholipids. The results obtained demonstrate that EPL are able to "receive" gram-negative bacteria like E. coli, P. aerug. and Morax. glucidol. after exposure to lethal concentrations of CPC for 30 min. While the "phenomenon of restoration" depended on the dose of phospholipids applied, the time of expsure to phospholipids proved irrelevant. The stabilisation of bacterial membranes due to EPL is discussed as a possible explanation of the phenomenon of restoration.


[Synthesis and characterization of some cardenolide glucuronides and sulphates (author's transl)]. Cardenolide glucuronides are synthesized in the following way: firstly cardenolide glucosides are prepared by the reaction with acetobromglucose; secondly the hydroxymethyl group of the glucose moiety is oxydized in presence of a platinum catalyst to the carboxyl group of the final glucuronic acid. Glucuronides of the following cardenolides are prepared and described: digoxin, digoxigenin, digitoxin, digitoxigenin-monodigitoxoside, digitoxigenin, and 3-epi-digitoxigenin. Sulphates of digoxigenin, digitoxigenin, and 3-epi-digitoxigenin are prepared by direct reaction of these cardenolides with chlorosulphonic acid in pyridine. The assumed structure of some conjugates has been confirmed by n.m.r. spectroscopy. A high water solubility (6.7-65.1 g/l), a minute chloroform solubility (0.0002-0.0005 g/l), and a low octanol/polar nature of these compounds. Inotropic or toxic cardiac activities of the conjugates are examined on isolated guinea pig papillary muscles and by the Hatcher method on cats. Conjugates with at least one digitoxose show cardioactivities comparable to digoxin or digitoxin. In contrast to that the conjugated genins indicate decreased activities which are at least one-tenth of the potency of the unconjugated glycosides.


[Affinity of polar digoxin and digitoxin metabolites for digoxin and digitoxin antibodies]. The affinities of some polar and non-polar digoxin and digitoxin metabolites to the related antibodies are largely dependent on the structure of their genin parts. Metabolites with unchanged genins show high cross reactivities towards their related antibodies when compared to the original immunogenic cardenolides. Towards the digoxin antibody the following cross reactivities were found: digoxin-16'-glucuronide 50%, digoxigenin 89.5%, and digoxigenin-3-glucuronide 85%. Values of the same order of magnitude were found with the corresponding digitoxin metabolites and the digitoxin antibody. In contrast, there is a marked decrease in cross reactivity caused by only minor changes in the genin part. With the digitoxin antibody the following cross reactivities are found: digoxin (i.e. 12-OH-digitoxin) 9.1%, 3-epi-digitoxigenin 5.6% and 3-epi-digitoxigenin-3-sulphate 1%. Bcause 12-hydroxylation has been reported to be one of several possible ways of digitoxin metabolisation in man, from a theoretical point of view erroneous results in the clinical digitoxin estimation by radioimmuno-assay are possible. In the case of all of the other metabolites the alterations in positive inotropic activity and cross reactivity run largely parallel.


The influence of polar and non-polar digoxin and digitoxin metabolites on the 86Rb-uptake of human erythrocytes and the contractility of guinea pig papillary muscles. The potency of various digoxigenin and digitoxigenin derivatives with different polarity was tested in two biological systems: First, in an 86-Rb-erythrocyte assay which allows to determine the influence on active cation transport (measured as the glycoside concentration exerting half maximal inhibition of 86-Rb-uptake of human erythrocytes = IC50). Second, with isolated guinea pig papillary muscle, which allows to determine glycoside effects on contractile force (measured as the glycoside concentration exerting 100% increase of contractile force = C+100%). The IC50 of the substances covered a range from 3.2 to 4800 X 10(-9) M, the C+100% from 0.7 to 978 X 10(-6) M. In both assay systems the glucuronides of glycosides and genins were between 1.4 and 11 times less potent than the original substances. A highly significant correlation (p less then 0.0001) was found between IC50 and C+100% (r = 0.9996) and between log IC50 and log C+100% (r = 0.9819), the slope for the latter correlation being nearly unite (= 0.9912). The results support the hypothesis that inhibition of active cation transport is and important step in glycoside incuced posite-inotropic effect.


[Fate of orally administered beta-acetyldigoxin in man (author's transl)]. After oral administration of 3H-beta-acetyldigoxin to four patients aspirates of gastric and duodenal contents were obtained with intestinal tubes. Concentration of label in the aspirates was measured. Radiochromatographic analysis of the aspirates showed that 90% of the beta-acetyldigoxin was unchanged during the period  it was in the stomach. In the duodenum a small part of the administered dose was transformed to 3H-alpha-acetyldigoxin. When given 3H-beta acetyl-digoxin intraduodenally to three subjects in the portal vein blood 93% of the labelled compunds was 3H-digoxin. According to these data the absorption of beta-acetyldigoxin can be described as follows: After oral ingestion beta-acetyl-digoxin rapidly passes the stomach with a half-life of 10 min. Most of the glycoside is absorbed unchanged in the duodenum. On passage through the intestinal wall the acetyl group is removed and digoxin is the active drug reaching the heart.


[Studies on the pharmacokinetic equivalence of pivampicillin base and hydrochloride in capsules and tablets (author's transl)]. Absorption and urinary excretion of pivampicillin as hydrochloride and as base were studied following administration of four different formulations to 12 healthy volunteers in a cross-over study. A fluorimetric assay of ampicillin was adapted to be used with an Auto Analyzer system. The plasma concentrations observed are comparable to those reported in the literature. The amount of drug absorbed is the same for all four medications whereas absorption is more rapid from tablets than from capsules. Base and hydrochloride of pivampicillin are equivalent with respect to pharmacokinetic behaviour. So, the formulation itself seems to be more important for biological equivalence than the ionisation of the drug used in the formulation.


[Biopharmaceutic investigations with D-norpseudoephedrine (author's transl)]. The concentrations of D-norpseudoephedrine in the plasma of 6 healthy persons were measured after the oral administration of 60 mg D-norpseudoephedrinehydrochloride in a hard gelatin capsule. One-compartment open-model parameters were derived from the blood levels. No gastric absorption was observed. The intestinal absorption started after a lag time of 0.31 h with an absorption constant of 1.75 h-1. The maximum of plasma concentration with 200 ng D-norpseudoephedrine/ml plasma was reached after 1.3 h. The following monoexponential decay of the plasma concentration curve had a half-life of 3 h. 24 h after ingestion no remaining D-norpseudoephedrine could be detected in the plasma. In vitro absorption constants were measured with the Sartorius-Resorptionsmodell. The in vitro results agreed with the in vivo results. The dissociation constant of D-norpseudoephedrine was determined (pKa = 8.92) with a non-logarithmic titration method.


Some laboratory aspects of hepatic tolerability of diftalone. The hepatic tolerability of phthalazine-(2,2-b)-phthalazin-5,12-(7H,14H)-dione (diftalone--administered at the dosage of 750 mg/day p.o. for a mean period of 23 days--has been studied in 40 patients by means of: total plasma protein, albumin, fibrinogen, serum glutamin-oxalacetic transaminase, serum glutamic-pyruvic transaminase, lactic dehydrogenase, creatine phosphokinase, alkaline phosphatase, glycemic curve after glucagon and plasmatic elimination of bromosulphalein. A statistically but not clinically significant increase of the SGPT level is the only change observed.


Effect of pyritinol-GCl on blood flow and oxidative metabolism of the brain in patients with dementia. In order to test whether and in what way pyritinon-HCl affects cerebral blood flow and oxidative metabolism in patients with organic brain disorders, the following parameters were measured in a group of 87 patients: cerebral blood flow using the Kety and Schmidt method, cerebral consumption of oxygen and glucose, and also CO2 and lactate ouptut. 45 out of the 87 patients were given pyritinol in a dose of 900 or 1000 mg/day, 42 out of 87 patients formed a control group and were given 500 mgof 5% laevulose i.v. daily for the average duration of the study of approximately 3 weeks. The results can be summarised as follows: 1. Cerebral blood flow and oxidative metabolism are changed in patients with organic brain disorders in different ways voth as regards quality and quanitity. Findings from earlier investigations could thus be confirmed. 2. When laevulose only was used, the parameters measured did not alter on average. In addition to deteriorations in the findings, spontaneous improvements or normalisationof previously disturbed cerebral blood flow and cerebral metabolism values were also abserved. 3. Pyritinol-HCl usually improved previously disturbed cerebral glucose metabolism significantly. An effect on disturbed cerebral blood flow or pathologically changed cerebral oxygen consumption was not found.


[On the clinical evaluation of therapy with nifedipine in association with various anithypertensive drugs (author's transl)]. During a double-blind cross-over study of 3 weeks duration 42 hypertensive outpatients with prevailingly mild angina pectoris received 30 mg daily of 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonic acid dimethylester (nifedipine, Bay a 1040, Adalat) daily or placebo, respectively. 30 patients (mean age: 47 +/- 10 years, mean weight: 79 +/- 13 kg, mean height: 169 +/- 7 cm) completed the whole study period. The mean recumbent blood pressure was 158 +/- 26 mmHg syst. and 101 +/- 16 mmHg diast., the heart rate averaged 74 +/- 12 beats/min. Under these criteria the two cross-over groups of 14 and 16 patients are well comparable. 6 patients dropped out because of side effects under nifedipind (compared to 2 patients under placebo). With one exception mean blood pressures were reduced by less than 10 mmHg during the application of nifedipine as compared to controls, this being true for systolic and diastolic pressures as well as for different positions during measurements. This result is also independent of the corresponding pre-values measured. The differences between the treatment phases did not reach statistical significance. Clinically a blood pressure reduction of this degree is rarely of consequence. But 3 patients reported hypotensive symptoms about 30 min after nifedipine. Nifedipine did not seem to influence the heart rate.


Effect of pirenzepine, a new gastric acid-inhibiting agent, on exocrine pancreatic secretion in man. The effect of orally ingested 5,1-dihydroxy-11- (4-methyl-1-piperazinyl)-acetyl-6H-pyrido(2,3-b)-I, 4-benzodiazepin-6-one dihydrochloride (LS 519, pirenzepine), a newly developed compound with gastric secretion-inhibitory action but without central-nervous sedation, on the secretion of fluid into the duodenum and on pancreatic enzyme output was studied by a marker perfusion technique in 10 human subjects. A short-lasting increase in duodenal volume was observed, while output of trypsin and lipase remained unchanged. Central and autonomic nervous actions seem unlikely, a possible release of endogenous secretion was discussed.tin was discussed.


Oral antipyretic therapy. Evaluation of mefenamic acid (short communication). The capacity of N-(2,3-xylyl)anthranilic acid (mefenamic acid) to reduce fever in children was compared with that of acetylsalicylic acid, paracetamol and amino-phenazone. The series of cases consisted of 71 patients in the age range from 3 months to 15 years and with rectal temperatures above 38.5 degrees C. Temperatures were recorded at 15 and 30 min, and 1, 2, 4 and 6 h after challenge with the drug. The antipyretic effect of mefenamic acid in a dose of 4 mg/kg was optimal: it was 2.5 times that of acetyl-salicylic acid or paracetamol and nearly similar to that of aminophenazone. It seems possible that the antipyretic effect of mefenamic acid is stronger than its anti-inflammatory and analgetic properties.


[Basic physiological requirements for therapy of coronary insufficiency (author's transl)]. The determining factors of coronary blood supply are described. The dependence of the coronary vascular resistance and the coronary extra-vascular resistance on the oxygen requirement and metabolism products of the heart muscles on one hand, and the various haemodynamic parameters on the other, are delineated. Based on this conception the principles for a therapy of coronary insufficiency are deduced. The difficulties, however, which limit this therapeutic procedure are also mentioned.


[Prophylaxis of myocardial infarction and follow-up treatment (author's transl)]. There is no specifique prophylaxis of myocardial infarction; it is identical to prophylaxis of coronary artery disease, that is elimination of risk factors and treatment of ischemic heart disease, if diagnosed in the preinfarction stage. Treatment in the postinfarction stage is dependent on symptoms. Of special importance is the diagnosis of life-threatening arrhythmias, which might necessitate prophylactic antiarrhythmic treatment. The value of "clinical" (hospitalised) rehabilitation is still debated, especially with regard to physiological and prognostic aspects. Surgery will be of increasing importance, especially aneurysmectomy (infarctectomy) and revascularization.


[Therapy with coronary dilators].

[Therapy with coronary dilators]. The pathophysiological basis of antianginal therapy with vasodilating agents is critically reviewed. The concept of specific coronary vasodilation should not be pursued in the search for new antianginal agents. Although controlled clinical trials with coronary vasodilators in patients have been successful, no inferences can be drawn as to the concept of coronary vasodilation since most of these compounds vasodilate only the coronaires of experimental animals after i.v. administration but not those of humans after oral ingestion. The stimulating influence of coronary vasodilators on coronary collaterals is an interesting but so far unproven claim. Nitroglycerine dilates the large epicardial coronary vessels. This effect can be of significance in excentric stenoses where the arterial wall is to a small part intact.


[Combined therapy with glycosides and Ca++-antagonistic agents (author's transl)]. Ca-antagonistic drugs increase cardiac oxygen supply by a coronary vasodilator action whilst they simultaneously lower myocardial oxygen demand. The latter drug effect is due to a decrease in cardiac contractile energy expenditure both directly (restriction of myocardial contractility) and indirectly (reduction of arterial blood pressure resulting from systemic vasodilation). In coronary disease all these factors can contribute to an improvement of the disturbed myocardial energy balance. As to the coronary vasodilator action of Ca-antagonistic drugs in particular, it is important to note that they readily relax the smooth musculature of the major extramural stem arteries where most of the occlusive atherosclerotic intima processes (about 95%) are located. In contrast, other coronary vasodilators such as adenosine, dipyridamole, chromonar, lidoflazine, theophylline, which lack Ca-antagonistic properties, are primarily acting on the small intramural resistance vessels of the heart whereas vascular smooth musculature originating from the major extramural arteries is less affected. Therefore, in elderly atherosclerotic patients the possible risk of glycoside-induced vasoconstriction in extramural coronary stem arteries (and also in arteries of systemic circulation) can be sufficiently eliminated only with the help of Ca-antagonists.


[Investigations of the reaction kinetics in the formation of 7-chloro-2N-nitrosomethylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide (author's transl)]. The influence of alcohol, ascorbic acid, phenol and thiocyanic acid on the formation of N-nitrosochlordiazepoxide from chlordiazepoxide and nitrous acid was investigated by means of high-performance liquid chromatography.


Synthesis, structure and antibacterial activity of some alkyltriazenopyrazoles. A series of bis-beta-chlorethyl-, dimethyl- and diethyltriazenopyrazoles (I-IV) were synthesized. By the method of IR spectroscopy the most probable transformation form of I was shown. The compounds were tested as antibacterial agents on a series of bacterial species. It was established that only one of them (VI) possessed a low inhibitory effect. All the rest inhibited strongly the growth of Staphylococcus aureaus 209 and E. coli 387.


Effects of chloroquine on the adrenocortical function. III. Sex differences in concentrations of cholesterol and ascorbic acid in the suprarenal gland after a single administration of chloroquine in the rat. Effects of single doses of 4-(4-diethylamino-1-methylbutylamino)-7-chloroquinoline (chloroquine diphosphate, Delagil Egyt) given orally (40, 80, 160 and 320 mg of base/kg) or s.c. (40, 80 and 120 mg of base/kg) upon cholesterol and ascorbic acid concentrations in the white rat suprarenal glands were followed up. The occurrence of signs of adrenocortical activation was found to be dependent on the route of application and sex of animals. Chloroquine given s.c. caused a decrease in ascorbic acid level only in doses close to LD50. The oral administration of chloroquine in doses of 80 mg/kg and more produced a significant decrease in cholesterol and ascorbic acid concentrations in the suprarenal glands of female rats, while in males chloroquine in any of the dose levels tested was without effect.


[Involvement of both H1- and H2-receptors in the depressor responses of blood pressure to histamine in the rat (author's transl)]. Histamine caused a dose-dependent fall in blood pressure. This dose-response curve could be shifted to the right by administration of dimethylaminoethyl-N-p-methoxybenzyl-N-alpha-aminopyridine (mepyramine; H1-antagonist). 1-Methyl-([(5-methyl-4-imidazolyl)-2-methylthio]-3-ethyl)-2-thiourea (metiamide; H2-antagonist) alone had no effect on the histamine dose-response curve. The combination of both antagonists caused a further dose-dependent shift to the right. These results found in anaesthetized rats indicate the presence of both histamine receptors in the circulatory system of the rat.


A new cephalosporin derivative (ST-21) orally administered in laboratory animals. The pivaloxymethyl ester of 7-(D-2-amino-2-phenylacetamido)-desacetoxicephalosporanic acid hydrochloride (ST-21) and cephalexin possess the same bacteridal activity. In fact, in the animal body ST-21 releases cephalexin. The acute toxicity study shows the good tolerance of both substances, whereas the tissue distribution is different, both after oral and i.v. administration. Cephalexin concentrations in some tissues of rats and rabbits, particularly in the lungs and kidneys, are higher and longer-lasting in the animals treated with ST-21 than in those receiving cephalexin, thus showing a different pattern of distribution in the body. For this reason ST-21 might be more suited for the treatment of lung and kidney infections.


Steroidal influence on the resynthesis of adrenomedullary hormones. Short communication. The role of glucocorticoid on the resynthesis of catecholamines was studied in the pigeon. Hydrocortisone was administered to the reserpinized pigeons. The steroid treated birds were autopsied along with the reserpinized controls. It was found that epinephrine production was considerably increased in the steroid treated group, which indicated that hydrocortisone had effectively triggered the methyl transferase activity during the restitution phase of catecholamines.


In vitro metabolism of lidoflazine by rat and dog liver fractions. Lidoflazine was metabolized very rapidly by 16000 g supernatant fractions of rat and dog liver. The rate and the extent of metabolism were considerably superior for rat liver. Lidoflazine metabolites were purified by extraction and thin-layer chromatography and identified by mass spectrometry. The main pathways of the in vitro metabolism by rat and dog liver fractions were the same. Oxidative N-dealkylation was the most important. An incubation of major metabolite 1-[4,4-bis(4-fluorophenyl)-butyl]piperazine, with rat liver fraction was performed. A hydroxylated metabolite and a ketopiperazine metabolite were detected only in the dog experiments.


Pharmacokinetics and metabolism of 14C-glipentide, a new antidiabetic, after oral and intravenous administration. The pharmacokinetic study of 14C-glipentide in male Wistar rats shows, at 0.2 mg/kg doses, that blood radioactivity drops quickly. The metabolization is effected in the liver and leads to four labelled metabolites which are eliminated mainly by the bile. The physiological disposition of unchanged glipentide can be described by a two-compartment open model. Autoradiography and quantitative studies have shown that the liver presents the highest concentration of radioactivity, that diminishes to a very low value 96 h after the administration. In the other tissues the radioactivity is never large, even following repeated administrations. The plasma protein binding does not change with the time, and it can be presumed that binding forces of glipentide and its metabolites to plasma proteins are similar. Glipentide is very well absorbed. The urinary and fecal elimination of radioactivity is similar after oral and i.v. administration.


[The value of radiographical examination for the evaluation adjuvant disease in the rat (author's transl)]. Radiographical examinations of the rat with adjuvant disease reveal characteristic changes in the joints and soft tissues which are useful for the evaluation of this experimental arthritis model. Sequential radiographical analysis with estimation of radiological joint score allows a close follow-up of the disease, which parallels some clinical parameters. Being objective and easy to be documented this method shows several advantages over the conventional evaluation methods. Furthermore, it enables an insight into the paraarticular and spine involvement, which otherwise remains uncovered. The radiographical evaluations might provide some additional and eventually essential information in the study of some drug effect in this disease. Our data should encourage the use of this method for the evaluation of the adjuvant disease in the rat.


Further evidence for the induction of proteolysis by coumarin in rats with various high-protein oedemas. It has been shown that coumarin can induce lysis of tracer protein injected into animals with normal limbs as well as such with various high-protein oedemas. Although this experiment greatly underestimates protein lysis, burn treated groups showed significant increases in protein fragments of both the body and limb. Although the reverse was the case for the group with lymphoedema and for the group with lymphoedema in combination with burn, the results could be explained by incorporation of the fragments into protein not precipitable with trichloroacetic acid (TCA) in the maturing phagocytes of the lesion. Coumarin alone cannot induce this proteolysis, it needs the tissues and the cells within them.


[Long-term infusion technique via tail vein in unrestrained rat. Technical short communication (author's transl)]. A technique is described that allows tail vein infusion in the rat up to several weeks without the risk of pressure necrosis of the tail. By the aid of a simple metallic device the catheter is protected against damage by the animal. Since this armament is well tolerated and the mobility of the rat remains unimpaired, psychic stress is minimized.


Absorption studies with the anti-diarrhoeal agent ethacridine lactate in laboratory animals and man. Tritiated 2-ethoxy-6,9-diaminoacridine (ethacridine lactate, Rivanol) has been orally administered to rat, dog, rabbit and man, and the distribution of radioactivity between urine and faeces determined. Complete recoveries of radioactivity were obtained from rat, rabbit and man. From direct measurement of levels of radioactivity, the maximum percentage of the dose excreted via the urine varied from 1.7% (man) to 6.1% (dog). Tritiated water accounted for nearly 50% of this amount. The low levels of radioactivity in plasma of dog and man and in the bile of rats following administration of 3H-ethacridine lactate suggested that there was only a low degree of oral absorption and substantiated previous reports that the drug is essentially unabsorbed in man. From fluorimetric measurements and the determination of levels of radioactivity in ether extracts of urine, it could be concluded that for all species less than 0.1% of the dose appeared in the urine as acridine-like material.


Haemodynamic effects of a new anti-anginal drug, diltiazem hydrochloride. The haemodynamic effects of a new anti-anginal drug, dilitazem HCl, were studied in 20 patients with angina pectoris. The 131I-dilution method was used. In two patients, one with atrial septal defect and the other with pulmonic regurgitation, heart catheterization was carried out. The drug exerted significant decrease in stroke volume, cardiac output, cardiac work, stroke work and cardiac output/circulating blood volume ratio. The patients who underwent direct cardiac catheterization disclosed no changes in Vmax and ejection fraction, but there were decreases in stroke volume. The decrease in cardiac work and stroke work after after diltiazem Hcl therapy was apparently due to diminution of venous return and prolongation of systemic circulation time. It is postulated that such a decrease leads to inhibition of myocardial oxygen consumption, which in turn has beneficial effects on angina pectoris.


Biological properties and clinical application of propolis. I. Some physico-chemical properties of propolis. The presence of 19 elements has been shown in the ethanol extracts of propolis (EEP). Three fractions have been obtained by filtration through a structural gel that did not show an initial antibacterial activity when investigated separately. Fractions 2 and 3 joined together have regained this activity. EEP solutions maintain their anitbacterial activity in acidic or neutral pH. Insensitivity of EEP solutions on temperautre of 75 degrees C for 30 min has been found.


Effect of prolactin and bromocriptine on growth of transplanted hormone-dependent mouse mammary tumours. Administration of ovine prolactin alone supported growth of hormone-dependent GR mouse mammary tumours. Growth of hormone-independent tumours was not stimulated. Furthermore, administration of bromocriptine, a compound that inhibits release of prolactin from the pituitary gland, was shown to inhibit the growth of hormone-dependent tumours in animals receiving treatment with progesterone + oestrone. Administration of prolactin or bromocriptine to mice bearing tumours that grew independently of progesterone + oestrone treatment had no influence on tumour growth. We conclude that direct as well as indirect evidence has been found for the involvement of prolactin in the growth of transplanted, hormone-dependent GR mouse mammary tumours.


How often is genital yeast infection sexually transmitted? We analysed data from a computer-based bank of clinical records of patients seen in a clinic for sexually transmitted diseases over a three-year period to investigate the association between genital yeast infections and sexually transmitted diseases (STDs). We classified STDs as primary and secondary syphilis; gonorrhoea; lymphogranuloma venereum; trichomoniasis; scabies; pediculosis; genital herpes; warts; and molluscum contagiosum. Of a total of 2984 disease episodes among women, 1054 (35-3%) included yeast infections, whereas only 382 (6-9%) of 5501 episodes in heterosexual men were associated with yeast infections, We found a significant association between yeast infection and STD and non-specific genital infection (non-specific urethritis (NSU) and procitis in men, and female contacts of men with NSU), which suggested that yeast infection was sexually acquired in 414 out of 1054 disease episodes in women (39%) and 110 out of 382 episodes in heterosexual men (29%). We conclude that sexually active patients with genital yeast infections should be screened for other STDs particularly non-specific genital infection.


Growth hormone, insulin, and prolactin secretion in anorexia nervosa and obesity during bromocriptine treatment. We studied secretion of growth hormone (GH), insulin, and prolactin in eight women with anorexia nervosa and nine women with refractory obesity before and during treatment with bromocriptine, 10 mg/day. In the anorexic patients the raised plasma GH concentrations occurring during an oral glucose tolerance test fell significantly while on bromocriptine treatment, but there was no change in plasma insulin or blood glucose concentrations. In the obese patients, however, plasma GH concentrations remained low during the oral glucose tolerance test, and were not modified by bromocriptine. Blood glucose and plasma insulin concentrations were also unchanged. Plasma GH and plasma 11-hydroxycorticosteroid responses to insulin-induced hypoglycaemia were unaffected. Serum prolactin concentrations which were raised in five anorexic patients and marginally raised in two obese subjects, fell significantly in both groups during treatment. We observed no consistent weight changes in either groups.


[Scintillography using tensio-active pulmonary iodine-131 (surfactant I-131)]. Using 200 microCuries of surfactant iodine 131, for the first time in the world, we took surfactant scan in 2 patient with hyaline membranes and compared with normal images. No intolerance, or radiotoxicity was found 3 months of clinical follow-up of the subjects. The results are very encouraging; a great variety of clinical situations, including hyaline membrane, can be now examinated with this new technic and radiocompound and given new perspectives in its study and diagnoses and through knowledge of its pathophysiology.


Caustic ingestions: a rational look at diluents. Treatment of lye ingestions by antidotes recommended on product labels includes the use of acid neutralizers. The possibility that heat produced by this exothermic reaction increased tissue damage was examined in vitro. Although Drano produced heat with all diluents including water and milk, acid antidotes prolonged the duration of high temperature. Clinitest tablets neutralized with milk produced no temperatures above 40 degrees C. The ready availability of milk or water, their acceptance by the child, and lack of toxic side effects make them diluents of choice for alkaline corrosive agents.


Tolamolol in the treatment of hypertension: an open evaluation study. The effect of tolamolol 50-300 mg three times daily in the treatment of 30 patients with mild-severe hypertension was studied. The duration of therapy in the majority of cases was 3-6 months. There was a highly significant reduction of mean blood pressure (p less than 0.001) for the group as a whole. Overall, 61% of patients became normotensive or showed a reduction in severity of hypertension, In the majority of cases, this improvement occurred within the first four weeks of therapy. There was not postural hypertension. Apart from one patient with Prurigo Besnier who developed asthma, another patient who developed severe headache and a third patient who stopped treatment without giving a reason, treatment was well tolerated and there were no other serious side or toxic effects.


More evidence for the recessive inheritance of selective adult type lactose malabsorption. Selective adult type lactose malabsorption appears in childhood or adolescence because of the great decline in jejunal lactase activity. There is strong evidence that this is a genetically determined disorder. Specifically, selective adult type lactose malabsorptions seem to be inherited by a single autosomal recessive gene. In the present prospective study the transition from the state of lactose absorption to that of lactose malabsorption was documented for the first time in two Finnish boys who were at risk for selective adult type lactose malabsorption because the parents of both boys had the disorder. At the age of 14 and 9 years, respectively, the boys had normal lactose absorption. Three years and 7 months and 4 years and 5 months later, respectively, the boys were shown to have lactose malabsorption. The period of documented transition averaged less than 4 years. These manifestations clearly strengthen the genetic model proposed.


[Needle biopsies of sarcomas of the breast: cytomorphology and DNA cytophotometry (author's transl)]. When needle biopsies are done on all palpable changes in the breasts, some sarcomas of the breast can be found. The cytomorphology of this mesenchymal tumor is described and the differential cytology is discussed. In some of our cases the relative content of DNS of the cell nuclei in the smear was determined by quantitative cytophotometry in a Feulgen Stain. It was found that the DNS  values of lymphosarcoma and spindle cell stromal sarcoma were within the norm of class 2C to 4C. The DNS content of angiosarcoma and polymorphous stromal sarcomas showed wide variations up to class 8 C. The result is discussed in view of automated cytological diagnosis.


Sex counseling of the elderly.

Sex counseling of the elderly. A sympathetic, nonjudgmental approach may reveal sexual dissatisfactions to be the basis of vague complaints about health, opening the way to counseling, changes in drug regimens, and referrals that can greatly improve quality of life.


A syntactic investigation of verbal autistic, mentally retarded, and normal children. The syndrome of childhood autism is typified by major abnormalities in language development, yet there are few systematic descriptions of autistic children's linguistic systems. We have, therefore, begun a comprehensive investigation of the language of verbal autistic children and concentrate in this paper on comparing the syntax used by 10 verbal autistic children matched for nonlinguistic mental age with a group of mentally retarded subjects and normal controls. Two different means of assessing syntactic development were utilized: Lee's Developmental Sentence analysis and Chomsky's Transformational analysis. The autistic group was found to rank significantly lower than either the mentally retarded or the normal groups in terms of Developmental Sentence Scores. When a transformational grammar was used to describe the language samples of our subjects the autistic children were typified by a higher error rate and lower level of complexity compared to the other two groups. However, the results also indicate that the grammatical system of autistic children is rule-governed and probably not unlike that of young normal or retarded children. In conclusion, it appears that the syntactic abnormalities characteristic of autism are attributable to an extreme delay in language development as well as to an impaired ability to make use of linguistic rules.


Communication training in mute autistic adolescents using the written work. The expressive and receptive use of three written words was taught to three mute autistic adolescents using a procedure based on Terrace's errorless discrimination model and Premack's language training with chimps. Expressive language was measured by the subject's selection of the appropriate word card from among the available alternatives when the corresponding object was presented. Receptive language was measured by the subject's selection of the appropriate object from among the available alternatives when the corresponding word card was presented. The sequence of the presentations and the order of placement of the available alternatives were randomized. The three subjects required 979, 1,791, and 1,644 trails, respectively, to master both the expressive and receptive use of the three words. The correct response rates for the three subjects over the entire training program were 92, 92, and 90%, respectively. It was concluded that, as concrete visual symbols, written words may provide a viable communication system for the mute autistic. The implications for treatment are discussed and suggestions for future research are made.


Hand preference in autistic children and their parents. Hand preference was tested in groups of between 40 and 50 autistic children and in sex-, age-, and ability-matched controls. Results were also compared with existing findings on normal children. Small differences occurred between the groups in the directions which would be predicted on the assumption that mental subnormality is associated with delayed development of normal patterns of handedness, and on the hypothesis that autistic children as a group will show a persistent slightly increased tendency to use the left hand. Parents of the autistic group were also assessed for handedness. Contrary to the prediction of slightly increased sinistrality in this group of subjects, some indication of increased dextrality occurred. Results were discussed in relation to possible genetic factors in the etiology of autism.


Thyroxine toxicosis in patients with iodine induced thyrotoxicosis. Serum concentrations of thyroxine (T4) and triiodothyronine (T3) were measured in 74 untreated hyperthyroid patients. Of these, 47 had Graves' disease, 12 had toxic nodular goiter and 15 had iodine induced thyrotoxicosis (IIT). The average serum T4 concentrations were, respectively, 13.5 microgram/100 ml and 13.3 microgram/100 ml (normal 4.5-10.3 microgram/100 ml). The average serum T3 concentrations were in the same order 732 ng/100 ml, 505 ng/100 ml and 378 ng/100 ml )normal 116-288 ng/100 ml). Of the 15 patients with IIT 5 had a pattern of T4-toxicosis (T4 larger than or equal to 10.5 microgram/100 ml; T3 less than 290 ng/100 ml). This pattern was not found in any of the patients from the other two groups. In IIT the ratio between the serum concentrations of serum T4 and T3 is similar to the one observed in normal individuals from non endemic areas. In patients with Graves' disease and toxic nodular goiter the increase in serum T3 is twice as high as the increase in serum T4. It is concluded that in IIT the serum concentrations of T3 and T4 increase in parallel while in the other two groups there is a preferential secretion of T3. As a consequence, a pattern of T4 toxicosis is a likely event in IIT and, when present, may constitute a biochemical characteristic of the condition.


Imaging of spontaneous canine tumours with ammonia and L-glutamine labeled with N-13. Ammonia and 6-glutamine, labeled with N-13, were tested as imaging agents for a variety of spontaneous canine tumors. The imaging capabilities of these compounds were compared with each other, with other scanning agents, and with radiologic and pathologic procedures. Good agreement between positive gamma images and postmortem findings occurred in 11 of 15 cases with [13N] ammonia as the localizing agent. Eight of the nine scans using [13N] glutamine as the imaging agent showed positive correlation with postmortem findings. In cases where both ammonia and glutamine were used to image the same lesion, no qualitative differences in tumor uptake were found between the two.


Immunologic aspects of human colostrum and milk. III. Fate and absorption of cellular and soluble components in the gastrointestinal tract of the newborn. A group of formula-fed infants were administered a single feed of poliovirus IgA antibody-rich human colostrum 18 to 72 hr after birth. Subsequently, the presence of IgG, IgA, and IgM immunoglobulin and poliovirus antibody activity was determined in serial serum and fecal samples of the neonates. Absorption of IgA immunoglobulin from the colostrum to the circulation was observed in three infants who were fed with colostrum between 18 and 24 hr after birth. Another group of infants of tuberculin-positive mothers who were being breast fed by their own mothers were followed for the development of in vitro correlates of cell-mediated immunity against tuberculin after prolonged breast feeding. Tuberculin-specific proliferative response was observed in the peripheral blood lymphocytes of two neonates after 5 weeks of breast feeding. The responses were undetectable after 12 weeks, although the infants continued to breast feed. No tuberculin reactivity was observed in the cord lymphocytes. These observations  suggest uptake of IgA immunoglobulin and components of cellular immunity in the intestine during the immediate neonatal period.


Toxicity kinetics and clinical potential of subarachnoid lymphocyte infusions. The feasibility of intrathecal lymphocyte infusions was examined since patients with gliomas are known to have circulating, tumor-specific, cytotoxic lymphocytes. Human (xenogenic) and syngenic lymphocytes were infused intrathecally into rabbits, and the toxicity and kinetics of the infused cells evaluated. Cerebrospinal fluid cell counts rose to as high as 70,000 lymphocytes/cu mm 12 hours after infusion and then dropped logarithmically over several days. No infiltration of host cells into the subarachnoid space in response to the lymphocyte infusions was detected. Evidence is presented that intrathecally infused lymphocytes may escape into the systemic circulation. Toxicity was minimal, especially following syngenic intrathecal lymphocyte infusions. A systemic allergic response, characterized by choroid plexitis and pulmonary edema was noted following a second xenogenic but not after a second or even a third syngenic lymphocyte infusion.


Iron absorption in infants: high bioavailability of breast milk iron as indicated by the extrinsic tag method of iron absorption and by the concentration of serum ferritin. Breast feeding is thought to result in a lower incidence of iron deficiency than does the use of unfortified cow milk forumalas, but there is scant documentation for this belief. The relationship of breast and cow milk feeding to absorption of iron and to iron status was investigated in a total of 45 term infants at about six months of age. Iron absorption was measured by total body counting. Laboratory assessment of iron status was based on the serum ferritin, hemoglobin, mean corpuscular volume, and transferrin saturation. The results indicated that infants fed breast milk during the entire first six to seven months of life attained greater iron stores than did those fed a cow milk formula. Breast-fed infants absorbed an average of 49% of a trace dose of extrinsic iron administered during a breast feeding in contrast to about 10% reported to be absorbed from cow milk under similar conditions. The data indicate that term infants who are breast fed may not require routine administration of supplemental iron.


Pharmacokinetics of methsuximide and a major metabolite in dogs. The pharmacokinetics of methsuximide and its major metabolite 2-methyl-2-phenylsuccinimide were studied in dogs after single intravenous doses. Plasma methsuximide levels were described by a two-compartment open model, and those of the metabolite were described by a one-compartment open model. An expression was derived that describes both methsuximide and metabolite plasma levels after methsuximide administration. Excellent fits were obtained between observed data and those predicted from the model. The metabolite accounted for 40% of the overall elimination of methsuximide, and the half-life of the metabolite (15 hr) was much greater than that of the parent drug (1--3.5 hr). The results suggest that pharmacological effects after methsuximide administration may be due primarily to the metabolite, which may accumulate in the body during repeated doses.


Plasma isosorbide dinitrate concentrations in human subjects after administration of standard and sustained-release formulations. After sublingual administration of 5 mg of isosorbide dinitrate, mean plasma concentrations (+/-SD) peaked (8.9+/-3.1 ng/ml) at 15 min after dosing and declined with a half-life of 30 min. After oral administration of 5 mg, mean concentrations peaked (3.1+/-0.7 ng/ml) at 30 min and declined with a half-life of 40 min. After oral administration of 20 mg in a sustained-release tablet, mean concentrations initially peaked (1.4+/-1.2 ng/ml) at 40 min, declining to 0.9+/-0.5 ng/ml after 8 hr. Mean concentrations were maintained above half the mean peak level during 10 hr. Because of probable rapid first-pass metabolism, the bioavailability of isosorbide dinitrate after administration of the oral dose of the standard tablet was 58% of that from the sublingual dose, and the bioavailability from the sustained-release tablet was 47% of that from the sublingual dose of the standard tablet. The time course of mean plasma concentration data could be described by a one-compartment model; but a more complex model, taking the pass effect into account, probably is needed for a better description of the pharmacokinetics of isosorbide dinitrate.


Nature and rate of neoplasia found in captive wild mammals, birds, and reptiles at necropsy. The nature and rate of neoplasia found at necropsy of captive wild animals of the Zoological Society of San Diego collection were studied. Neoplasia was present at necropsy in 2.75% of 3,127 mammals, 1.89% of 5,957 birds, and 2.19% of 1,233 reptiles. Neoplasms were not detected during 198 necropsies of amphibians. Gross and histologic examinations were performed on the 92 mammalian, 111 avian, and 28 reptilian neoplasms. The lesions were diagnosed. The findings findings included a high frequency of lymphosarcomas in birds and reptiles, multiple lung adenomas in mammals, multiple endocrine tumors in 2 European mouflons (Ovis musimon), and proliferative lesions of the biliary and pancreatic ductal systems in several species.


Chlamydia and non-specific urethritis.

Chlamydia and non-specific urethritis. Chlamydia organisms were found in 42 per cent of patients with non-specific urethritis and these organisms probably were the cause of the urethritis. Contact is by venereal means. The drug of choice is 500 mg. tetracycline every 6 hours for 10 days.


Purified duck embryo rabies vaccine. An accelerated schedule for preexposure immunization against rabies. Seroconversion and adverse reaction rates were studied in 92 persons given four or five doses in a two-week period of duck embryo rabies vaccine (DEV) or duck embryo rabies vaccine purified by ultracentrifugation (P-DEV). Mouse-neutralizing antibodies developed in 78 of 92 (84.8%) persons in these accelerated schedules. There were no significant differences in the frequency of antibody conversion or in geometric mean titers of antibody between persons given either vaccine. However, local and systemic adverse reactions were substantially less common with P-DEV. These data suggest that four of five doses of DEV or P-DEV given in a two-week course can be used for preexposure prophylaxis in situations where the more drawn-out regimens would result in continuation of a high-risk of rabies exposure. The antibody response of persons given this more accelerated regimen must be determined.


Ultrasound. A new diagnostic approach to the jaundiced patient. Evaluation of the jaundiced patient's condition frequently can be difficult. Clinical history, physical examination, liver function tests, and other laboratory data are often inconclusive in differentiating extrahepatic obstruction (surgical jaundice) form intrahepatic cholestasis (medical laundice). During a 14-month period, we have evaluated 40 cases of jaundice of unknown causes. Ultrasound was able to correctly diagnose pathologically proved extrahepatic obstruction in 23 of 24 patients and intrahepatic cholestasis in 15 of 16 patients. There was one false-positive and one false-negative result in this series.


Causes of perinatal mortality in the US Collaborative Perinatal Project. The underlying causes of 80% of perinatal deaths were identified in a study of 53,518 pregnacies in the United States: 17% of the deaths were due to amniotic fluid infections, 11% to abruptio placentae, 10% to premature rupture of the membranes, 9% to congenital anomalies, 6% to large placental infarcts, and the rest to more than 20 other specific disorders.


Dieting and peroneal nerve palsy.

Dieting and peroneal nerve palsy. In seven patients, peroneal nerve palsies developed while they were on weight-reduction diets. Five palsies were unilateral; two, bilateral. All patients recovered following diet modification. Therapeutic weight loss, of itself, can cause foot-drop. The prognosis is uniformly good.


Hyperthyroidism after propranolol withdrawal. Classic features of thyrotoxicosis developed in three patients with no prior history of thyroid disease shortly after the discontinuation of therapy with or decrease in doseage of propranolol hydrochloride. Graves' disease probably developed fortuitously after propranolol therapy was instituted, but the beta-adrenergic blockade masked the clinical features of hyperthyroidism. On discontinuation of propranolol therapy or decrease in propranolol dosage, previously latent thyrotoxicosis became manifest. If hyperthyroidism masked by beta-blockade is not recognized before withdrawal of propranolol therapy in patients with ischemic heart disease, the sudden appearance of thyrotoxicosis may lead to symptoms of increased myocardial ischemia.


Guillain-Barré syndrome in Greater New York-New Jersey. Epidemiologic data on 176 patients with acute Guillain-Barré syndrome observed over a nine-year period in the New York-New Jersey metropolitan area are presented. A striking predilection for patients aged 16 to 25 years, with a second lesser peak between ages 45 to 60, was found. Seasonal clustering of patients occurred, with nearly half the patients afflicted during the four-month period of late summer and fall. The distribution between men and women was equal. In this series 23% of the patients required tracheostomy, and 5% had a fatal course.


Essential hypertension in childhood.

Essential hypertension in childhood. Fifteen patients, aged 8 to 17 years, were found to have hpertension and were studied from February 1974 to Decemober 1975. Hypertension was defined as supine diastolic blood pressure repeatedly above 90 mm Hg. Five patients had a family history of hypertension. Extensive diagnostic evaluation performed in all cases failed to show an underlying cause for the hypertension. Patients with target-organ involvement were treated with hydrochlorothiazide; five of them are currently normotensive. Of the remaining nine untreated patients, four became spontaneously normotensive within eight to 14 months of the initial evaluation. These results suggest that extensive studies in children with hypertension may not be necessary in every case if clinical findings meet the critiera for the diagnosis of essential hypertension. These studies might be desirable, however, if target-organ involvement is present.


High elevations of creatine phosphokinase in hypothyroidism. An isoenzyme analysis. In hypothyroidism, slight elevations of serum creatine phosphokinase (CPK) levels are common. In contrast, we describe six hypothyroid patients with extreme elevations (17- to 160-fold) of CPK levels. Enzyme analysis showed only MM isoenzyme in four cases and MM plus trace MB isoenzyme in two patients. Hypothyroidism should, therefore, be considered when elevated CPK levels, even extreme, are found. Isoenzyme analysis in such a case will show primarily an MM pattern, although trace MB fraction can also be seen. This isoenzyme pattern suggests that the sources of the CPK elevations is skeletal muscle.


Malignant mesenchymoma and birth defects. Prenatal exposure to phenytoin. Malignant mesenchymoma developed in an 18-year-old patient with phenytoin-associated cleft lip and palate. Although these conditions may be related by chance, the possibility of transplacental carcinogenesis by phenytoin should be considered, especially since neuroblastoma was reported recently in two children with phenytoin-induced malformations. Following combination chemotherapy for metastases, the patient experienced a 7-year disease-free interval, which is consistent with recent improvement in the treatment of soft-tissue sarcomas.


Common cardiac prosthetic valves. Radiologic identification and associated complications. The development of prosthetic heart valves has been an important advance in the treatment of patients with serious valvular cardiac disease. Because there are many types of prosthetic valves, we have prepared a diagram of the valves currently or previously used and list their potential complications. Prosthetic valves were identified according to photographic and radiologic features, valve replacement location, and reported associated complications. Data have been compiled in tabular form for quick reference; valves have been identified according to valve base, cage, and poppet. They may be categorized as caged-ball or low-profile valves. Such information helps to provide recognition of the valve that has been inserted and permits the clinician or radiologist to be alert to possible complications with the various prosthetic devices.


Thyroid uptake of radioactive iodine in hyperthyroidism. We compared the 24-hour uptake of radioactive iodine (RAIU) in hyperthyroid patients diagnosed from 1970 to 1972 (Group A) and from 1975 to 1976 (Group B). Mean RAIU values in Group B decreased from those in Group A. In 1969 we lowered the normal range for the RAIU test to 0% to 24%, and used the new range for the diagnosis of hyperthyroidism in both groups of patients. The RAIU in Group B is within normal limits in 14% of the patients with Graves' disease and 80% of the patients with toxic nodular goiter (TNG). This study demonstrates that in our geographic area, the 24-hour RAIU has become a poor test for the diagnosis of hyperthyroidism, particularly TNG. However, the test should be performed before radioactive iodine therapy because it is necessary in calculating the therapeutic dose.


Factor VII deficiency and surgery. Is preoperative replacement therapy necessary? A patient with congenital factor VII deficiency (factor VII was 12%) had gynecologic surgery performed without prophylactic blood-product replacement therapy. Blood loss was not excessive. A review of 12 additional patients with factor VII deficiency who underwent surgery without replacement therapy showed that surgical bleeding was uncommon and that there was no relationship between factor VII levels and hemorrhage. It is proposed that patients who bleed may be those who also have a prolonged bleeding time or who have ingested aspirin shortly before surgery. It is all proposed that replacement therapy be available for use if required, but that its routine preoperative use is probably unnecessary in this disorder.


The mechanism of hypophosphatemia in acute heat stroke. Severe heat stroke may be associated with hypophosphatemia and hypocalcemia. Hypophosphatemia is generally observed within hours after onset, but hypocalcemia usually occurs on the second or third day, and after hypophosphatemia has undergone spontaneous correction. A young man displayed respiratory alkalosis during the course of severe heat stroke. The hypophosphatemia abated spontaneously as metabolic acidosis and acute renal failure supervened. Hypocalcemia became prominent and was more severe than that ascribable to uremia. Hypocalcemia was probably the result of calcium phosphate and calcium carbonate deposition in injured skeletal muscle.


Safe transfer of civilian burn casualties. The advisability of transporting severely burned civilian patients to a definitive burn-care facility during the first hours following injury is discussed and methods providing safe transport for 353 civilian burn patients are described. Feasibility of and methods for transporting patients over various distances are outlined and the problems of jet transportation presented. Adequate communication between referring and receiving physicians is imperative, as are adequate preparation before evacuation and maintenance of intravenous fluid resuscitation, intake and output records, and sterile technique during transport.


Predicting coronary heart disease in middle-aged and older persons. The Framington study. Of 1,025 men and 1,445 women, aged 49 to 82 years, who were free of coronary heart disease (CHD), 79 men and 63 women subsequently had CHD. Using a risk function based on cholesterol in the high density and low density lipoproteins, systolic blood pressure, left ventricular hypertrophy, and diabetes, less than 2% of the subsequent CHD cases were found in the lowest decile of risk, whereas 25% of the cases for men and 37% for women were found in the highest decile. Predictability held for each specific age group. This predictability was at least as good as that obtained by the usual CHD risk profile at younger ages.


Liver toxicity after acetaminophen ingestion. Inadequacy of the dose estimate as an index of risk. With increasing frequency, the physician is confronted with the problem of determining the risk of liver toxicity in a person who may have ingested an overdose of acetaminophen. To be effective, antidotal therapy must be given early after acetaminophen ingestion when the patient, despite the toxic injury occurring in his liver, may appear quite well. We have reviewed the cases of the first five persons who came to our institution with a history of having ingested a large overdose of acetaminophen. In each case plasma or serum acetaminophen levels were low and substantial liver injury did not occur. Measurement of acetaminophen levels, indicating the amount of drug absorbed, were a more reliable index of the risk of toxic liver injury and the need for antidotal therapy than the estimate of the dose ingested.


Maternal primary hyperparathyroidism of pregnancy. Successful treatment by parathyroidectomy. Primary hyperparathyroidism of pregnancy may result in spontaneous abortion, neonatal hypocalcemia, or neonatal tetany if appropriate treatment is not instituted. Of great importance in prevention of these complications is an awareness by physicians that this disease exists and is of clinical importance. Parathyroidectomy performed during the second trimester of pregnancy offers the best chance for fetal and neonatal survival. This operation results in little risk to either the mother or the fetus. Normal calcium homeostasis is restored to the fetus and the risk of hypocalcemia in the neonatal period is virtually eliminated.


Bile acid deconjugation in intestinal obstruction studied by breath test. Bile acid deconjugation was assessed by measuring specific activity of expired 14CO2 after the oral administration of cholyl-glycine-1-14C in 17 cases of intestinal obstruction, i.e. 15 mechanical and two paralytic. In the former, nine cases were operated and the remaining six cases were managed by the conservative treatment. Cumulative output of 14CO2 in breath for six hours before the treatment was 40.20=11.30 (mean+/-SEM) (control 2.96+/-1.16) but decreased to 6.86+/-3.64 after the treatment. Enteric bacteria capable of splitting amino moiety of the conjugated bile acid were found to be present more than 10(5)/ml. in the obstructed bowel content. Cumulative output of 14CO2 in breath for six hours in two paralytic ileus was lower than in controls. Deconjugated bile acid reported to inhibited water and electrolytes absorption in the small intestine may play an important role in fluid retention in intestinal obstruction.


The prophylactic treatment of retrolental fibroplasia. 10 premature infants with stage 3 retinopathy of prematurity have had photocoagulation and/or cryocoagulation therapy to one eye and have been followed for a period of 1-6 years. Although the long-term results of this therapy are not known, particularly in the prevention of retinal detachment, early observations suggest that treatment is neither harmful nor particularly beneficial. Macular dragging does not seem to be influenced by treatment. The refractive error, as one would expect, does not appear to be altered by this form of therapy. Marked amelioration of the vascular dilatation and tortuosity at the posterior pole is apparent shortly after treatment. It is stressed that this is a trial project and until more definite beneficial results are obtained, treatment of stage 3 retinopathy should be deferred. Retinal detachments (stage 4) may be quite amenable to a buckling procedure.


EEG and visual evoked responses in children with learning disorders. A study was made of 58 children with learning disorders, in all of whom a spontaneous EEG as well as a Visual Evoked Response (VER) was registered. The latencies in the secondary complex of the VER were increased and the amplitudes of waves II and III were increased as compared with normal subjects. Two subgroups--children with a good and children with a poor clinical test score--did not differ in VER parameters. A spontaneous EEG evaluated as abnormal was present in 45% of the children. These children showed more absence of peaks in both VER complexes and more increased latencies in the primary complex than children with a normal EEG. The findings show that the VER is a valuable supplement to EEG in demonstrating organic changes in children with learning disorders.


Cisternography with isotopes following posterior fossa surgery in children. Surgery of posterior fossa tumors is afflicted with some important problems. One of these is the postoperative communicating hydrocephalus. According to the literature this form of hydrocephalus is found in 10-30% of all children operated on; but a permanent shunt is necessary in only 8-18%. Aim of the present investigation was to find out disturbances of cerebrospinal fluid (CSF)--circulation and--reabsorption after posterior fossa surgery. Therefore 25 children ranging in the age from 3 to 12 years were examined on the basis of isotope cisternographic studies 8 to 21 after the operation. In 4 cases all parameters of pathological CSF-dynamics were found which required a permanent ventriculo-atrial shunt. 21 children showed a minimal or significant accumulation of the isotope in the posterior fossa but a normal circulation and a sufficient clearance on later scans. In these cases neither a temporary nor a permanent shunt was necessary. These findings are confirmed by follow-up examinations between 2 and 3 years.


Fucosidosis. II. Ultrastructure.

Fucosidosis. II. Ultrastructure. The ultrastructural changes of a sural nerve biopsy, liver biopsy and the autopsy of a case (I) of fucosidosis are described. Light microscopy revealed the presence of foam cells in various organs. The contents of the vacuoles stained positive with P.A.S. and Sudan. Electron microscopical examination showed inclusions in hepatocytes, Schwann cells and neurons. These inclusions had a single limiting membrane and contained heterogeneous structures, vesicular, multivesicular and membrane like structures, forming concentric lamellae. In another patient (case III) with a different clinical presentation and a different enzyme pattern (a reduced alpha-L-fucosidase activity, in combination with a reduced arylsulfatase A activity) similar abnormalities as in case I were found in a sural nerve and liver biopsy. It is suggested that the combined reduction of enzyme activity is responsible for the disease.


Basic rest activity cycle and stereotyped behavior of a mentally defective child. Stereotyped acts of a mentally defective girl, 6 1/2 years old, were observed from 6 a.m. til 8 p.m. during 16 days. Alternating phases of more or less frequent hand waving showed intervals of about 1 1/2 hours. Sleep stages were also determined by polygraphic recordings during 10 nights. As statistically proved the mean peak-to-peak interval of stereotyped activity at days corresponded with the mean REM-to-REM period of consecutive nights. This suggests, that the stereotyped hand waving of this child was driven by the BASIC REST ACTIVITY CYCLE (BRAC) already described by Kleitman. The mean periodicity of sleep cycles was represented by model rhythms adapted to the scored sleep stages. If the model rhythms of all 10 nights were extended backward to the preceding days, they paralleled the stereotyped activity. Thereby half periods found in phase with REM-stages approximatly corresponded to maxima of stereotyped activity. It will be discussed that the BRAC triggers motor and sensory mechanisms characterizing both the phases of enhanced stereotyped activity at day and REM stages at night.


Intoxication with primidone: continuous monitoring of serum primidone and its metabolites during forced diuresis. An 18 year old girl is reported, who ingested 15 g of primidone (Liskantin), 330 mg/kg, to commit suicide. Continuous monitoring of the serum levels of primidone, PEMA, and phenobarbital revealed increased elimination of primidone by forced diuresis (6000 ml/24 hours). It is concluded that forced diuresis inhibits the otherwise mandatory increase in primidone metabolites, PEMA and phenobarbital. It is suggested that even after improvement of the clinical symptoms forced diuresis should be continued for at least 48 hours. In epileptic patients the reinstitution of primidone therapy should be considered only on the third day after accidental ingestion, if the clinical symptoms have improved, and if there is no possibility of immediate determination of primidone serum levels.


Periodic lateralised epileptiform discharges in a case of diffuse cerebral cysticercosis. A case of diffuse cerebral cysticercosis is described. The case is of interest because the involvement of brain was extensive and bilateral but electro-encephalographically unilateral periodic epileptiform complexes were recorded on 3 different occasions. Possible mechanisms of these lateralised periodic epileptiform discharges are discussed.


[Preliminary results of treatment of hormone-dependent metastatic carcinoma of the breast with the bromocriptin-medroxyprogesterone acetate combination]. A brief account of the concept of hormone dependence in breast neoplasia is followed by the presentation of results obtained with an association of medroxyprogesterone acetate (MAP) and 2-bromo-alpha-ergocriptine (CB 154) in 14 women with metastatic cancer of the breast, hormone dependent due to the presence of the cytoplasmic receptor for 17-beta-oestradiol. All patients, in fertile or premenopausal stage, were subjected to prior surgical ovariectomy. MAP was given i.m. at a dose of 1 g/day for 30 days and then 150 mg/day. In the same time 2.5 mg CB 154 were administered every 6 hr per os. Evaluation in accordance with the criteria proposed by the Coop Breast Cancer Group showed that rapid improvement was obtained in all cases, persisting (at the time of writing) for a minimum of 6 months to a maximum of 2 yr of observation. In addition, rapid disappearance of pain was noted, particularly in subjects with secondary bone lesions. Side-effects were in all cases of slight consequence and suspension of the treatment was never necessary. The mechanism of the two drugs and the advantages of their association are discussed.


Visual abnormalities in a pregnancy following bromocriptin medication. A patient with hyperprolactinemia, amenorrhea, and an enlarged sella turcica, but without galactorrhea, was treated with Bromocriptin to effect restoration of ovarian function. The subsequent pregnancy was without problems from an obstetric point of view, but visual field abnormalities developed progressively, leading to termination of the pregnancy in the 39th week. However, within 1 week after delivery, the field defects disappeared and the visual acuity returned to normal.


Rapid prediction of pulmonary maturity by amniotic fluid lipid globule formation. Utilizing the surface tension (ST) lowering properties of an amniotic fluid lipid extract, it was noted that the amniotic fluid lipid layer formed a subsurface globule when the ST reached 36.9 dynes/cm +/- 0.1877 (SEM). The amount of required extract to achieve globule formation varied with the degree of fetal pulmonary maturity and the volume required could be used to differentiate pulmonary maturity (less than or equal to 320 microliter), transitional status (340 to 440 microliter), and pulmonary immaturity (greater than 460 microliter), as related to fetal outcome (amniotic fluid obtained within 48 hours of delivery). Of the 70 patients studied, the 7 (100%) who developed respiratory distress syndrome (RDS) were predicted correctly. Nine of 70 (12.1%) gave false negative results (predicted pulmonary immaturity, no RDS developed); there were no false positives. Globule measurements of a separate series of 74 samples were compared with their L/S ratios. Twenty-two of 24 (91.7%) samples termed mature had an L/S greater than 2.0, while 32 of 42 with a value termed immature had an L/S less than or equal to 1.9. The physical events in the establishment of the monolayer and subsequent globule formation are discussed. This method now provides a rapid and reliable screening indicator of fetal pulmonary maturity.


Pulmonary surfactant and amniotic fluid insulin. Immunoreactive insulin was measured in 66 amniotic fluid samples and the level compared to two indices of pulmonary surfactant activity, namely, lecithin sphingomyelin ratio and lecithin palmitic acid. An apparent inverse relation between lecithin and insulin was demonstrated after 34-35 weeks' gestation. These results tend to support the hypothesis that insulin can inhibit lecithin synthesis.


Coeliac disease and goitre.

Coeliac disease and goitre. Two cases of coeliac disease associated with thyroid enlargement are presented. One had a large simple adenomatous goitre which was removed surgically and the other had histological confirmation of lymphadenoma (Hashimoto's disease).


Metrizamide computed tomography cisternography: pediatric applications. The methodology and clinical use of metrizamide (Amipaque) computed tomography (CT) cisternography are described as applied in the cases of 22 children with morphologic and physiologic abnormalities affecting the cranial portion portion of the central nervous system. In contrast to pneumoencephalography, CT cisternography affords equivalent or superior visualization of the basal cranal subarachnoid spaces with simpler technique and low morbidity. Intrathecal metrizamide enchancement in children causes a very low incidence of side effects.


Mycotic aneurysm of the hepatic artery. Case diagnosed with radionuclide imaging and ultrasound. The authors report a case of hepatic mycotic aneurysm following Staphylococcus aureus septicemia and subsequent bacterial endocarditis. The diagnosis was made preoperatively using serial radionuclide imaging and ultrasound and confirmed by angiography and surgery.


The chromosomes of the transmissible venereal tumour of dogs in Ibadan, Nigeria. Cytogenetic studies on 11 transmissible venereal tumours in seven dogs in Ibadan, Nigeria, are reported. The number and the morphology of the chromosomes, as shown by the metaphase cells, revealed that the tumour cells have similar cytogenetic features to those reported in other parts of the world. The suggestion of common sources of infection for the animals in the different geographical locations of the world was supported.


Use of brom-ergocryptine in treating amenorrhea/galactorrhea. Seven women with amenorrhea and galactorrhea, and no evidence of pituitary adenoma, were treated with brom-ergocryptine for two to 24 weeks. All seven patients had the resumption of regular menses within eight weeks, but six patients required 24 weeks of therapy to completely cease lacting. Two of the five women attempting to conceive became pregnant. Four of the five nonpregnant patients had a total recurrence of their symptoms after discontinuing the drug. Brom-ergocryptine appears to be very effective in inhibiting prolactin secretion and thus reestablishing normal ovulatory menstrual cycles and fertility.


Evaluation of a new anti-fibrinogen-coated latex particle agglutination test in the measurement of serum fibrin degradation products. A new latex particle agglutination test (FIBROTEX) has been compared with the Thrombo-Wellcotest and the tanned red cell hemagglutination inhibition immunoassay (TRCHII) for sensitivity to purified fibrinogen and plasmic degradation products and for reactivity with 31 normal sera and 170 sera from patients with thrombotic disorders. The latex particles in the FIBROTEX are coated with antibodies against fibrinogen and fragment E (anti-FE), in contrast with the anti-fragment D and anti-fragment E antibodies which coat the latex particles of the Thrombo-Wellcotest (anti-DE). The relative sensitivities of the TRCHII and the anti-FE and anti-DE latex tests were, respectively, 0.5, 2.5 and 7.5 microgram/ml for fibrinogen; 0.5, 0.5 and 4.0 microgram/ml for fragment X; and 1.25, greater than 30 and 8.0 microgram/ml for fragment D. Compared with anti-DE, the anti-FE particles demonstrated fewer false-positive results with sera and urines of normals and higher titers, fewer false negatives and better overall correlation with the TRCHII results (r = 0.89 vs. 0.75) on pathologic sera. The FIBROTEX is simple and rapid (5 minutes) and provides a more sensitive and accurate determination of serum fibrin degradation products than the Thrombo-Wellcotest.


Soluble fibrin complexes in early fibrin digests. Early fibrin digests were analyzed in the ultracentrifuge and were found to contain compounds with molecular weights up to 3 X 10(6); these compounds are considered to be soluble fibrin complexes. Their similarity with intermediate polymers in inhibited clotting systems has been stressed. Their viscosity at low shear rates is extremely high; therefore, a rapid method to establish their presence in plasma would be the measurement of plasma and serum viscosity at low shear rates, moreover, they shorten the clotting time (thrombin time) of fibrinogen considerably.


The half-life of plasmic degradation products of human fibrinogen in rabbits. Human fibrinogen and purified plasmic degradation fragments X (stages 1 and 2), D and E were labelled with 125-I using the lactoperoxidase method. The chromatographic, electrophoretic and immunologic properties of the labelled proteins were found to be similar to those of non-labelled fragments. All the degradation products diffused rapidly (T 1/2 0.27-0.75 hours) from the intravascular space of rabbits, as compared with fibrinogen (4.26 hours). In addition, the metabolic half-life was found to be 49.3 hours for fibrinogen, as compared with only 5.6, 6.1, 2.3 and 1.4 for fragments X (stage 1), X (stage 2), D and E, respectively. The metabolic half-life roughly reflects the molecular size of the degradation products.


A new method for the determination of plasma activators fibrinolysis. The term "effective activator" of plasminogen is proposed, to denote the resultant of activator-antiactivator interaction, and a method for the determination of the level of these activators is described. By adding axcess plasminogen to the euglobulin fraction of plasma the influence of the level of endogenous plasminogen and of the antiplasmin is eliminated. It is shown that the level of fibrinogen has very little bearing on the results. An effective activator unit is defined as equal to 1 CTA unit of urokinase activity on a fibrinogen-plasminogen substrate.


Controlled trial of the sequential use of streptokinase and ancrod in the treatment of deep vein thrombosis of lower limb. Treatment with streptokinase ('Kabikinase') was given to 26 patients with venographically confirmed deep vein thrombosis extending into the popliteal vein or above. Treatment was continued for 4 days and the patients were allocated randomly to oral anticoagulant therapy or a course of treatment with ancrod ('Arvin') for 6 days followed by oral anticoagulant therapy. The degree of thrombolysis as judged by further venographic examination at 10 days was not significantly different between the 2 groups. The majority of patients showed clinical improvement but there was no appreciable difference between the groups at 3 and 6 months. Haemorrhagic complications were a more serious problem during the period of treatment with ancrod than during the equivalent period in the control group.