Effects of ethyl apovincaminate on the central nervous system. Side effects of ethyl apovincaminate (RGH-4405, Cavinton), a cerebral vasodilatory agent, on the central nervous system were studied on mice and rats. Anticonvulsive effect in electroshock was observed as major CNS effect, locomotor activity was reduced due to muscle relaxant effect. The compound had no sedative effect on rodents. Its analgesic effect was negligible. Cavinton had neither antidepressive, nor anticholinergic activity.


Pharmacokinetic data on tritium labelled ethyl apovincaminate. Absorption, tissue distribution and excretion of tritium labelled ethyl apovincaminate (RGH-4405, Cavinton) were studied. Both oral and i.p. administration resulted in a relatively rapid elimination of tritium activity, suggesting that neither the original drug nor its metabolites remained in the organism of rat. 50% of radioactivity was recovered in urine and 30% in faeces during 48 h. At this time only liver and kidneys contained measurable quantities of radioactivity among the organs tested. Biliary route of elimination seemed to be important, since 20% and 4% of radioactivity appeared in bile during 9 h following i.p. and p.o. administration, respectively. Enterohepatic circulation was of no consequence. Radioactivity was hardly adsorbed to or absorbed by blood cells and was almost completely bound by plasma protein(s).


Metabolism of ethyl apovincaminate in the rat. Ethyl apovincaminate (RGH-4405, Cavinton) is well metabolized in rat, and only a small fraction of the original compound is excreted in urine. The main urinary metabolite is apovincaminic acid, hydrolytical product of Cavinton produced partly by plasma esterases. In plasma only the original compound and free acid are detectable. Several other metabolites have been isolated from bile and characterized by mass spectrometry. Cavinton is hydroxylated at the indole moiety and forms conjugates (possibly glucuronide and sulfate). The glycine derivative of apovincaminic acid containing two hydroxygroups has been detected in significant amounts, analysed by mass spectrometry. Among minor metabolites vincaminic acid ethyl ester has been found. More than 80% of total urinary and 50% of total biliary metabolites have been identified by radiochromatography, mass and IR spectroscopy.


Summary of safety tests of ethyl apovincaminate. Subchronic toxicity test (4-week p.o. on rats with 25 and 100 mg/kg; 3-month i.p. with 5 and 25 mg/kg; 3-month i.v. with 2 and 5 mg/kg daily doses on dogs) and chronic toxicity tests (6-month p.o. on rats with 25, 50 and 100 mg/kg and on dogs with 5 and 25 mg/kg daily doses) were performed with ethyl apovincaminate (RGH-4405, Cavinton), a cerebral vasodilatory compound, to study adverse effects in adult age. Reproduction tests (male and female fertility test on rats p.o. with 10 and 50 mg/kg; teratogenicity test in midpregnancy on rats p.o. with 12.5, 25, 50 mg/kg, 15, 50, 150 mg/kg, and 15, 45, 135 mg/kg daily doses, i.v. with 3.13, 6.25 and 12.5 mg/kg daily doses; on rabbits p.o. with 6, 12 and 18 mg/kg daily doses; peri- and postnatal studies in late pregnancy on rats p.o. with 15, 45 and 135 mg/kg i.v. with 4.13, 6.25, and 12.5 mg/kg daily doses) were carried out to study harmful effects in various early phases of life. Local tolerance was studied after i.m. and i.v. application. It was concluded that the planned 3 X 5 or 3 X 10 mg daily oral dose, 1 X 10 mg i.v. dose of Cavinton were safe for human application in adult age. Although the compound proved not to be teratogenic, it is not recommended for administration to pregnant women because of liability of increased sensitivity in pregnancy. Therapy of women in fertile age should be interrupted in case of pregnancy.


Effect of ethyl apovincaminate on the cerebral circulation. Studies in patients with obliterative cerebral arterial disease. The effect of ethyl apovincaminate (RGH-4405, Cavinton) on the cerebral and systemic circulations has been studied in detail in ten cases of cerebrovascular disease. 10 mg doses of Cavinton were given as infusion within 4-6 min; circulatory tests were carried out prior to administration of the drug and 3-6 min after. The principal results showed the following: On Cavinton cerebral vascular resistance was strongly reduced, while cerebral fraction of cardiac output significantly increased. On acute effect of the drug arterial mean pressure slightly decreased but cerebral blood flow nevertheless increased in general. Total vascular resistance also decreased but this decrease was less marked than that registered in cerebral vascular resistance.


Rheoencephalographic and psychological studies with ethyl apovincaminate in cerebral vascular insufficiency. The effect of ethyl apovincaminate (RGH-4405, Cavinton) on the rheoencephalogram and memory functions was studied in 50 patients with ischaemic disturbances of cerebral circulation. The drug was administered in a single i.v. dose of 10 mg and orally three times daily 5 mg for a month. Improvement of cerebral circulation was observed after i.v. and oral medication. Blood flow was most markedly increased in the gray matter. The effect on arterial pressure was negligible. Improvement of memorizing capacity evaluated by psychological tests was recorded after one month of Cavinton treatment, associated with alleviation or complete disappearance of symptoms. No side-effects attributable to the drug were observed. It is pointed out that Cavinton is indicated in the treatment of ischaemic disorders of the cerebral circulation, particularly in chronic insufficiency.


Study on the vasodilator effects of ethyl apovincaminate in neurosurgical patients. Studies have been performed in a series of 44 neurosurgical cases. The patients were subjected to detailed neurological examination and EEG after admission and before being discharged. The effect of ethyl apovincaminate (RGH-4405, Cavinton) on cortical electric activity was investigated after the administration of 10 mg i.v. Cavinton. In cases on long-term courses of three times daily 5 mg Cavinton in tablets, control EEG was performed one and two months, respectively, after the start of medication. The state of vessels of the eye-ground was also checked. In cerebral angiography attention was concentrated on width of the vascular lumen and visualization of Cavinton effect on vessels which on account of narrowing or spasm had not filled up with contrast medium prior to Cavinton. During angiography the patients were given i.v. 10 mg. Cavinton diluted to 10 ml with physiological saline. In the cases where investigations failed to reveal any change requiring neurosurgical intervention and insufficient cerebral circulation had to be held responsible for the patient's condition, three times 10 mg Cavinton i.v. was administered daily as long as the patient was at our Department. After having been discharged these patients took three times daily 5 mg Cavinton in tablets. Duration of the course of oral Cavinton depended on the degree of improvement in the patient's condition. Cavinton was used with success in cases where cerebral circulation was damaged for functional or organic reasons. Allergic hypersensitivity did not occur in any of the cases, either on single doses or long-term use of parenteral or oral Cavinton.


The effect of ethyl apovincaminate on the circulation of the eyeground. Ethyl apovincaminate (RGH-4405, Cavinton), contrary to the active vasodilators used up to the present, increases blood pressure of the eyeground. Dynamics of the eyeground circulation has been investigated with fluorescein angiography performed at certain points of time. Blood supply of the macula lutea was increased in the first place by Cavinton.


Use of ethyl apovincaminate in ophthalmological therapy. Ethyl apovincaminate (RGH-4405, Cavinton) has been administered to 100 predominantly arteriosclerotic patients to increase circulation in the eyeground. Visual acuities improved in 88 cases, by 73% in average; in twelve cases there was no change, but deterioration did not occur. Improvement was still more significant (267%) in occlusions and retinopathies associated with atherosclerosis of the central retinal artery. The dose of Cavinton was 20 mg in drop infusion or three times daily 10 mg i.v. Side-effects, if any, disappeared spontaneously upon reduction of the dose. The improvement paralleled the increases of the blood pressures in the central retinal arteries. This increase of pressure head is suggested to dilate passively the vessels.


Preliminary report on the use of ethyl apovincaminate in affections of the eyeground. 26 ophthalmological patients have been given daily doses of three times 1 tablet (15 mg) ethyl apovincaminate (RGH-4405, Cavinton) for periods of from two weeks to three months. Improvement of visual acuity lasted as long as the course of treatment, in agreement with the results of other authors. On Cavinton effect blood flow increased in the retinal precapillary and capillary system, supply of hypoxic areas improved. Improvement noted in choroid sclerosis bears witness to the effect of Cavinton on choroid capillaries.


Vasodilating effect of ethyl apovincaminate on conjunctival vessels and simultaneous observation of parameters indicating adverse effect. The vasodilator effect of ethyl apovincaminate (RGH-4405, Cavinton) on conjunctival vessels and its possible adverse effects have been studied in 17 patients of varying age (16-78 years) and diagnosis, as well as in healthy individuals. Intravenous 10 mg doses of the drug increased the arteriolar lumen in each case, the most markedly at 30 sec after administration of the drug, but at 90 sec effect was still significant. Before starting Cavinton, on the next day following injection and on other mornings after administration, haemoglobin, the leukocyte count, SGOT, SGPT, thymol turbidity, and blood sugar were determined. In the eight cases of juvenile hypertension urinary serum proteins were also registered after quantitative testing. The parameters investigated did not reveal any sign pointing to toxicity.


Ethyl apovincaminate in the treatment of sensorineural impairment of hearing. Ethyl apovincaminate (EGH-4405, Cavinton) treatment has been used in various sensorineural impairments of hearing as well as in ear diseases associated with vertigo. As shown by experinces, presbyacusis, vascular impairment of hearing and in certain cases toxic hypacusia are improved by Cavinton. Besides audiometric improvement of pure tone, significant improvement was noted in the speech-audiogram in all three groups of disease. Certain affections of the ear accompanied by vertigo responded to Cavinton. In Menière's disease it has proved to be superior to the vasodilators used up to now.


Comparative study of the effect of ethyl apovincaminate and xantinol nicotinate in cerebrovascular diseases. Immediate drug effects on the concentrations of carbohydrate metabolites and electrolytes in blood and CSF. Randomly selected 34 cerebrovascular patients were treated with ethyl apovincaminate (RGH-4405, Cavinton) and 109 with xanitinol nicotinate. The effects of drugs given in slow i.v. infusions on the concentration of carbohydrate metabolites and electrolytes in serum and CSF were observed. Cavinton improved the paresis in 60.6% of patients while xantinol nicotinate did so only in 47.1%. On the basis of the biochemical changes it can be concluded that Cavinton enhances both the glycolytic and the oxidative glucose breakdown in CNS.


Ethyl apovincaminate therapy in neurovascular diseases. Of a series of 100 patients 46 were given combined (i.m. and oral) treatment with ethyl apovincaminate (RGH-4405, Cavinton) in daily doses of 10-30 mg; 54 were put on oral Cavinton (30-45 mg daily). Significant and relatively quick improvement was obtained in reversible vascular diseases, such as hypertensive encephalopathy, intermittent vascular cerebral insufficiency, in the early stage or light cases of cerebral endarteriitis and cerebral arteriosclerosis. On Cavinton effect hypoxic character of the EEG improved, and so did performance in psychodiagnostic tests, alertness and memory in the first place, furthermore changes of the eyeground. The doses administered did not damage parenchymal organs, they did not cumulate and when used in combination incompatibility could not be observed.


Quantitative structure-activity relationships. IV. Non-linear dependence of biological activity on hydrophobic character: a new model. A new model is derived for the dependence of biological activity on hydrophobic character from a simple hypothetical system. Unlike the parabolic Hansch model this model can explain the peculiar effect that for homologous series of compounds the logarithms of biological activities of the lower homologs are linearly dependent on hydrophobic character, while for the higher homologs the relationship between biological activities and hydrophobic character changes to a parabola. Although these relationships are known and several appropriate models were proposed, the bilinear model presented in this paper is the first which can be described by a simple and generally valid equation: log 1/C = a log P--b log (beta - P + 1) + c While the parameters a, b and c can be calculated by linear multiple regression analysis, the non-linear term beta must be derived by a stepwise iteration process or ty Taylor series iteration. Examples are given for comparison of the bilinear model and the parabolic Hansch model.


Metabolic degradation of propanidid by various tissues. Short communication. The very short anaesthetic action of 3-methoxy-4-(N,N-diethylcarbamoyl-methoxy)-phenylacetic acid propylester (propanidid, Epantol) is due to its rapid hydrolysis in vivo. In this study, the rates of degradation of this drug under the influence of various isolated tissues have been established. The drug was hydrolysed much more rapidly by liver homogenate than by whole blood or serum. It is concluded that inactivation of propanidid in vivo occurs mainly by the liver, whereas blood esterases play an insignificant part in hydrolyzing the ester. Moreover, it was demonstrated that cardiac tissue is able to hydrolyze the drug as well. It is postulated that the inactivation of propanidid by heart muscle might partly compensate for the severe cardiodepressive action of the anaesthetic agent. A gaschromatographic determination of propanidid has been developed.


[N-Methylphenethylamine, an indirect sympathicomimetic agent in vegetables (author's transl)]. N-Methylphenethylamine, a secondary amine present in vegetable foodstuffs, in concentrations up to 6.6 ppm, is an indirectly acting sympathomimetic amine; on i.v. injection the circulatory effects correspond to 1/80 to 1/100 of those of epinephrine. Following enternal application pressoric and positive chronotropic effects are observed during appr. 30 min; the no-effect level amounts to about 7 mg/kg.


[The course of blood pressure and organ changes in rats with DOCA-hypertension]. In 45 control rats and 47 nephrectomized, DOCA-implanted, hypertensive rats (hypertensive phase), blood pressure, weight gain, development of pathologic-anatomical histological changes as well as changes in the myocardial enzyme pattern were studied over 24 weeks and after absorption of the DOCA tablet the return of the animals to normal conditions (follow-up phase) for another 14 weeks. During the hypertensive phase, blood pressure rose to 233 mm Hg on the average within 10 weeks and remained constant up to the 22nd week. In the follow-up phase, it dropped sharply, at first, and then slowly returned to normal. Weight gain was the same in DOCA and control rats. Relative weights of heart, kidneys and liver were elevated in the hypertensive phase but fell again in the follow-up phase. The pathologic-histological changes formed in the hypertensive phase, such as myocardial hypertrophy, glomerular hyalinization, tubular dilation and perivascular fibrosis, were remitted in part. Unchanged, however, the enhanced heart score persisted evidencing a proliferative vasoconstriction. Except for a pronounced, reversible increase in MAO activity, the cardial enzyme pattern remained unchanged during the experiment.


[Study on novel morphine antagonists in the animal experiment (author's transl)]. The morphine-antagonistic properties of 5 novel compounds, (--)N-(3-Furylmethyl)-nordesomorphine-hydrochloride-monohydrate (Wa 494-Cl), (--)N-(3-Furylmethyl)-3-hydroxy-morphinan-methansulfonate (Mr 1257 MS), (--)2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-dimethyl-6,7-benzomorphan-methansulfonate  (Mr 1452 MS), (+/-)-2-(3-Furylmethyl)-2'-hydroxy-5,9alpha-diethyl-6,7-benzomorphan-hydrochloride (Mr 1302 MS), (--)-N-(3-Furylmethyl)-noroxymorphon-methanesulfonate (Mr 1767 MS), have been examined with different methods on mice and cats. Their properties have been compared with those of naloxone, cyclazocine and nalorphine. The new test compounds showed a profile of action like naloxone.


[Studies on the metabolism and distribution of 14C-sodium nitroprusside in rats (author's transl)]. Studies on the in vivo degradation of 14C-labelled nitroprusside (NP) were conducted in rats and indicated that the primary product was cyanide and not thiocyanate. With the administration of higher doses of sodium nitroprusside (NNP; Nipruss) cyanide, thipcyanate, Fe++ and Fe+++ were evident in the blood plasma, whereas [Fe(CN)6]4- and [Fe(CN)6]3- were not detected. The biological half-life for the disappearance of nitroprusside was about 2 min with a dose of 0.4 mg NNP/kg and was 28 min with a dose of 6.25 mg NNP/kg. Nitroprusside and its degradation products, cyanide and thiocyanate, were eliminated mainly in the urine. Significant accumulation of nitroprusside did not occur either in blood vessel walls, in smooth muscles, or in parenchymal organs.


[Studies on the interactions of chlordiazepoxide, nitrazepam, and diazepam with phenprocoumon (author's transl)]. The interaction of benzodiazepine derivatives with phenprocoumon (Marcumar) was investigated after a single dose of the combination of phenprocoumon/diazepoxide (Librium), phenprocoumon/diazepam (Valium) and phenprocoumon/nitrazepam (Mogadan) had been applied to rats. By means of the high pressure liquid chromatography (HPLC) the change of concentration of these pharmaceutical agents per unit time in serum was determined and related to the corresponding change of prothrombin-time. Hence it can be concluded that the benzodiazepine derivatives influence the distribution of phenprocoumon in the organism.


[Distribution and excretion of a glycosaminopolysulfate in the rabbit after parenteral application (author's transl)]. The pharmacokinetics of unlabelled and tritium-labelled glycosaminoglycan polysulfate (GAGPS) was examined by gel chromatography, electrophoresis and radiometry. The compound was given i.m. and, for comparison, i.v. In both cases (dose: 7.5 mg/kg) blood levels after 1 h reached maxima of approx. 6 mug/ml and remained between 2.0 and 1.5 mug/ml for between 24 and 48 h. The question of threshold-limited excretion is discussed. The concentration curves of the synovia were almost identical to those of the blood. The cartilage of the joint had a comparable level after 48 h (1.7 mug/g), whilst the level was lower in rib cartilage (1.1 mug/g). Urinary excretion within 24 h amounted to 45% of almost unchanged GAGPS. A further 10% were excreted within the following 24 h. The residue was distributed chiefly in the kidneys, liver, skin, spleen, gut, and bone marrow. In the course of the elimination time the excreted substnace showed a lower molecular weight as was found by gel chromatography.


Effects of chloroquine on the adrenocortical function. II. Histological, histochemical and biochemical changes in the suprarenal gland of rats on long-term administration of chloroquine. White female Wistar rats were used in order to study the influence of long-term oral application of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline (chloroquine) in doses of 30, 40 and 80 mg of base/kg upon the suprarenal gland. Histological, histochemical and biochemical findings give evidence of adrenocortical activation induced by chloroquine at all dose levels tested. The differences between the signs of adrenocortical activation as observed after the various doses were only those of quantity and time onset. The results indicate that the stimulation of the suprarenal cortex produced by repeated administration of chloroquine is not solely a manifestation of toxic action of chloroquine.


Serum kinetics and urinary metabolism of dimethophrine in rat. The serum kinetics and urinary metabolism of an a-sympathomimetic amine 1-(3,5-dimethoxy-4-hydroxyphenyl)-2-monomethyl-amino-ethanol (dimethophrine) were studied. For serum kinetics, seven groups of 6 rats were sacrificed at 0.083, 1, 2, 2, 4, 6 and 12 H, respectively, after tail administration of dimethophrine-7-3H. Only 1 group of 6 rats was placed into metabolism cages to collect urine at 12-h intervals during the 72 h after dimethophrine-7-3H administration as above. The metabolic identification was made by thin-layer chromatography (TLC) and the radiochromatograms were obtained by the "scraping" method. This work shows dimethophrine to be unchanged in the urine of rat.


The mechanism of the vasodilator effects of histamine and 4-methylhistamine in the hindquarters of the cat. Intraarterial administration of histamine and 4-methylhistamine induced a fall in perfusion pressure of perfused hindquarters of the chloralose-anesthetized cat. Mepyramine which is a histamine H1-receptor blocker competitively inhibited the depressor effect of histamine without altering that of 4-methylhistamine. Continuous intravenous infusion of metiamide, which is a histamine H2-receptor blocker, to the mepyramine treated cats caused a further inhibition in response to histamine as well as 4-methylhistamine. These results indicate that both histamine H1- and H2-receptors are present in the vasculature of the cat hindquarters and both of them are responsible for the vasodilator effect of histamine.


Effect of 4-methylumbelliferone on the oxidative metabolism of liver mitochondria in jaundiced rats and its relationship of choleretic action. The effect of 4-methylumbelliferone (4-MU) on the oxidative metabolism of liver mitochondria and its relationship to choleretic action were investigated on 40 bile duct-ligated rats and 40 rats after biliary decompression. The oxidative metabolism of liver mitochondria fell rapidly to 50% of controls within 7 days after bile duct-ligation, whereas that in rats with 4-MU fell only slightly. Such effect of 4-MU on the liver mitochondrial metabolism was most prominent when it was administered to rats after biliary decompression. In rats with 4-MU the depressed oxidative metabolism of cholestatic liver mitochondria recovered rapidly toward normal with accelerated amelioration of serum total bilirubin as compared to that in rats without 4-MU after biliary decompression by loosening of the ligation of the common bile duct. Thus, 4-MU appeared to exert some stimulation or amelioration of the impaired liver mitochondrial metabolism due to jaundice, which may have a close relationship to its choleretic action or effective bile excretory action.


[Specific incorporation of labelled tissue homogenates into the homologous organs of the rat (author's transl)]. The time course of the incorporation of radioactivity into the liver, kidney, heart, spleen, lung, adrenal glands, and testes following subcutaneous application of L-histidine-2,5-T-labelled homogenates of liver, kidney and heart has been measured in 105 male Sprague-Dawley rats aged 3 months (weight: x = 350 g). The homogenates had been prepared from organs of rats of the same age, sex and weight, each labelled with 400 muCi L-histidine-2,5-T. The maximal incorporation of activity from the homogenates into the organs investigated has been found 24 h after injection. In the kidney, however, an additional peak appeared already 5 h post applicationen. The comparison of the activities of the liver, kidney and heart, taking into account the differences in organ metabolism, revealed a significantly higher incorporation into the homologous than in the non-homologous organs. This specific incorporation appeared 2 h after the injection and could be found until about 24 h. The type of labelling, the method of sample preparation and the time of absorption allowed to conclude that the specific affinity to the homologous organs might have been due to a relatively small amount of short peptides. The functional significance especially for the regeneration of impaired organs has been discussed taking into account earlier results.


Effect of 1,5-dicaffeoylquinic acid on ethanol-induced hypertriglyceridemia. Short communication. Male Wistar rats were administered acutely and chronically ethyl alcohol. The effect of 1,5-dicaffeoylquinic acid (cynarine) on ethanol induced hypertriglyceridemia and on hepatic concentration of triglyceride was investigated. In rats treated acutely with ethanol the serum and hepatic triglycerides showed significant rise by 216 and 111%, resp. The prolonged administration of ethanol caused insignificant increase of the serum triglyceride concentration by 40%, while its hepatic content was significantly increased by 100%. In rats receiving ethanol and cynarine simultaneously, distinct reduction of the serum and hepatic triglyceride concentration was observed.


Pharmacological aspects of pyrazoline derivatives from 2-hydroxy-butenolides. A series of pyrazoline derivatives was synthetised and evaluated for toxicological and pharmacological effects; analgesic, hypnotic, anti-inflammatory, antipyretic and cardiovascular properties were screened. Tested compounds were found to have a low toxicity; one of them showed a good analgesic activity without side effects.


Inhibition of gluconeogenesis by sodium nitroprusside in the perfused guinea pig liver. Sodium nitroprusside was found to be a very strong inhibitor of the glucose formation from lactate in the perfused guinea pig liver. Hepatic cell respiration and oxidative phosphorylation appeared to be simultaneously suppressed by this compound. The pattern of some hepatic metabolite concentrations was similarly affected by nitroprusside as described for biguanides and pyridinium chloride derivatives. Cyanide had to be added to the perfusion medium in a tenfold higher concentration to achieve a comparable inhibition of gluconeogenesis from lactate.


Absorption and disposition of econazole nitrate after application to the skins and vaginas of rabbits. 1. The absorption and tissue distribution of radioactivity has been studied in rabbits after application of a cream containing 10 mg of the 3H-labelled 1-(2,4-dichloro-beta-[(p-chlorobenzyl)oxy]phenethyl) imidazole nitrate (econazole nitrate, Pevaryl) to the normal or abraded skins of rabbits. 2. Approximately one-third of the dose was absorbed through the occluded normal skins of rabbits during 8 days, mainly during 7 to 24 h. In the same time interval, slightly more of the dose was absorbed through the occluded abraded skins of rabbits at slightly greater rates. Co-formulation of triamcinolone acetonide in the cream reduced and delayed the peak rates of absorption through normal and abraded skin, but the extent of absorption during 8 days was similar in the presence or absence of triamcinolone acetonide. 3. After application to normal skin or abraded skin, the peak of mean concentrations in the plasma of 220 ng/ml (range 132-276 ng/ml) or 307 ng/ml (range 270-321 ng/ml), respectively, occurred at 24 h. Tissue distribution of radioactivity was similar after application to normal or abraded skin, and concentrations were highest in the liver, kidneys and gastrointestinal tract (which are the organs of biotransformation and excretion) and also in the adrenals and to a lesser extent in the uterus, ovaries and untreated skin. 4. After application of a cream containing 5 mg of 3H-econazole nitrate to the vaginas of rabbits, approximately one-third of the dose was absorbed during 8-24 h, and rates of excretion were higher through the more permeable vaginal membrane. 5. After vaginal doses of 5 mg, a peak concentration of 209 ng/ml occurred at 6 h in the plasma. Tissue concentrations of radioactivity after vaginal doses were highest in liver, kidneys, gastrointestinal tract, adrenals and ovaries, and the tissue distribution was similar to that observed after cutaneous doses.


Self-administration of caffeine by the rat. Rats with permanently implanted right jugular vein cannulae were either pre-treated with increasing doses of caffeine for up to 98 h, or underwent no pre-treatment. Both groups were then presented with a lever, the pressing of which caused a self-injection of a caffeine solution. For both groups, some of the rats self-administered caffeine for up to 4 days and then their activity stopped; the other rats did not self-administered caffeine.


[A contribution to the subject of the parameters PQ, QRS and QT being functions of heart rate in the ECG of the beagle dog (author's transl)]. We examined the degree of dependency of the ECG parameters PO, QRS and QT on the heart rate. In 252 beagles of standardised breeding and accommodation (strain: Chbi : BEAGLE), a total of 1456 ECG recordings was made from the three Einthoven extremity leads, and the heart rate and PQ-, QRS-, and QT-times were measured. The animals used were dogs from eleven subacute toxicity studies. 683 of the registrations were obtained from control animals and 773 from drug-treated animals whose ECG curves had remained unchanged and in which no histopathological changes were found in the heart at the end of the toxicity studies. The data obtained were biometrically evaluated by regression and correlation analyses. The range of the heart rate was 34-238 actions/min, median value 108. The range of the PQ interval was 0.07-0.18 sec, the QRS interval 0.03-0.09 sec and the QT interval 0.14-0.26 sec. The median values were 0.11, 0.05 and 0.19 sec, respectively. Positive skew distributions were found. The data were transformed to obtain values with normal distribution. The various correlation coefficients were then heart rate/PQ time: -0.408 (p less than 0.001), heart rate/QRS time: -0.057 (p less than 0.05), heart rate/QT time: - 0.611 (p less than 0.001). This means that the PQ and QT intervals clearly decrease as the heart rate increases, whereas the QRS interval is only minimally affected. Correlation ellipses were also calculated and presented graphically. These show areas within which 50, 75, 90 and 95% of our values are to be expected.


[Suitability of various food mixtures for breeding and rearing of beagle dogs. 3. Methods and results for the Ingelheim team]. Two different modes of nutrition during breeding and rearing of dogs are investigated to determine which of them has the better effect. The use of a complete feed for breeding and maintenance (Altromin H) was compared with the use of a special breeding feed (Zahn Z), respectively, together with a special maintenance feed (Zahn H). A palatability test was made, a 2-year test for the effect on breeding, observation of weight gain and food consumption in the rearing phase on all the dogs of the strain Chbi:BEAGLE. The palatability test showed no preference for either diet. Initially, on changing diets, the dogs ate more of whichever new food was given. From 22 parameters which characterize the breeding effect the only statistically significant difference determined was an 11% higher consumption in the Altromin H group. Although in the rearing phase the food consumption in the Altromin H group was higher, male dogs in the younger age group made more weight gain on the special food (Zahn Z) and older bitches fed Altromin H were heavier for a time.


[A quantitative gaschromatographic method for the determination of p-chlorophenoxyisobutyric acid (clofibrinic acid) in human plasma (author's transl)]. The report describes a sensitive and selective GLC-method for the plasma level estimation of p-chlorophenoxyisobutyric acid (CPIB), the biologically active metabolite of clofibrate. After addition of an internal standard substance the acid is extracted and converted to its methylester by diazomethane. Following oral administration of equimolar doses of clofibrinic acid and clofibrate (445 and 500 mg, respectively) to 4 normal volunteers plasma concentrations could be measured for 72 h. A comparison of different pharmacokinetic parameters indicated that the two compounds gave almost identical absorption profiles in respect of CPIB. CPIB disappeared from plasma with a mean half-life of 17.6 h.


[Studies on the biotransformation of 5-vinyl-5-(1-methylbutyl)- and 5-vinyl-5-(1-ethyl-propyl)-barbituric acid (author's transl)]. After taking 5-vinyl-5-(1-methylbutyl)-barbituric acid (vinylbital, Speda) another not yet known metabolite (Sp 1) was isolated from urine and was identified as 5-vinyl-5-(1-methyl-3-carboxy-propyl)-bartiburic acid. Compound Sp 2a is 1-methylhydantoin. Presumably this compound is an artifact from creatinine. We have not yet been able to identify a third mercury(I)-nitrate-positive substance Sp 2b. The supposition that this compound were a metabolite of 5-vinyl-5-(1-ethyl-propyl)-barbituric acid could not be upheld. The three mercury(I)-nitrate-positive substances appearing in the urine after taking 5-vinyl-5-(1-ethyl-propyl)-barbituric acid, behaved in chromatographic analysis completely differently from the unknown compound Sp 2b. The substances were isolated. Two of them are the metabolites 5-vinyl-5-(1-ethyl-2-carboxy-ethyl)-barbituric acid and 5-(1-ethyl-propyl)-barbituric acid. We are not sure whether the third compound identified as 5-hydroxy-5-(1-ethyl-propyl)-barbituric acid, is formed in vivo, as the substance could have developed by oxidation or by the influence of peroxide contained in ether, as well. A product hydroxylized in the side chain, like in vinylbital, was not found in the metabolite urine of 5-vinyl-5-(1-ethyl-propyl)-barbituric acid.


[Pharmacokinetics and metabolism of trazodone in man (author's transl)]. After intravenous, intramuscular and oral administration of 25 mg 14C-labelled 2-(3-[4-(m-chlorophenyl)-1-piperazinyl]-propyl)-s-triazolo[4,3-a]pyridin-3-(2H)-one-hydrochloride (trazodone), plasma levels, elimination and metabolite pattern in plasma and urine were investigated. The plasma levels after all routes of administration are almost identical. The absorption of the compound is fast and complete. The elimination of radioactivity occurs in a biphasic manner with a half-life of 1 h for the earlier and 13 h for the second phase, no matter what application route had been chosen. The comparison of the plasma levels of fasted and non-fasted subjects shows a shift of the plasma maximum from 1.5 to 2.5 h following administration and a decrease in the maximum level of 30%. The radioactivity is excreted predominantly by renal processes (70-75% within 72 h). The main product in plasma is unchanged trazodone, whereas in urine it is found only in minute amounts. The radioactivity in urine is represented by conjugates that had formed after hydroxylation on the chlorophenyl residue (20%), by a dihydrodiol-metabolite of trazodone (15%) and by a carboxylic acid originating from oxidative cleavage of the parent compound (35%).


A comparative study of the hemodynamic effects of single intravenous doses of 3-hydrazino-6-[N,N-bis-(2-hydroxyethyl)-amino]-pyridazine-dihydrochloride and hydralazine. The new pyridazine derivative 3-hydrazino-6-[N,N-bis(2-hydroxyethyl)-amino]-pyridazine-dihydrochloride (DL 150 IT) was administered to five hypertensive patients at the dose of 50 mug/kg by i.v. bolus injection. A parallel group of five patiens received 250 mug/kg of hydralazine. Hemodynamic measurements were obtained before treatment, and then after 30--60 and 80-120 min. Cardiac output was evaluated by radiocardiography and myocardial perfusion by clearance of 86Rb. The antihypertensive effect of DL 150 IT was most pronounced 2 h after the injection, whereas by this time the increased heart rate and cardiac output tended to revert to the baseline values. On the contrary, the magnitude of these effects did not change during the observation period after hydralazine treatment. Both drugs increased myocardial perfusion. The new compound appears at least five times more potent than hydralazine and, possibly, has a longer duration of action.


[Intestinal absorption from therapeutic iron doses (author's transl)]. On a total of 105 persons with normal iron stores, iron depletion, and iron deficiency the intestinal absorption from therapeutic iron doses (100 mg Fe and 50 mg Fe as ferrous glycocoll sulphate) of a special galenic form was measured. The measurements were performed by means of a whole-body counter and preparations labelled with radio-iron (59Fe). Mean values of absorption rates from 100 mg Fe in healthy males were 5.0% and in healthy females 5.6% whereas in latent iron deficiency and in iron deficiency anemia mean values of 10% and 13% were obtained, respectively. The maximum absorption rate of 20 to 25% is reached already in the late stage of latent iron deficiency. Advancing severeness of iron deficiency is not followed by an increase of iron absorption. Investigations on 21 persons showed no significant difference between absorption rates of the galenic preparations used when administered orally before or after breakfast, respectively.


Effect of an ergot derivative on human lymphocyte chromosomes in vivo. Chromosome examination was made from 12 healthy adult male volunteers by using human lymphocyte cultures twice before, and 8 and 12 weeks after continuous intake of 3 X 1.5 mg Hydergine, an ergot derivative, per day orally. The mean frequency of cells with aberrations and the number of aberrations per 100 cells after 12 weeks' medication corresponded well with those of control cultures. However, for unknown reasons, significantly different values were found after 8 weeks of medication at a level of 5%, i.e., the values of capillary blood culture C8W were lower than those of CI, CII and C12W.


[Polygraphic sleep recordings in patients with endogenous depression before and after treatment with amitriptyline-N-oxide (author's transl)]. 15 endogenous-depressive patients were treated with 3 X 20 mg amitriptyline-N-oxide for 20 days. Polygraphic sleep recordings were taken during the first seven and last six nights. In a single-blind study the patients were given placebo for the first four days, amitriptyline-N-oxide was applied during the following 13 days and on the last three days placebo was given again. The statistical evaluation showed the following results: a) Latency times up to the first deep sleep and to the first REM-phase decreased under the effect of the substance. b) Relative sleep duration (without wakefulness) increased. c) Actual sleep duration (without wakefulness and stage A) was similar. d) The frequency of awakenings during the night diminished under amitriptyline-N-oxide and increased somewhat when placebo was given again. The original values were not reached. The frequency of awakenings from REM-phases increased during the first three nights of medication and decreased in the last three nights the substance was administered. When placebo was given again, the original values were exceeded. e) Duration of wakefulness after waking up during the night decreased under amitriptyline-N-oxide and increased when the medication was discontinued. Here again the original values were not reached. After waking up during the night most waking time was spent in stage C. A placebo effect can be excluded. The effects of amitriptyline-N-oxide are compared to those of hypnotics, other antidepressants, antipsychotics and tranquilizers in the discussion.


A sub-chronic study of the subjective quality of sleep and psychological measures of performance on the morning following night time medication with temazepam. A sub-chronic study of 7-chloro-2,3-dihydro-3-hydroxy-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (temazepam, Euhypnos) at three dose levels was carried out in 30 healthy volunteers. A matching placebo was given before and after the 4 nights of active compound. The subjective response was measured by means of a sleep evaluation questionnaire, and the objective measurements used were the critical flicker fusion threshold and choice reaction time. A clear dose-response relationship was seen in the subjective and objective measurements with the three doses used. A rebound phenomenon was seen only at the high dose levels in two subjective measures, viz. getting to sleep and behaviour following waking.


Pharmacology of dihydroxy-dibutylether, a specific choleretic drug. The choleretic and the general pharmacological properties of dihydroxy-dibutyl ether (Discinil) were investigated in several animal species. Discinil (DHBE) increased the bile flow in conscious rats and dogs, after both oral and i.v. administration. A choleretic effect was also observed after i.v. injection into anaesthetized rats and guinea pigs. A dose-response relationship was always obtained, the threshold dose being 25--100 mg/kg. No evidence of tachyphylaxis was observed in rats after repeated treatments. The bile hyperflow was generally accompanied by an increased excretion of the total dry residue in guinea pigs and dogs. The choleretic effect in rats was still present after pretreatment with either DL-ethionine (causing parenchymal liver damage) or atropine (blocking the cholinergic control of bile production). At low doses (25--100 mg/kg i.v.) eliciting a definite choleretic response, DHBE did not show spasmogenic and spasmolytic effects in vivo on the smooth muscles of the gallbladder of guinea pigs and dogs, neither on the stomach and intestine of mice and dogs; while it constricted the pylorus sphincter of rats. At larger doses (200--400 mg/kg i.v.) the compound showed a mild relaxing activity on Oddi's sphincter of guinea pigs and a weak spasmogenic activity either on gall bladder or on small intestine. In vitro, it caused an unspecific antagonism against the spasm induced by acetylcholine, barium chloride, histamine, 5-hydroxytryptamine and norepinephrine. In anaesthetized rats, rabbits and dogs, DHBE caused a moderate and short-lasting hypotension, and tachycardia. The threshold doses for these effects were 2--4 times superior to those being choleretic. In conscious dogs, the compound was slightly hypertensive. DHBE did not provoke important respiratory and ECG changes, neither showed diuretic nor antiphlogistic effects.


[On the determination of triamterene, hydroxythiamterene and hydroxytriamterene sulphate ester in biologica material by direct evaluation of thin-layer chromatograms (author's transl)]. The quantitative measurement of 2,4,7-triamino-6-phenylpteridine (triamterene), as well as its metabolites hydroxytriamterene and hydroxytriamterene sulphate ester, is described. Estimation of urine, plasma and faecal samples was achieved by a direct fluorometric method following separation on kieselgel plates. The procedure allows the simultaneous assay of the three substances on the plate without the need for previous chromatographic separation or derivatisation.


Synthesis and pharmacological study of diphenylalkylamines with cycloaliphatic residues. New coronary vasodilators. The paper describes the synthesis and the pharmacological evaluation of some derivatives of prenylamine, all with a cycloaliphatic ring within or instead of the isopropylamine moiety. Their general formulas are: (C6H5)2CH-CH2-CH2-NH-CH-CH2-R CH2 (I) (C6H5)2CH-CH2-CH2-NH-R' (II) where R contains and R' is a cycloaliphatic ring. Several compounds and particularly those of formula (I), and of formula (II), where the alicyclic ring had a bulky substituent in para were more active than prenylamine as coronary vasodilators on isolated guinea-pig heart (Langendorff). The most interesting derivative was M.G. 8926 [N-(3,3-diphenylpropyl)-alpha-methyl-beta-cyclohexylethylamine], which was more active than prenylamine on Langendorff's heart and in enhancing the pressor response to catecholamines and inhibiting the isoprenaline induced hypotension. Moreover, it had almost the same effects as prenylamine as spasmolytic, local and general anesthetic, on heart rate and arterial pressure and against coronary spasm from pitressin.


[Anaerobic serum ultrafiltration--a new method for determination of protein-binding rates of drugs under physiological conditions (author's transl)]. Only the free and not the protein-bound fraction of a drug shows pharmacologic activity. Therefore the rates of drug-binding to serum proteins are of great importance for clinical and pharmacological purposes. A basis prerequisite for accurate measurements are experimental designs giving the possibility of keeping the most important factors influencing the protein-binding rate within physiological ranges. In vivo these factors are, among others, the concentration of albumin, the absorption of different exogenous and endogenous substances to albumin, the type and the amount of ions present, the total ionic strength, the pH-value and hence the pCO2 as well as the temperature. An experimental set-up was described giving the possibility of keeping all these factors absolutely constant under in vivo conditions by means of a newly developed and simply to handle ultrafiltration device. From withdrawing the blood sample from the vein to the complete separation of the protein-bound fraction the blood sample can be processed under strictly anaerobic conditions (to prevent loss of CO2!). Compared to common methods generally used for the determination of protein-binding rates, such as equilibrium dialysis, column chromatography and ultracentrifugation, this new procedure saves a considerable amount of time. Within 1 h up to 8 samples can be processed in a single device. Besides short filtration times there is no need for any additional sample preparation such as buffering or adding antibacterial substances, etc.


[A new fluorometric method for the determination of drugs in biological material (author's transl)]. A description is given of a new method for fluorometric determination of drugs in biological material. The assay is based on photochemical transformation of non-fluorescent compounds in fluorophors by short-wave UV light. The pharmacokinetics of the 2-[4-(4'-chlorophenoxy)-phenoxy]-propionic acid (HCG 004) serves as an example to demonstrate the usefulness of this method; reference is also made to analogously successful studies of other drugs.


The effect of etafenone on the subcellular distribution of calcium and some oligoelements in heart muscle. Ultracytochemical and x-ray microanalytical study. In order to detect the subcellular localization of calcium in the myocardium of laboratory animals (rats and guinea-pigs) under the influence of 2'-(2-diethylaminoethoxy)-3-phenyl-propiophenone (etafenone, Baxacor) (4 mg, 20 mg and 100 mg/kg body weight) two ultracytochemical methods, with lead acetate and with potassium pyroantimonate, were used. In addition, X-ray microanalysis of myocardial fragments was performed. The correlation of ultrastructural, ultracytochemical and X-ray microanalytical findings provides direct evidence of the hypothesis that etafenone acts on myocardium as a so-called "calcium antagonist". The subcellular targets of etafenone action are mainly the sarcoplasmic reticulum and mitochondria. Etafenone modifies also the concentration of copper, zinc and selenium in myocardium. The effect of etaferone on myocardial calcium and oligoelements appears to be dose-dependent.


Oscillations and cysteine metabolism in aortic strips of hypertensive rats. Aortic strips of normal and hypertensive rats were used for the study. In comparison with normal rats hypertensive rats show a low cysteine and high homocysteine level and vascular auto-oscillations. The auto-oscillations are damped by cysteine, cAMP, theophylline and heparin but not by ADP.


[On the mode of action of heptaminol (author's transl)]. The effect of heptaminol, an aliphatic amine with an alcoholic group on carbon 2, on sympathetic nerves and on isolated chromaffine granules was infestigated. In cats, heptaminol caused long-lasting, dose-dependent pressor effects accompanied by tachycardia and contractions of the nictitating membrane. In comparison with tyramine, heptaminol was 100 times less potent in increasing blood pressure and 10 times less effective in inducing contractions of the nictitating membrane. The rise in blood pressure as well as tachycardia and contraction of the nictitating membrane were diminished by cocaine. After pretreatment with cocaine, heptaminol in high doses caused short-lasting depressor effects. Also in rats the pressor effect of heptaminol was weaker but of longer duration than that of tyramine. The dose-response curve was depressed by pretreatment with reserpine. The tachycardia induced by heptaminol was markedly diminished after pretreatment with reserpine. After repeated injections heptaminol reduced the norepinephrine content of the rat heart by 20-40%, Tyramine and hexylamine were more effective than heptaminol in depleting the norepinephrine stores of the heart (50-60%). In fluorescence microscopic investigations on sympathetic nerves (rat iris) depleted of norepinephrine by reserpine, the uptake of alpha-methylnorepinephrine could be inhibited or prevented by heptaminol. The spontaneous release of catecholamines from isolated bovine chromaffine granules was enhanced (+30%) by heptaminol or methamphetamine in high concentrations. In lower concentrations, however, both drugs reduced the uptake of 14C-epinephrine in isolated medullary granules by 20-40%. In addition a non-specific papaverine-like spasmolytic effect of heptaminol could be demonstrated. The results suggest that heptaminol exerts its pharmacological action by interfering with release and uptake of norepinephrine.


Vasodilator profile of a new 1,4-dihydropyridine derivative, 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)]-ethyl ester 5-methyl ester hydrochloride (YC-93). A new 1,4-dihydropyridine derivative, 2,6-dimethyl-4-(3-nitrophenyl)-4,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)]-ethyl ester 5-methyl ester hydrochloride (YC-93), when i.v. injected into anesthetized dogs, exhibited not only a greated vasodilation in both cerebral and coronary than in femoral vessels, but also about 100 to 300 times higher potency as well as longer durability than any of reference drugs such as isoxsupurine, papaverine and cinnarizine. YC-93 was also effective in vasodilation by i.m. and i.d. administration. When administered into vertebral and coronary arteries, YC-93 caused vasodilation at the doses that did not affect systemic blood pressure. YC-93 did not potentiate the vasodilator effect of adenosine, and vasodilation by YC-93 was influenced by neither propranolol, atropine, diphenhydramine nor aminophylline. Acute toxicity (LD50) of YC-93 was almost the same as that of papaverine in mice and rats. Thus, YC-93 is a potent bu low-toxic vasodilator agent acting preferentially and perhaps directly on cerebral and coronary vascular beds and is well absorbed from gastrointestinal tract into blood stream.


[Comparative studies in vivo and in vitro on the formation of phenolic biphenyl metabolites in various animal species (author's transl)[]. The enzymatic hydroxylation of biphenyl in the liver microsome fractions of rabbits, guinea pigs and rats has been studied. They hydroxylated biphenyls were detected by thin-layer and gas chromatography. By the aid of gas chromatography all the hydroxybiphenyls could be quantitatively determined simultaneously. The following results were obtained: 1. 3-Hydroxybiphenyl, 3,4-dihydroxybiphenyl and 4,4'-dihydroxybiphenyl were detected along with the already known biphenyls with hydroxy groups in o- and p-positions. 2. Beside the prevailing p-hydroxybiphenyl, the m-hydroxy derivative was found in greater amounts than the o-hydroxybiphenyl. 3. The ratios of the amounts of the individual biphenyl metabolites versus one another varied with the animal species. Differences were shown among both young and old animals within a single species. With rats, the hydroxylation pattern was found to depend on the race. 4. Orientation studies of the conjugate fractions of rabbits and mice fed with biphenyl indicated that, in addition to the metabolites mentioned, the glucuronosides of 2-, 3- and 4-hydroxybiphenyl and 4,4'-dihydroxybiphenyl could be detected in urine.


Effect of hexachlorophene on the coagulation process in beagle dogs. In a dermal toxicological study the effect of hexachlorophene on the blood coagulation process in dogs over a period of 12 weeks was investigated. The thrombelastographic results revealed a reduction in reaction time, coagulation time and an increase in maximal amplitude supplemented with subsequent increase in the number of platelets and the enhancement of ESR.


Xanthine oxidase activation in animal liver during infectious processes. Short communication. A relevant increase in xanthine oxidase in the liver was constantly found in the couse of the study of enzyme variations in infected mice. This effect seems to be due to bacterial toxins and not related with microbial pathogenicity. Xanthine oxidase is suspected to play a role in host defence mechanisms.


New hepato-protective agents. I. Maleopimaric acid-4alpha-carboxamides. A number of amide derivatives of maleopimaric acid were synthesised and preliminary results on their protective activity against galactosamine-induced liver damage in the rat are described. The compounds (2, 6, 9 and 15) were found to display the highest level of protective activity producing significant lowering of serum GOT and GPT levels at a daily dose of 250-300 mg/kg. The LD50 of these compounds was typically in excess of 2000 mg/kg.


New hepato-protective agents. II. Maleopimaridyl morpholides. A further series of derivatives of maleopimaric acid, the maleopimaridyl morpholides, has been prepared and results on their protection against galactosamine-inducted liver damage in the rat are described. The compounds (3, 4, 8 and 10) were found to display the highest levels of hepato-protective activity in the series. Compound 8 (LD50 greater than 10 g/kg) which exhibited significant, dose-related protection at a daily dose in the range of 50-400 mg/kg, was selected for detailed investigation.


Preliminary studies on the absorption, distribution and excretion of N-(2-hydroxyethyl)-maleopimarimidyl morpholide (3H-RU 18492) in the female rat and dog. Following the oral administration of 3H-labelled N-(2-hydroxyethyl)-maleopimarimidyl morpholide (3H-RU 18 492) to rats and dogs, radioactivity was detected in plasma and the various tissues examined. However, the major fraction of the dose remained unabsorbed and the highest concentrations of radioactivity were found in the liver. In both species the major route of excretion of radioactivity was via the bile.


The protective effect of a novel compound RU 18492, on galactosamine-induced hepatotoxicity in the rat. A novel compound N-(2-hydroxyethyl)-maleopimarimidyl morpholide (RU 18 492), was investigated for its effect against galactosamine induced hepatitis in rats. It was found to be active in reducing both serum transaminase levels and morphological changes due to the hepatotoxin. The protection was shown to be dose related and a significant reduction in liver damage was seen at doses of 50-400 mg/kg p.o. RU 18 492 was ineffective against carbon tetrachloride induced hepatitis in rats. It was suggested that the protective effect of RU 18 492 was due to its ability to stimulate the smooth endoplasmic reticulum thus inducing a more rapid detoxification of galactosamine.


[The effect of tri-iodinated contrast media on acetylcholinesterase of human erythrocytes (author's transl)]. The side effects of water soluble iodinated contrast media often mimic the clinical picture of acetylcholine intoxication. This prompted us to determine the amount of inhibition of human acetylcholinesterase by the following contrast media in vivo and in vitro: methyl glucamineiodipamide (Biligrafin forte), methylglucamine iothalamate (Conray 60), sodium-iothalamate (Conray 80). In vivo no correlation could be found between clinically manifest adverse reaction and enzyme inhibition after contrast media application. The in vitro values for 50% inhibition of erythrocyte acetylcholinesterase are: methylglucamine-iodipamide: 0.036 M, methylglucamine-iothalamate: 0.158 M, sodium-iothalamate: 0.3 M. Since in vitro, the maximal inhibitory effect of a given dose of contrast media can only be registered after a time interval when most of the contrast media in vivo has already been excreted by the kidneys or extracted by the liver, it seems very improbable that the enzyme inhibition seen in vitro should have any consequence whatsoever under clinical conditions. The in vitro inhibition of acetylcholinesterase is quickly reversible, with nearly all the activity regained 15 min after the removal of the contrast media.


[Studies on the absorption of benzilic acid esters of homologous dimethyl-(2-hydroxyethyl)-alkylammonium bromides through buccal mucosa. 5th communication: On optimum bioavailability of homologous quaternary ammonium compounds (author's transl)]. Distribution studies in vitro predict increasing absorption rates in vivo with increasing distribution coefficients up to a limiting value. Buccal absorption tests with homologous, quaternary cholinesterbromides of benzilic acid do not confirm this hypothesis. The reasons could be the rather hydrophilic properties of the mucosal membranes and thus adsorption of drug to the mucosa. The evaluation of results with undissociated homologous carboxylic acids, however, shows a good correlation between the prediction from in vitro studies and the buccal absorption test.


[Changes in hemodynamics and contractility during supraventricular tachycardias and after electrical or aprindin-induced termination (author's transl)]. Alterations of hemodynamics and contractility were studied in 6 patients in whom two consecutive runs of supraventricular tachycardias (SVT) were electrically induced. Following initiation there was an abrupt decrease of arterial blood pressure, left ventricular systolic pressure, dp/dtmax, cardiac index and stroke work index (SWI). These parameters -- with the exception of SWI -- increased in the course of the SVT, however, control values were not reached. Mean pulmonary artery pressure steadily increased and remained on an elevated level until the tachycardia was stopped. When the SVT was electrically terminated, there was a transient overshoot of mean arterial and left ventricular systolic pressure, while mean pulmonary artery pressure slowly returned to control values. When the tachycardia was stopped by i.v. infusion of N-)diethylamino-3-propyl)-N-phenyl-indanamine-2 (aprindin, Amidonal) -- started at the 7th minute -- there was no statistically significant difference, neither during the SVT nor after cessation as compared to the values of the first run. Only mean pulmonary artery pressure remained at a higher level after SVT was stopped. It may, therefore, be concluded that in patients with otherwise normal hearts aprindin applied in a dosage sufficient to stop the SVT, does not exhibit noteworthy inotropic side effects.


[Studies on the bioavailability of the individual components from a combination of dilazep and beta-acetyldigoxin (author's transl)]. Original tablets of Cormelian [= 50 mg 1,4-bis[3-(3,4,5-trimethoxybenzoyl-oxy)-propyl]-perhydro-1,4-diazepine (dilazep)] and Cormelian-Digotab (= 50 mg dilazep + 0.2 mg beta-acetyl-digoxin) were produced with 3H-dilazep as prescribed in the special galenic technique. After application of a single oral dose of two tablets dilazep to 9 patients serum concentration was analysed at different times up to 24 h p.a.; the renal excretion rate of dilazep and metabolites was determined up to 48 h. Two tablets of the combination were given to 4 of these patients 4 days after application of dilazep and the corresponding analysis were repeated; in the serum of these patients the concentration of glycoside was determined by radioimmuno assay. The following results were obtained. 1. Differences in serum concentrations and renal excretion rates of dilazep and metabolites were not observed after application of the mono- and combination product. In comparison to results after oral application of pure dilazep in gelatin capsules the serum concentrations 1 h after application of Cormelian and Cormelian-Digotab were statistically significantly higher. With reference to comparable total absorption rates these results may be representative for a possibly retarded absorption rate of dilazep given as pure substance. An influence of the different galenic techniques on the intensity and direction of metabolites could not be substantiated. 2. By large dispersions of the single values high absolute and relative concentrations of beta-acetyl-digoxin were found in the serum of all the 4 patients after application of combination. Contrary to two commercial products, applied to each of 10 test persons under comparable conditions, statistically higher serum concentrations of glycoside were analysed 1 h after application of the combination. The results of these studies confirm a positive influence of the galenics on the biological availability of both the components in the combination drug Cormelian-Digotab.


[Sputum viscosity and pulmonary function measurements during a one-week parenteral treatment with a standardized oxidation product of oil of turpentine and terpin hydrate]. In 23 patients with chronic obstructive lung diseases, viscosity, airway resistance, arterial blood gases and acid-base balance, and sputum aspect were measured before and after one-week treatment with Ozothin, a substance from oxidation products of ol. terebinth. and terpinum hydratum. Within this time, viscosity of the sputum was reduced, airway resistance decreased, and arterial oxygen pressure slightly increased, whereas arterial carbon dioxide tension obvious change of sputum aspect could be observed. Correlation calculations revealed no significant relations between viscosity and the above cited lung function values. The results indicate that administration of Ozothin may liquefy viscous secretion and reduce sputum viscosity.


[Clinical experience with metered aerosol of beclometasone in patients with obstructive lung disease (author's transl)]. 142 patients suffering from chronic obstructive lung disease were treated with 9-chloro-11beta,17,21-trihydroxy-16beta-methyl-pregna-4,4-diene-3,20-dione-17,21-dipropionate (beclometasone) metered aerosal. Between 3 subgroups: chronic infectious obstructive lung disease, allergic obstructive lung disease and chronic bronchitis without airway obstruction, there was no difference in the results. Three times per day three puffs of the metered aerosol can substitute about 6 mg prednisolone p.o. The systemic effects of the beclometasone therapy with metered aerosols are clearly less than those which are seen with a comparable oral dosage. Side effects are seen dose dependently as hoarseness and as relatively harmless Candida infection of the throat. For most of the patients with obstructive lung disease who are dependent on glucocorticosteroids beclometasone as metered aerosol should be given as basic therapy. In case higher dosages are necessary they should be given orally or parenterally.


[Experimental study on the tracking behaviour with a view to differentiating the effects of an antidepressant in various doses compared to placebo (author's transl)]. In a double-blind cross-over study 15 highly motivated, healthy male subjects (Ss), aged from 23 to 29 years, were given 200 mg and 400 mg p-methoxy-phenoxyaceticacid-diethylaminoethylamide-hydrochloride (mefexamide) and a placebo. On each of the three days the Ss were tested in different tracking devices and the integrated absolute error was measured in the tests of a duration of three hours each. Influences of practice, leading to unwanted and disturbing effects were excluded by a preceding period of four training sessions on different days. The main result of the investigation was that performance in tracking was ambivalent. The single dosage (200 mg mefexamide) caused small improvements in tracking in the range of about 5%. These differences from placebo partly could be determined to be significant at the level of 5% compared to placebo. The double dosage (400 mg mefexamide) deteriorated tracking performance significantly (5%-and partly 1%-level, two-tailed test) in the range of about 10% on the average. Differences in performance between the two dosages were correspondingly larger and could be determined at a higher level of significance, too.


[Comparative studies on oral glucose tolerance and serum lipids under the influence of a new oral contraceptive (SH B 209 AB: 2 mg cyproterone acetate + 0.05 mg ethinyl estradiol), the combination D-norgestrel/ethinyl estradiol and in a control group (author's transl)]. 24 healthy women given the combination of cyproterone acetate (2 mg) + ethynyl estradiol (0.05 mg) [SH B 209 AB] and D-norgestrel (0.25 mg) + ethinyl estradiol (0.05 mg) [Neogynon] were compared with a control group in oral glucose tolerance tests. The volunteers were divided into three groups. Two received alternately both preparations with each treatment cycle preceded by one cycle without medication. The third group served as an independent control. On the 25th day of each cycle blood was withdrawn before and 15, 30, 45, 60, 90 and 120 min after the carbohydrate load. Blood glucose and insulin and free fatty acids in serum were determined. Fasting values of triglycerides and cholesterol in serum were determined. The following results were obtained: 1. The mean fasting levels of blood glucose, serum insulin and free fatty acids were unchanged. 2. The total area under the blood glucose curve over the initial value was not altered 2 h after treatment with SH B 209 AB or Neogynon. The total area under the insulin and free fatty acids curves were also unchanged after the oral glucose load. 3. There was no change in serum cholesterol. 4. Serum triglycerides were significantly increased after SH B 209 AB. 5. The implications of the structural differences between both gestagens are discussed.


Quantitative cell culture biocompatibility testing of medical devices and correlation to animal tests. The biocompatibility of a wide variety of biomaterials was quantitatively assessed, in a physiologically normal environment" as to cytotoxicity induced in WI-38 cells by cell culture medium extracts. Materials tested included PVC plastic, rubber, silicone rubber, polyethylene, polypropylene, acetal, polyurethane, Teflon, nylon, epoxy, and polystyrene. Cell culture test results were correlated to U.S.P. animal tests. Potential test artifacts, lead, barium, cadmium, and endotoxin were tested for cytotoxicity in WI-38 cells. Cell culture methods yielded more positive tests, particularly rubber, PVC plastic and silicone rubber compounds, than observed in U.S.P. animal tests. Positivity in animal tests did not correlate quantitatively to cytotoxic titers in cell culture. Discrepancies between cell cultures tests and animal tests, specifically rubber compounds, were attributable, in some instances, to differentials in elution efficiency between saline, cottonseed oil, and complete MEM cell culture medium. In other instances, particularly PVC plastics, differences between cell culture and animal test results were due to an inherent difference in the two indicator systems to respond to specific toxic moieties.


Phase II trial of cytembena in patients with advanced ovarian and breast cancer. Thirty women with histologically proven advanced ovarian or breast cancer were treated with cytembena. Of nine patients with ovarian cancer and 21 with breast cancer none had worthwhile objective remissions. Cytembena was given at a dose of 250 mg/m2/day for a course of 5 days repeated at weekly intervals. Improvement, particularly relief of pain from skeletal metastases, was observed in 16 of the patients; an additional seven patients had stable disease while treated with cytembena. Cytembena has no hemopoietic toxicity, but nausea and vomiting and an "autonomic storm" phenomenon are dose-limiting factors. Further studies incorporating this drug in combination regimens seem warranted.


Acute effects of tolamolol on renal function in hypertensive patients. The renal heamodynamic effects of a single i.v. administration of tolamolol were studied in 9 hypertensive subjects. No change of GFR and ERPF was observed after tolamolol, while urine output decreased and urine creatinine concentration increased. A reduction of the heart rate was confirmed. Blood pressure was unchanged.


The use of drugs for behavior modification as it relates to the practice of optometry--Part I. Medications used in behavior modification can result in untoward side effects, including ocular and visual changes. As in many other aspects of health care, optometrists can serve as the first line of defense to guard their patients against permanent damage from side effects they may not associate with use of their medication. Optometry's responsibility and role in management of side effects is delineated. Areas of behavior modification of concern to optometrists are discussed. These include: (1) learning problems and mental retardation; (2) mental disorders, menopause, and alcoholism; and (3) drug abuse.


Determination of trace amounts of mercury in water by neutron activation analysis with lubricating base oil as extractant. This paper deals with a convenient method in the determination of trace amounts of mercury in water. After being irradiated with neutrons, water sample was treated with 7.0M HCIO4 solution and mercury was extracted with lubricating base oil. In such a simple operation, the sensitivity can reach 10(-8)g Hg/4ml H2O.


Clinical hematological progression of hereditary lymphosarcoma in rabbits. Considerable diversity exists in the clinical progression data for lymphosarcoma both between and within species. Thirty-four rabbits with hereditary lymphosarcoma were used to define the clinical progression of this condition under controlled genetic conditions. Changes in the erythropoietic cells of the rabbit hemogram in cases of hereditary lymphosarcoma (ha/ha) follow a fairly well defined clinical course of about one-and-one-half months duration. Data are presented showing that these changes are subsequent to schanges in the granulocytic cells of the leukocyte series both peripherally and in the bone marrow.


Interaction of radionuclides with organic matter dissolved in seawater. Interaction of radiocobalt with some amino acids. The interaction of radiocobalt with glycine, alanine or aspartic acid dissolved in seawater was investigated by means of adsorption on Chelex 100, solvent extraction with dithizone or gel filtration chromatography. Although the distribution coefficients of Co on Chelex 100 decreased gradually with ageing even in the absence of organic matter, much more decreases were observed in the presence of the amino acids. The distribution coefficients on the resin reached equilibrium states in about 20 days. The extraction of cobalt with dithizone in carbon tetrachloride was also inhibited in the presence of the amino acids. Alanine and aspartic acid showed a similar interfering tendency in both adsorption on Chelex 100 and dithizone extraction, while glycine inhibited dithizone extraction more than adsorption on Chelex 100. From the fractionation of Co by Sephadex G-10 gel filtration chromatography, the higher molecular species of Co associated with the amino acids occurred after several days ageing and then increased together with decreasing in the lower molecular species.


[Particle size determination by radioisotope x-ray absorptiometry with sedimentation method]. The possibility of radioisotope X-ray absorptiometry to determine the particle size of powder in conjunction with sedimentation was investigated. The experimental accuracy was primarily determined by Cow and X-ray intensity. where Co'=weight concentration of the particle in the suspension w'=(micron/rho)l/(mu/rho)s-rhol/rhos rho; density micron/rho; mass absorption coefficient, suffix l and s indicate dispersion and particle, respectively. The radiosiotopes, Fe-55, Pu-238 and Cd-109 have high w-values over the wide range of the atomic number. However, a source of high micron value such as Fe-55 is not suitable because the optimal X-ray transmission length, Lopt is decided by the expression, micronlLopt approximately 2/(1+C'ow') by using Cd-109 AgKX-ray source, the weight size distribution of particles from the heavy elements such as PbO2 to light elements such as Al2O3 or flyash was determined.


[Analysis of errors in radiation relay. (I) Optimum setting of time constant]. The statistical error of liquid level controlled by radiaiton relay is analysed and a method of minimizing the error is proposed in this paper. This method comes to the problem of optimum setting of the time constant of radiation relay. The equations for obtaining the value of time constant are presented and the numerical results are shown in a table and plotted in a figure. The optimum time constant of the upper level control relay differs entirely from that of lower level control relay.


[Clinico-morphological characteristics of surgically removed thyroid gland of the residents of Primorskii territory]. The authors carried out a histological study of 150 thyroid glands removed for various forms of goiter. Nodular and mixed goiter with frequent signs of degeneration prevailed in residents of the Primorsk region. Histological structure of the majority of them corresponded to the colloidal, mostly to the macrofollicular goiter. A lower percentage of morphological signs of the goiter activity in comparison with the clinical data revealed in the hospitalized patients can be attributed to the efficacy of antithyroidal therapy causing involution of the hyperactive glands. Various types of adenomas chronic thyroiditis and the initial stages of the node malignization were determined only by histological examination.


[New method of anatomic localization of scintigram of various organs by simultaneous combination of emission scanning and transmission scanning]. When the photoscintillo-roentgenography is used for relating the scintigram of internal organs to the anatomic structures, this method is found to have some defects--the difference of magnification between the emission scan and the roentgenogram, the inaccuracy due to the geometric distortion of the X-ray image, the impossibility of the simultaneous photographing of the scan and the X-rays, etc. Then, to diminish the influence of these defects we improved on the photographic recording system of a dual-heal scanner, and made use of the transmission scanning method. That is, we combined the recording parts, Ch1 and Ch2, into one system, using Ch1 for the light source of transmission scan and Ch2 for that of emission scan. In this way, we managed to make the two incident rays from those light sources converge into a focus upon a film. Thus we could perform a simultaneous emission-transmission scanning, by moving, at the same time in the same direction, the scanning detector over the patient and the small radioactive source (241Am) under him. This method can be applied to any radioactive nuclide to be used in transmission scanning and emission scanning. As the result of applying this method clinically in our department, the method has proved to be very useful for anatomic localization.


Drug treatment of venereal disease: analysis of 273 cases in Ghana. The presence of non-gonococcal urethritis, resistant to penicillin therapy was noted by Ikejiani in Nigeria as early as 1955. This syndrome is now known as non-specific urethritis, or non-specific genital infection in the female. Sarrat (1973) has shown the effectiveness of penicillin plus probenecid, specti nomycin, and cotrimoxazole in male cases of gonorrhoea in Dakar. Sogbetun and Osoba (1974) have shown the effectiveness of metronidazole in trichomoniasis in males in Nigeria. Our study was made on a mixed University population of 2,700 students seen in one clinic during the year 1975. There were 273 cases of sexually transmitted diseases including gonorrhoea, non-specific urethritis or genital disease, trichomoniasis and chronic urethritis or vaginitis. Treatment of gonorrhoea with penicillin alone or with spectinomycin was only 50% effective. But good results were obtained with penicillin plus probenecid or penicillin plus cotrimoxazole. Good results were obtained in non-specific urethritis, or non-specific genital disease, when tetracycline or its derivatives were used. Good results were obtained in the treatment of trichomoniasis with metronidazole in males and females. It was concluded that in gonorrhoea penicillin should be given (in adequate dosage) with probenecid or cotrimoxazole. Spectinomycin should be used at a dose level of 4 g instead of 2 g. The management of chronic urethritis and vaginitis was very difficult. The drug treatment of venereal disease in Ghana has not revealed any unique characteristics except, perhaps, an increased resistance of the gonococcus to spectinomycin.


[Architecture of collagen fibers in the meniscus of the human knee joint, with special reference to the medial meniscus and its connection to the articular ligaments]. 1. To understand the meniscus-tears the architecture of their collagenic fibers is of interest, particularly so the connection of the fibers of the medial meniscus with the collateral ligament. 2. The ligaments of 12 knee joints have been studied macroscopically and with the aid of thick serial sections under polarized light. 3. The main portion of the tibial collateral ligament passes the articular space without any connection with the capsule or the meniscus. The upper oblique portion of the ligament runs inside the external zone of the meniscus to the posterior attachment of the latter. Immediately inferior to the articular space the oblique fibers have another attachment. 4. The findings in respect of the arrangement of the fibers in the menisci differ from those in earlier studies. Only in the external zone the fibers run approximately parallel to the outer border. After leaving the external zone the fibers run in an arched way through the middle zone. In the internal zone these fibers have nearly a radial direction. 5. The architecture of the menisci is discussed under functional aspects. It does not correspond to a "spring" but to a tendon, which is extended over a hypomochlion. 6. Forms and localisations of meniscus-tears have been discussed under viewpoint of architecture and compared with clinical results: The typical tear of the posterior segment of the medial meniscus is the horizontal cleavage. The present opinion according to which longitudinal tears are the typical meniscus lesion, seems to be doubtful.


[HLA B8 and Graves' disease (author's transl)]. HLA typing has been carried out in 100 caucasions with Graves' disease and compared with 270 healthy controls. 25 HL-A antigens were characterized using a lymphocytotoxicity micro-technique. Analysis of the results reveals an increased incidence of HLA-B8 antigen (35% in patients as compared to 16.3% in controls) with a high degree of statistical significance: p = 0.0002 and corrected p (X 25) = 0.005. We did not observe a clear-cut correlation between the presence of HLA-B8 and different characteristics of the disease: sex, age of onset, familial history, exophtalmia, goiter, severity. The knowledge of the relationships between the HLA B8 gene and several auto-immune diseases is a strong argument in favor of the auto-immune nature of Graves' disease. The association between HLA B8 and Graves' disease could be explained by a close linkage between the second HLA locus and one or several Ir-IrG loci, occupied in predisposed individuals by "predisposing" alleles. In these subjects, an antigenic contact with an exogenous etiological agent would induce a pathological immune response, with production of thyroid stimulating IgG.


Congenital and acquired heart diseases: (A survey of 7062 persons). A survey was carried out amongst 7062 people of different age groups in Dacca city and in a village. It was found that 207 (2.92%) persons had some sort of heart disease. Hypertension was present in 83 (1.10%) persons. Rheumatic heart disease, ischaemic heart disease and cardiac arrhythmia were detected in 53 (0.75%), 24 (0.33%) and 16 (0.22%) persons respectively. Congenital heart disease was found in 13 (0.18%) individuals, and 18 (0.25%) persons were suffering from cardiomypathy or corpulmonale. Rheumatic heart disease was common in poor people of younger age. More ischaemic heart disease was found in well-to-do people but poor people were not immune from this.


Studies on the nutritional status of expectant mothers and newborn babies. Heights, weights, haemoglobin, total proteins and albumin-globulin (A/G) ratio of 157 pregnant women in their last trimester of pregnancy are reported along with heights, weights, haemoglobin and albumin-globulin ratio of newborn babies. The results have been discussed.


Echinococcosis in cattle and goats.

Echinococcosis in cattle and goats. In the 500 cattles examined, 90 (18%) had hydatid cysts in one or more organs whereas only 12(2.4%) goats, out of 500 had the disease. This is considered to be due to shorter period of longevity and age of slaughter of goats compared to catte. Since dog is an important definitive host responsible for the spread of echinococcosis, a survey on the incidence of hydatid cyst in dogs is necessary from public health point of view.


Experience with norethisterone enanthate as injectable contraceptive. Norethisterone Enanthate (NE) was used in 151 women as injectable contraceptive. Pregnancy due to method failure was 2% whereas the overall pregnancy was 4%. The results have been discussed.


Effects of norethisterone enanthate on certain body functions. Effects of Norethisterone Enanthate (an injectable contraceptive) on body weight, blood pressure, blood cell count, level of haemoglobin, fasting blood sugar and serum cholesterol were studied in 31 women. It was observed that in the successful acceptors the pregnancy rate was nil. No appreciable change could be found in the body functions studied.


Non-association of ABO blood groups with diabetes mellitus in Bangladesh. Confirmed diabetics (2312) were tested for ABO blood groupings and the results of frequency compared with normal (8936) subjects. The data were analysed statistically to detect any possibility of an association between ABO blood groups and diabetes mellitus. No such association is apparent in the subjects studied.


Cancer of male breast. (A report on incidence). During a retrospective study of 1843 patients with malignant lesions, 83 were identified as breast cancer. Of these, 4 turned out to be male breast cancer showing a male to female ratio of this neoplasms to be 1:19.7.


Peptic ulcer: (Analysis of predisposing and associated causes). Age incidence, food habits and socio-economic condition were studied in a series of 478 predominantly male peptic ulcer patients. Age incidence of peptic ulcer increased in the second decade of life, reached a peak at the third decade and tapered off towards the end of fourth decade. As many as 57% of the patients belonged to the low socio-economic group and 78% were having only two meals a day. A ratio of 21 : 1 for duodenal ulcer to gastric ulcer was revealed from laparotomy findings.


Malignant diseases. (A review of 115 cases). A review of 115 malignant lesions (proven histologically) is presented. Good number of malignant lesions were found confined to female sex organs.


Hypertension in a mixed community.

Hypertension in a mixed community. Casual blood pressure was studied in a mixed community above 20 years of age and records of hospitalised patients for hypertension and/or its complications were analysed. It was found that about 2 percent of people examined were unaware that they had elevated blood pressure. High incidence of hypertension was found in the age group of 40-50 years in the hospitalised patients.


[Isolation of Thogoto virus from Amblyomma and Boophilus ticks in Central Africa]. A survey has been carried out in the Cameroons and the Central African Republic about the role of the ticks in the ecology of arboviruses in Central Africa. Attempts for virus isolation were made for 12,678 Amblyomma variegatum, 3,276 Boophilus decoloratus and 1,769 Boophilus annulatus, by inoculation into suckling mice. From 968 pools which were inoculated, 20 yielded isolates which were identified to Thogoto virus. Considering previously published results concerning tick-borne virus isolations in the Central African Republic, it appears now that five arboviruses are present in the ticks in central Africa : Dugbe, Jos and Thogoto (in A. variegatum, B. decoloratus and B. annulatus), Bhanja (in A. variegatum) and Chf. Congo (in Hyalomma nitidum).


[Report on first 2 cases of rhinosporidiosis in Cameroon]. The authors report the first two cases of rhinosporidiosis in Cameroon. The patients were females from Cameroon southern-center or littoral areas, damp regions, and presented a conjunctival localization of this mycosis.


[Significance of passive hemagglutination and its prospectives in lymphatic filariasis]. The authors analyze the data concerning 219 sera, that they have tested in passive hemagglutination, with as antigen a Dirofilaria immitis proteic extract, in French Polynesia. Besides its light sensitivity, this method does appear very interesting. It points out: --First, that there is a gaussian distribution of the results found at various dilutions, both by "filarian" and "non filarian" people. Therefore, this distribution is a feasible and practical parameter for evaluation of the Filariasis transmission in different populations. --On the other hand, that there is an inverse correlation between the presence of microfilaria in the blood and the level of immunological response for lymphatic Filariasis.


[Activity of levamisole (Solaskil) in lymphatic filariasis caused by Wucheria bancrofti (variety pacifica]. A 6 mg./kg. daily dose of levamisole was given during three days to ten carriers of microfilarias Wuchereria bancrofti in Tahiti. No action against adult worms was noticed. The immediate microfilaricid action was at least equivalent to the action of DEC. However the decrease of microfilaremia was not so long with levamisole than with DEC given to a lower dose. Lastly the amount of reactions after a treatment by levamisole is notable.


A new blackfly (S. (W.) golani n. sp. (Diptera, Simuliidae)) from the Eastern Mediterranean basin. S. (W.) golani n. sp. Beaucournu-Saguez and Braverman is described from material collected in the Golan region, Israël (35degrees42' E, 32DEGREES57' N). It is related to S. (W.) paraequinum Puri 1933 but is distinguished by the morphology of the pupal respiratory filaments and by details of the structure of the male genitalia.


Karyometric study of benign and malignant diseases of the thyroid gland. The results of the karyometric measurements in different thyroid diseases (both benign proliferative processes and cancer) have shown that this method may be useful in differential diagnosis of these diseases. It was also found that there are evident differences between the shapes of histograms in various forms of cancer. The shape of the histogram depends not only on the histological structure of the tumour (follicular, papillary, undifferentiated cancer), but also on the type of the cells of which it consists (A,B or C cells).


[Rapid determination of 137Cs in environmental samples--purification of 137Cs by ammonium molybdophosphate column separation]. A rapid method for the determination of 137Cs in environmental samples was proposed. The principal technic employed in this study is based on column separation of 137Cs using ammonium molybdophosphate mixed with glass fiber to eliminate contribution of natural radionuclides such as 40K and 87Rb. The separation of cesium from potassium and rubidium was performed by the elution with 0.5m ammonium nitrate solution. The time required for separation of cesium was five hours as compared with the conventional cation exchange separation which required thirteen hours. The chemical yield of cesium carrier was normally more than 90 percent. The results obtained were compared with that by the conventional methods using Bio-Rex cation exchange separation and the good agreement between the two methods was obtained.


[Experimental and clinical studies on the accuracy of geometry-independent counter]. For the purpose to conduct precise geometry-independent radioassay of large biological samples, the authors constructed an apparatus with the "peak+scatter" counting method slightly modified from that of Gibbs, et al. and studied its accuracy from the basic and clinical aspects. The apparatus, an opposed-head counter, consisted of two matched 2 x 2-in. NaI crystal detectors and photomultipliers that were connected in parallel to a pulse-height spectrometer. The crystal faces were separated by 54 cm. The detectors were enclosed in 5cm-thick shield built with lead and the sample chamber was a 15 cubic cm-box type of 3 mm-thick Lucite. A 13 cmphiX7.7 cm styrene topper container was used for the sample container. It was found that the relation of primary gamma energy of six radioisotopes and geometry-independent counting threshold turned out to be linear. The assay accuracy with 131I was about +/- 5% in fluid samples irrespective of its sizes (up to 500 ml) or homogeneity. In solid samples the accuracy approached that of fluid by the addition of water up to the height of it. The range, in which the activity could be measured within 5% error originating from statistical fluctuations or loss of counts due to instrument dead time, proved to be about 34 approximately .06 micronCi with 57Co in assay time of 10 min. On the basis of the basic investigations, the geometry-independent counting was used for the radioassay of stool and urine. Since the assay could be done simply up to a relatively large volume without need of material adjustment, it served well in the assay of urine and stool of clinical practice as well as in animal radioassay.


[Advantages, disadvantages and selection methods of thyroxine measurement--comparison of CPBA and RIA]. Although recent progress in radioimmunoassay (RIA) permitted direct RIA for thyroxine (T4), there appeared few reports evaluating clinical applicability of T4 RIA as routine method. The authors evaluated advantage, disadvantage of methods for T4 measurement in comparison between CPBA (competitive protein binding analysis) and RIA, and tried to discuss about selection of methods for T4 measurement. Res-O-Mat T4 was chosen as CPBA, and RIAMAT-T4(St) and T4-RIAKIT(Sp) were chosen as RIAs. Detailed descriptions about both RIA methods appeared elsewhere [2, 3]. From the basic experiments, reproducibility of CPBA, St and Sp within assay were 5.8% (C.V.), 4.0% (C.V.), and 8.5%(C.V.) respectively, and mean recovery rates were 92.2%, 100.7% and 96.1% respectively. T4 value measured by both RIAs correlated well with CPBA, and St showed slightly lower value and Sp showed slightly higher value than CPBA. The normal ranges for RIAs were 3.7-11.7 microng% (St) and 4.6-15.2 microng% (Sp). Diagnostic accuracy for hyperthyroid state were 83.3% (CPBA), 85.7%(St) and 69.2% (Sp), and for euthyroid state were 92.0% (CPBA), 98.8% (St) and 95.7% (Sp). The diagnostic accuracy for hypothyroid state in three methods were lowest. From the economical point of view, cost performance, time performance and total time for single assay were analysed and mathematical equations were obtained from actual assay by each methods. When the number of samples per single assay was less than 10, CPBA was most economic in terms of cost and time performance and total time required. In the assay of more than 20 samples, RIAs were efficient in each point of views. In the point of view of sample volumes required, RIAs were most promising. The authors concluded that guides for selection of methods in T4 assay were as follows: A) CPBA was most efficient in local use especially when less than 10 samples were frequently to be assayed. B) RIAs were efficient in batch processing more than 20 samples, especially in automated laboratories.


[Study on tumor affinity of technetium-99m-labeled radiopharmaceuticals. (2) 99mTc-Sn-diphosphonate (99mTc-EHDP), 99mTc-Sn-dimercaptosuccinic acid (99mTc-DMSA), and 99mTc-Sn-diethyl stilbestrol diphosphate (99mTc-DSDP)]. The authors have examined the tumor affinity of various 99mTc-labelled radiopharmaceuticals to Ehrlich's tumor for the purpose of delineating positively human malignant neoplasm. This paper includes biologic distributions of 99mTc-Sn-diphosphonate (99mTc-EHDP), 99mTc-Sn-dimercaptosuccinic acid (99mTc-DMSA) and 99mTc-Sn-diethyl stilbestrol diphosphate (99mTc-DSDP, 99mTc-Honvan) as the second report on the tumor affinity to the Ehrlich-bearing mice. (a) Tumor concentration of 99mTc-EHDP was lowest and the positive delineation of implanted tumor with 99mTc-EHDP was poorest in sequential images, though the active accumulation to some soft tissue maglinant neoplasms, the breast cancer and the thyroid cancer, has been reported. (b) Tumor concentration and tumor to blood ratio of 99mTc-DMSA were not so high on the contrary of our expectation that 197Hg-DMSA may show the high tumor concentration and the high tumor to blood ratio like 197Hg chlormerodrin as same renal scanning radiopharmaceuticals. (c) Tumor concentration of 99mTc-DSDP was highest. Tumor to blood concentration ratio, however, was lower than that of the above mentioned radiopharmaceuticals but tumor to liver ratio and/or tumor to lung ratio was over 1.0 at the earlier time. Biologic distribution of 99mTc-DSDP was similar to that of 32P labeled DSDP and then it is presumed that 99mTc is labeled at phosphate ester of DSDP which is dephospholytated immediately by phospholylase in vivo following the intravenous injection. Therefore, it may be assumed that the accumulation mechanism of 99mTc-DSDP to Ehrlich's tumor is related to the phospholylase activity in neoplasms but is not known precisely.


[Affinity of the elements in group VI of the periodic table to tumors and organs]. In order to investigate the tumor affinity radioisotopes, chromium (51Cr), molybdenum (99Mo), tungsten (181W), selenium (75Se) and tellurium (127mTe)--the elements of group VI in the periodic table--were examined, using the rats which were subcutaneously transplanted with Yoshida sarcoma. Seven preprarations, sodium chromate (Na251CrO4), chromium chloride (51CrCl3), normal ammonium molybdate ((NH4)299MoO7), sodium tungstate (Na2181WO4), sodium selenate (Na275SeO4), sodium selenite (Na275SeO3) and tellurous acid (H2127mTeO3) were injected intravenously to each group of tumor bearing rats. These rats were sacrificed at various periods after injection of each preparation: 3 hours, 24 hours and 48 hours in all preparations. The radioactivities of the tumor, blood, muscle, liver, kidney and spleen were measured by a well-type scintillation counter, and retention values (in every tissue including the tumor) were calculated in percent of administered dose per g-tissue weight. All of seven preparations did not have any affinity for malignant tumor. Na251CrO4 and H2127mTeO3 had some affinity for the kidneys, and Na275SeO3 had some affinity for the liver. Na2181WO4 and (NH4)299MoO4 disappeared very rapidly from the blood and soft tissue, and about seventy-five percent of radioactivity was excreted in urine within first 3 hours.


[Biological fate of 3H-labeled penfluridol. (3) Correlation between concentration of 3H-penfluridol in the brain and its anti-methamphetamine activity]. The Penfluridol (PFL) is a potent and long-acting neuroleptic belonging to the diphenylbutyl piperidine series. The purpose of the present study is to investigate a correlation between the brain concentration of unchanged 3H-PFL and its neuroleptic activity in the methamphetamine-antagonism test. The experimental animal comprised adult male Wistar rats weighing about 200 g. All the rats were administered 3H-PFL orally and killed at appropriate times after administration. After killing blood samples were collected and the brain and liver were excised. The blood was extracted with 4 volumes of ethanol. The brain and the liver were homogenized in 9 volumes of ethanol. The amount of 3H-PFL in the ethanol extract was determined by thin-layer chromatography. The result showed that the drug level in the brain was relatively constant when the dose was the median effective dose (ED50) for the test at those time intervals after administration.


[Chemical composition and protein value of some baby foods (author's transl)]. The determination of lipids, available carbohydrates and unavailable carbohydrates, and of various minerals has been carried out on some baby foods; the value of the protein fraction has been similarly determined by the ultrafiltration method of the enzymic hydrolisate in vitro. Both the total protein content and the essential amino acid availability of the foodstuffs are satisfactory although generally speaking a slight decrease of the protein value has been found in this material as compared to the crude samples, due particularly to the breakdown of sulfur-containing amino acids. This breakdown is due probably to the high temperature reached during the technological processes at industrial level.


[Influence of rapeseed oil on lipoprotein lipase activity in pigs (author's transl)]. Toxic activities in various animal species have shown for rapeseed oil. In this paper the influence of this oil on lipoprotein lipase activity of heart, liver and lung of pigs has been examined. The animals were fed with rapeseed oil with 40% erucic acid for 7, 15, 20 and 40 days. The control animals received olive oil. The results have shown a slight increase in the lipoprotein lipase activity in the heart of the pig after 20 days with rapeseed oil. In the liver this increase is particularly large in the pigs having been fed for 15 days both with rapeseed oil and olive oil. No differences were observed in the lung in the test and control animals with the only exception of animals fed for 20 days.