Conditions influencing the dose-response effect of growth hormone on longitudinal bone growth in the hypophysectomized rat. Various factors that might influence the dose-response effect of growth hormone on the longitudinal bone growth were investigated with tetracycline as intravital marker of the bone growth in hypophysectomized rats. These are of practical importance for the bioassay of growth hormone. The growth response was found to be almost the same for subcutaneous and intraperitoneal injection, whereas the intravenous route resulted in significantly lower growth response. The administration of growth hormone in various volumes subcutaneously did not significantly influence the dose-dependent growth response. Freezing of the dissolved growth hormone or addition of NaOH to the solution had no significant effect on growth response. Cortisone acetate 0.5 mg/kg given at hypophysectomy increased the post-operative survival somewhat, without having any post-operative depressing influence on the growth hormone-induced longitudinal bone growth. The present investigation showed that in standardized conditions the dose-dependent growth response is constant.


An analysis of an apparent sex difference in the desoxyribonucleic acid content of rat liver. Using the extraction procedure of Schmidt & Thannhauser (1945) and the indole reaction for DNA according to Ceriotti (1952), the DNA content of female rat liver was about one and a half times that of male liver. Castration of male rats, with or without administration of testosterone propionate, had no effect on the liver DNA content. Spaying of female rats (5-6 weeks of age) caused a decrease of the liver DNA content. Substitution with oestradiol benzoate restored the amount of DNA. No significant sex difference was observed in the DNA content of either rat brain, kidney, spleen and thymus, or mouse liver. Dische's diphenylamine reaction showed no significant sex difference in the rat liver DNA content. It was concluded that rat liver may contain a substance which is controlled by oestrogens and which interferes with the indole reaction. The interfering factor is present in the protein fraction of the liver extract. The possible nature of this interfering substance is discussed.


Human placental lactogen concentration during physiological fluctuations of serum glucose in normal pregnant and gestational diabetic women. Oral glucose tolerance tests (OGTT) were carried out in 9 normal pregnant women and 11 non-obese gestational diabetics in late pregnancy. All samples were analysed for the content of glucose, insulin and placental lactogen hormone (HPL). Furthermore, spontaneous changes in the serum HPL concentration during a 3 h period were studied in 6 normal women in the 2nd half of pregnancy. During OGTT only small and insignificant changes in the level of HPL were observed in both the normal subjects and the gestational diabetics. Furthermore, the mean HPL concentration curves of the normal subjects and the gestational diabetics were superimposed although the mean glucose concentration curves were significantly different. The study of spontaneous changes in HPL revealed only small and insignificant fluctuations in the serum HPL level, and the mean concentration curve resembled those obtained from the OGTT-study. It is concluded that neither the absolute serum glucose level, nor physiological fluctuations in the serum glucose concentration seemed to influence the serum concentration of HPL in this type of patients.


Non-identical reaction of undissociated HCG and HCG-beta subunit with anti-HCGbeta serum. Based on gel-filtration experiments, estimates of the content are given of undissociated human chorionic gonadotrophin (HCG) and HCG-beta subunit in HCG preparations. Radioimmunoassay of three HCG preparation using an antiserum against HCG-beta subunit showed that the slope of displacement curves was dependent on the ratio of HCG-beta subunit to undissociated HCG, the slope being steeper (negative) with increasing ratio. The implication of this observation on the choice of a suitable standard for HCG-beta radioimmunoassay is discussed.


Glucocorticoid effect on repair processes in vascular connective tissue. Morphological examination and biochemical studies on collagen RNA and DNA in rabbit aorta. Male rabbits were injured by a single mechanical dilatation of the aorta and then injected with prednisone 2 mg/kg saline for 14 days or starved. Morphological studies and biochemical measurements of the collagen metabolism, the content of alpha-amino nitrogen, RNA, DNA, water and fat, and the aorta to serum ratio of 125I-albumin were performed on the intima-media layer of the descending thoracic aorta. Prednisone inhibited the intimal thickening. In the media the infiltration by mononuclear cells, the proliferation and regeneration of the smooth muscle cells and the calcification were reduced. Prednisone caused a decrease in 0.45 M NaCl soluble collagen as well as in the dialysable and non-dialysable 14C-hydroxyproline fractions. The total amount of collagen, elastin and alpha-amino nitrogen was unchanged, whereas the 14C-proline incorporation in the non-dialysable protein fraction was inhibited to a greater extent than the 14C-hydroxyproline synthesis. The findings indicate that prednisone inhibits the biosynthesis of collagen, which is inhibited to a greater extent than the general protein synthesis. Prednisone increased the dialysable to non-dialysable 14C-hydroxyproline ratio consistent with a relative increase in the catabolism of newly synthesized collagen. The aortic content of RNA and DNA was reduced consistent with the inhibition of protein synthesis and cell proliferation. Finally prednisone decreased the aortic content of water when related to the wet weight and increased the aortic content of fat. The aorta to serum ratio of 125I-albumin was not influenced by prednisone. It is concluded that administration of glucocorticoid for 14 days exerts an inhibitory action on the histological reaction to injury as well as on the biosynthesis of collagen of the repair processes in vascular connective tissue. A comparison with the effects of prednisone on undamaged rabbit aorta (Manthorpe et al. 1974) demonstrates that the metabolism of collagen of vascular connective tissue during repair is more sensitive to the antianabolic effects of prednisone than collagen in the non-injured aorta. Starvation caused an increase of the aortic percentage of water but otherwise had no influence on the repair processes in the vascular connective tissue.


Lipoatrophy produced in mice and rabbits by a fraction prepared from the urine from patients with congenital generalized lipodystrophy. Urine from 5 patients with congenital generalized lipodystrophy has been fractionated by protein precipitation and Sephadex gel filtration. A fraction with a molecular weight in the range of 1000 was observed to be metabolically active in mice, rats, and rabbits. Hypophysectomized rats got hypoglycaemia following an injection, and the lipolytic-hyperglycaemic effect of ACTH was reduced after injection into intact mice. This effect was probably due to insulin release, because no insulin-like activity was observed on isolated fat cells in vitro. Persistant changes were observed in the animals after 3 weeks of daily injections of the urinary fraction. Adult mice and rabbits developed lipoatrophy with decrease of body weight in spite of a doubling of the food consumption. The metabolic rate and the body temperature were raised. Infantile animals developed a lipodystrophic state with increased growth velocity, and 50 per cent increase of the body weight, although no fat depots were observed. The treated animals got hyperglycaemia, hypertriglyceridaemia, hyperinsulinaemia, and insulin resistance. The rabbits developed manifest diabetes. The corresponding fraction prepared from the urine from the lipoatrophic rabbits produced lipoatrophy after injection into the mice. It is suggested that the lipodystrophic urinary fraction is of hypothalamic origin, and that it acts through the pituitary gland. The fraction is still heterogenous, and was observed to contain thyrotrophin releasing activity.


The noncontact tonometer. Clinical evaluation on normal and diseased eyes. The measurement of intraocular pressure with a noncontact tonometer was correlated to a Goldmann tonometer in 20 normal persons, 20 glaucomatous patients, and 8 patients suffering from corneal diseases. In normal persons the error in measurement for the noncontact tonometer was related to their skill in fixation, and in eye patients to height of pressure and corneal state. Acceptable correlation was found between noncontact tonometry and Goldmann applanation tonometry when the cornea was normal and the pressure below 35 mmHg (Goldmann), otherwise noncontact tonometry was only a guide, and in the presence of corneal disease, unreliable. Good fixation reduced the method error. The standard deviation was 1.09 mmHg at poor fixation and 0.60 mmHg at good fixation. Repeated measurements on the same eye with noncontact tonometry did not alter the intraocular tension.


The immediate response in applanation pressure to intravenous acetazolamide in primary glaucomas and glaucoma suspects. The decays in the applanation pressures of both eyes, after a reduction of the aqueous secretion by means of intravenous acetazolamide, are studied with respect to shape and steepness by comparison with reference curves calculated from different values of the facility of aqueous outflow. The pressure decays in three out of four eyes with narrow-angle glaucoma exhibited "breaks" possibly resulting from a stepwise reopening of the chamber angle during the decompression. Twenty patients with intraocular hypertension and open angles could be divided into two groups according to the facility of aqueous outflow (in mul mmHg-1 min-1), estimated from approximately matching reference curves: Nine patients with facilities above 0.15 had normal visual fields and nearly indentical pressure curves of the two eyes. Out of 11 patients with facilities below 0.15, seven patients had glaucomatous visual field defects and excavated optic discs. The pressure curves of eye pairs in this low facility group showed asymmetry, and breaks were seen in approximately half of the curves. These might be caused by changes in the outflow facility due to a decompression of collapsed outflow channels. However, the morphological basis for such an interpretation is not as well founded as in the case of narrow-angle glaucoma.


Glucose, pyruvate, L-lactate, and citrate concentrations in the aqueous humour of fasting rabbits in relation to age. Results are reported of determinations of glucose, pyruvate, l-lactate and citrate concentrations in aqueous humour from 42 fasting albino rabbits aged from 8 months to 9 years. The glucose concentrations decreased significantly with increasing age. The pyruvate and l-lactate concentrations as well as the ratios of l-lactate/pyruvate did not change significantly with age. However, the pyruvate concentrations were higher and the l-lactate/pyruvate ratios were lower in the 2-year-old rabbits than in the others. The citrate concentrations were found to rise with increasing age. Because of wide ranges of variation between individuals of the same age groups, the parameters in question have limited value in the evaluation of the energy metabolism of the anterior eye segment.


Normal values in clinical electrooculography. 1. Material, method, methodological investigations and distribution of the potential and time parameters. For the evaluation of normal EOG potential and time parameters a case series (142 eyes) is presented. An EOG technique aiming at the largest possible amplitude between the dark trough and the light peak is described. It is shown that the light-induced response following a 20 min period of adaptation to a very low degree of illumination (about 1/10 lx, allowing a rough orientation on the displayed trace) does not differ from that produced after 20 min of total darkness. Also, the independence of the pupillary area for the light-induced response is demonstrated, which means that the light stimulus employed (2500-4000 lx) is supramaximal. Furthermore, the good quality of the gaze fixation in the actual test situation with respect to the recording of equidistant saccades is proven. A DC amplification of the signal is used, which secures independency of inter- and intra-individual differences in the saccadic velocity and makes possible accurate measurements of deflections disfigured by correcting movements. The following EOG parameters are recorded: A base value after 10 min of preadaptation with the light stimulus, the dark trough and the light peak potentials. Also the periods between the beginning of the dark adaptation and the dark trough and between the dark trough and the light peak are noted. The frequency distribution and the general level of the various parameters are discussed in the light of comparable figures of previous publications.


Effect of hard contact lenses on corneal sensitivity and thickness. Corneal sensitivity and central corneal thickness were measured on 11 subjects before and after 8 hours of hard contact lens wear. Both factors were monitored for 30 min after removal. It was found that hard contact lenses affect both corneal sensitivity and thickness, significantly. After 8 hours the reduction of sensitivity was found to be, on average, 94% in the centre and 116% in the periphery, and the average increase increase in thickness was 6.9%. Thirty minutes after removal corneal sensitivity had recovered 82% and 100% in the centre and periphery, respectively, and corneal thickness had decreased by 6.3%. A high correlation was found between central and peripheral corneal sensitivity. This investigation shows that corneal sensitivity measurements offer an alternative method of assessing corneal integrity which is simple and precise.


Histology of the iris in geese and ducks photosensitized by ingestion of Ammi majus seeds. Geese and ducks were photosensitized by the ingestion of Ammi majus seeds, and exposure to sunlight. Mydriasis was a characteristic clinical feature of this syndrome in both species. Histologically the iris of the affected birds showed vacuolisation and varying degrees of atrophy of the muscle of the sphincter pupillae. The effect of pilocarpine and physostigmine on the normal and mydriatic eyes was studied. The possible mode of action of photosensitization and the significance of these findings in the light of the use of psoralens in human medicine is discussed.


Chronic progressive external ophthalmoplegia, pigmentary retinopathy, and heart block (Kearns-Sayre syndrome). Report of a case. Chronic progressive external ophthalmoplegia associated with a pigmentary retinopathy and heart block was described by Kearns & Sayre in 1958. They suggested that the triad represented a syndrome. The cases recorded since then are reviewed and summarised, and several common features are noted. Little attention has previously been paid to the retinopathy. A similar case is presented, and the pigment changes, retinal function, annd fluorescein angiography are examined. There is no clinical evidence for the diagnosis of classical retinitis pigmentosa. The prognosis and aetiology of the condition are discussed.


Follow-up results of occlusion and pleoptic treatment. Fifty cases of amblyopia, including some cases of eccentric fixation, which had previously been successfully treated by various therapies (conventional occlusion, red filter occlusion and pleoptics) were followed up from 12 to 68 months. Fifteen cases (30%) deteriorated to pretreatment level during the follow up. Deterioration was found to be greater in cases over the age of 15 years and in cases who did not follow the instructions given to them after cessation of therapy.


Remarks on the aqueous humor/plasma ratios for amino acids and related compounds in patients with various chronic ocular disorders. The concentration of 19 amino acids and related compounds was simultaneuosly determined by means of ion exchange chromatography in the aqueous humour (Caq) and blood plasma (Cpl) of 40 patients with various chronic ocular disorders. The physiological aspects will be published elsewhere. It is of interest to note that very few significant differences have been found between the Caq/Cpl ratios for the groups into which the material could be clinically divided. This enables the conclusion to be drawn that determination of Caq/Cpl for amino acids and related compounds are not of diagnostic importance in the chronic ocular disorders which were studied.


Corneal diameter in Greenland Eskimos. Anthropometric and genetic studies with special reference to primary angle-closure glaucoma. In a population survey the corneal diameter (DC) was measured in 1,211 adult Greenland Eskimos from six districts. Using a Wessely keratometer, trnasversal and vertical readings were performed, and the CD value taken as the average. The unimodal distributions obtained were found to differ from normality. The results suggested a small decrease of CD with age whereas the sex difference (0.2 mm) was highly significant. Geographical variation was found, a West Greenland group (Umanaq) being below the others, while the purest Eskimos (from Angmagssalik) showed higher mean values. A Danish control sample had significantly larger corneae, about 0.5 mm above the Eskimos, and agreed with other reports on Europeans. The CD values and the anterior chamber depth (ACD) were positively correlated. The Eskimo primary angle-closure glaucoma patients showed a slight deviation towards the lower CD classes. The familial CD distributions suggested a mainly genetic determination of corneal size.


Biometric correlations of corneal thickness. Central corneal thickness, depth of anterior chamber, thickness of lens, length of vitreous, axial length, applanation (Goldmann) and indentation (Schiotz) tension and rigidity (Friedenwald) were determined in three groups of patients; (1) 16 patients with glaucoma simplex, (2) 25 patients with ocular hypertension, and (3) 26 patients with fibrillopathia epitheliocapsularis (so-called pseudoexfoliation of the lens). Average data and computed correlations between the parameters are given in tabular form. Corneal thickness was normal in glaucoma simplex, but significantly increased in ocular hypertension. Corneal thickness was positively correlated to applanation tension but not to indentation tension, nor to any other of the studied parameters. It is suggested that corneal thickness can be considered as a biometric parameter which yields new information about the eye not covered by the conventional parameters.


Prognosis of primary rhegmatogenous retinal detachments. 1. Associations between clinical detachment characteristics, subretinal fluid butyrylcholinesterase and visual outcome following scleral buckling procedures. Thirty-five patients with primary rhegmatogenous retinal detachments were followed for at least 6 months after scleral buckling procedures with subretinal fluid (SRF) drainage, in order to define factors influencing anatomic and visual outcome. Thirty-two cases were surgically reattached; three were not. Among the reattached cases, final visual acuity was poorer in patients with: older age; longer standing, more extensive detachments; detachment of the macula (with or without the development of a visible macular lesion); macular lesions; and higher SRF butyrylcholinesterase activity. These factors were themselves interrelated. Follow-up duration was only weakly related to final acuity, probably because of the long post-surgical follow-up. Phakic/aphakic status bore little relationship to final acuity. The type or timing relative to drainage of inflammation producing treatment was not related to final acuity.


Iron deficiency and dietary factors in Finland. In connection with a multiphasic screening program carried out in Finland, over 7,000 persons participated in a dietary survey. The method was a diet history interview concerning food consumption and habits during the previous year. The mean intake of meat products was lower in anemic women (Hb less than 12.0 g/100 ml or PCV  less than 36 vol%) than in the others and in the intake of liquid milk products was higher in the anemic women. The meat product intake was lower in anemic men (Hb less than 13.0 g/100 ml or PCV less than 41 vol %) than in other men, but the milk consumption of the groups was almost equal. The intake of meat products in iron-deficient women )serum iron less than 50 mu g/100 ml or TIBC larger than or equal to 400 mu g/100 ml) was lower and the intake of milk products higher than in the other women. The intake of meat products in iron-deficient men (serum iron less than 50 mu g/100 ml or TIBC larger than or equal to 400 mu g/100 ml) was lower than in the other men and the milk consumption was almost equal. The results support earlier studies that dietary habits are significant in the etiology of iron deficiency. In the light of this population study the intake of vitamin C also seems to influence iron metabolism.


Effect of high crude fiber intake on transit time and the absorption of nutrients in South African Negro schoolchildren. Transit time (using carmine as marker) averaged about 9.5 hours in rural South African Negro children aged 9-12 years, when ingesting a mean of 10 g crude fiber per diem on their everyday diet. A: in subgroups of 40-50 pupils, supplements of maize and wheat bran, and of wholemeal bread--each affording about 2 g fiber--also of oranges, affording 4 g fiber, decreased transit time only slightly, to about 8.5 hours. Hence, pupils current daily fiber intake, in its effect on transit time, is already acting maximally. B: mean respective fecal nitrogen and fat concentrations on everyday diet were not significantly affected when the subgroups ate one of the following fibre-free foods: 1) 40 g protein from skim milk; 2) 40 g fat from butter; 3) 40 g carbohydrate afforded by sugar. Additionally, on their usual diet, also following the ingestion of 40 g uncooked maize flour, starch was extremely seldom detected in feces. C. feces collections for 5-day periods were made on small groups of pupils (8 per group) when consuming first their everyday diet, and next when including each day one of the following: 1) 40 g protein from skim milk; 2) 40 g fat from butter; 3) 40 g sugar. On these regimens, there were no significant changes, compared with respective data on everyday diet, in mean amount of dry feces excreted daily, in concentrations of nitrogen and fat, nor in amounts of nitrogen and fat excreted daily. Yet a daily supplement of 350 g oranges (5-7 oranges), although virtually nitrogen- and fat-free but containing 4 g fiber, resulted in slightly shorter transit time but highly significant increases in mean amounts of dry feces, nitrogen and fat excreted daily. Observations suggest that the protein, fat and carbohydrate (excluding unassimilable fiber) in the supplements were virtually fully digested and absorbed. Discussion suggests that this also applied to nutrients in the everyday diet. It is judged that the large stools voided by these people (and others consuming diets high in fiber) are composed, apart from unassimilable fiber, almost wholly of endogenous products.


Comparison of central effects of noradrenaline and dopamine injected into the lateral brain ventricle in rats. Noradrenaline and dopamine injected into the lateral brain ventricle exerted a significant effect on the behavior of rats. Both amines caused a slight rise in the basic locomotor activity which was significantly increased in the animals with inhibited monoamine oxidase activity. Besides that, they suppressed the behavior of rats in the open-field test, inhibited the conditioned avoidance response, decreased body temperature and increased amphetamine-induced motor hyperactivity. Noradrenaline, in contrast to dopamine, changed the intensity of amphetamine-induced stereotypy and prolonged the action of hypnotics. The central action of both catecholamines (in higher doses especially) seemed to have a biphasic course: in the first phase after administration depression was observed which was more pronounced after noradrenaline administration, in the second phase a stimulating effect b


The efficiency of aquocobalamine as an antidote in cyanide poisoning when given alone or combined with sodium thiosulfate. The antidotal activities of aquocobalamineacetates and sodium thiosulfate were tested in guinea pigs and cats. The animals were attached to artificial respirators throughout the experiment and were poisoned with a continuous infusion of sodium cyanide solution (4.1 muMol/kg.min NaCN). The rate of action of each antidote was determined from the time taken for the HCN exhalation to drop below the level of 100 nMol/kg.min in quinea pigs, and to values below 25 nMol/kg.min in cats; the detoxifying capacity of each antidote was determined from the time taken for the HCN exhalation to rise above the said values and the time interval for normal function of heart activity to be restored. Aquobalamine was characterized by its rapid rate of reaction in both the animal species; its detoxifying capacity showed, however, according to our expectations, variations corresponding to the applied doses. The combination of the antidotes aquocobalamine (100 mg/kg) and thiosulfate (500 mg/kg) proved to possess high rate of reaction and a large detoxifying capacity in guinea pigs. Similar results were obtained in cats with antidote doses of 200 mg/kg aquocobalamine combined with 500 mg/kg thiosulfate. The slow rate of reaction and large detoxifying capacity of thiosulfate were confirmed in our experiments. It combination with aquocobalamine showed no undesirable change in its antidotal action providing a time interval of 1 min was maintained between the 2 injections.


[Isolation of drugs from blood with macroreticular resins (author's transl)]. The use of Amberlite XAD resins for isolation of drugs from blood without preliminary precipitation of proteins is described. Compared with the usual methods of precipitation this method gives better yields and cleaner extracts in a shorter time. In combination with specific methods of detection, e.g. with GC and Nitrogen detector, the use of XAD promises to be efficient in the screening for drugs in the forensic and clinical field.


The surface tension of upper airway secretions in patients with and without respiratory disease. The alveolar-arterial oxygen partial pressure (PAaO2) difference and surface tension of upper airway secretions (UASST) were simultaneously measured in 33 intubated patients. Patients without respiratory disease had UASST and PAaO2 gradients significantly lower than those with chronic obstructive lung disease. Patients in respiratory failure had UASST and PAaO2 gradients significantly higher than when they were out of failure. Correlation of UASST with PAaO2 was good (r = 0.81). These findings demonstrate that UASST closely correlate with the severity of pulmonary disease and suggest that their measurement may be a simple, clinically applicable method of assessing alveolar surfactant function.


[Clinical experience with benzene sulfonyl chloride (author's transl)]. The clinical development of a percutaneous benzene sulfonyl chloride absorption, which can also occur on the mucous membrane, has a biological effect on the skin and results in reversible toxic damage to the liver; three such cases are described. Two patients experienced very severe shock which was brought under control after 1 to 1.5 hrs. A possible allergic genesis reaction of an immediate type is discussed.


[Psychomotor responses under standardized trichloroethylene load (author's transl)]. 20 volunteers were exposed for 4 hrs to a concentration of trichloroethylene in room air of 95 ppm. Before and after exposure the Wiener Determinationsgerät, the Wiener Reaktionsgerät, and the motorische Leistungsserie (Schoppe) were used to perform 6 tests, each of which gave 15 measurements. A comparison with the results of a blank test which had been obtained 1 week before with the same volunteers under the same conditions, but without the use of trichloroethylene, yielded no statistically significant impairment of the psychomotorial function by trichloroethylene. Further investigations are being carried out.


A comparison of two types of acute carbon monoxide poisoning. In 47 patients treated at the Toxicological Clinic in Krakow for coal stove-gas poisoning, the aspartate aminotransferase, lactate dehydrogenase, LDH1 isoenzyme activities, and the lactate level were studied. Findings were compared with those of earlier investigations carried out on a group of patients poisoned by lighting gas; qualitatively changes in both groups were similar. The biochemical parameters studied aided in quantitative evaluation of the patients' condition: a threefold increase in lactate level on admission to the hospital and a likewise threefold increase in aspartate aminotransferase activity after 24 hrs of treatment are indications of severe poisoning.


Acrylonitrile biotransformation in rats, mice, and chinese hamsters as influenced by the route of administration and by phenobarbital, SKF 525-A, cysteine, dimercaprol, or thiosulfate. Female wistar rats, conventional albino mice, and Chinese hamsters were given a single dose of acrylonitrile, 0.5 or 0.75 mM/kg body weight. The elimination in the urine of thiocyanate, which is the main metabolite of acrylonitrile, indicated a decreasing proportion of biotransformation after oral (over 20%), intraperitoneal, or subcutaneous (2 to 5%), and intravenous (1%) administration in rats. Oral administration of acrylonitrile in hamsters and mice was also followed by higher biotransformation than intraperitoneal administration. Pretreatment of rats with phenobarbital, SKF 525 A, cysteine, or dimercaprol did not significantly influence elimination of thiocyanate in the urine after the administration of acrylonitrile, but simultaneous administration of thiosulfate significantly increased the metabolized portion of acrylonitrile given intraperitoneally in rats (almost twice) and mice (more than three times). Acrylonitrile was found to be strongly bound in blood. The study confirmed the marked effect of distribution (first-pass metabolic phenomenon) on the metabolic fate of foreign compounds. The strong acrylonitrile binding and cyanoethylation are apparently responsible for the unusually high influence of the different routes of administration on the metabolic fate of acrylonitrile. Acrylonitrile was more effectively metabolized to thiocyanate in mice than in rats after oral, intraperitoneal, and intravenous administration. A greater response of acrylonitrile to thiocyanate metabolism and a larger decrease in its acute toxicity after thiosulfate in mice than in rats indicate possible differences in the mechanism of acrylonitrile toxicity in these animals. Cyanide apparently plays a minor role in the acrylonitrile toxicity in rats, but may play quite an important one in mice.


[The mutagenicity of desmethyltrichlorphone in dominant lethal test on mice (author's transl)]. After i.p. administration to AB mice of 405 mg/kg desmethyltrichlorphone (sodium salt) in a single dose and 54 mg/kg daily for 3 weeks, the mutagenic effect in the dominant lethal test was at least the same as that of trichlorphone. these findings indicate that the genotoxic effect of trichlorphone is not likely to be due to its alkylating properties.


Tetracyclines and lead metabolism in rats. The effects of oral, parenteral pretreatment, and posttreatment with tetracyclines on lead metabolism were studied in 7 to 9 week-old female rats. In animals receiving different doses of tetracyclines orally (30 to 600 mg/kg daily) for 12 days the retention of an oral dose of 203Pb applied on the 4th day of the treatment was, at the end of the experiment, the same as in the controls. In animals receiving daily intraperitoneal doses of tetracycline (18.8 to 75 mg/kg for 12 days) the retention of an intraperitoneal dose of 203Pb applied on the 4th day of treatment was, at the end of the experiment, the same or higher than in the untreated group. This indicates that tetracyclines are not likely to be useful in the prevention or treatment of lead poisoning.


[Age determination of post traumatic changes in menisci and synovium (author's transl)]. Morphological examinations on 259 surgically removed menisci, 67 for trauma after soccer. Degenerative changes in menisci are more pronounced after a longer time intervall between trauma and surgery.


[Chemotherapeutic effects of nitro compounds. 1. Nitroanilines]. More than 200 nitro compounds, most of them nitroaniline derivatives substituted with one or more radicals having a basic reaction, were prepared and investigated as to their therapeutic activity against bacteria, fungi, protozoa, helminths, viruses and tumors. Several mono-nitrobenzenes with a radical having a basic reaction showed weak in-vitro activity against gram-positive bacteria and against Crocker's sarcoma 180; they also showed systemic activity against nematodes (Aspiculuris tetraptera) and viruses. The majority of therapeutically active compounds with pronounced in-vivo activity against Trichomonas fetus, Entamoeba histolytica, Schistosoma mansoni, cestodes, nematodes (Ancylostoma caninum), viruses (influenza, MHV, SAV and EMC) and various types of carcinoma (Ehrlich's carcinoma, leukemia 1210, Crocker's sarcoma 180) were dinitrobenzene derivatives with one radical having a basic reaction and electropositive groups or unreactive or reactive chlorine atom, and di-nitrobenzene with two equal or two different radicals having a basic reaction. Compound No. 70 revealed a marked in-vitro activity against fungi (Trichophyton; Microsporum, Candida albicans). Other nitro compounds such as bis-mono- and bis-dinitrobenzene derivatives likewise showed a systemic action against E. histolytica, viruses and, in particular, carcinoma (Crocker's sarcoma 180, Ridgway's osteosarcoma). Oxygen and sulfur analogue compounds as well as compounds produced by reduction also possessed a distinct activity against E. histolytica and viruses. On the basis of the present results particularly the dinitrobenzenes substituted with two radicals having a basic reaction include a number which have in common that a structure/activity relationship is recognizable in respect of E. histolytica, Schistosoma mansoni and different types of viruses. The activity against viruses in this class of compounds is probably due to an increased interferon production in the host animal. Whether the mechanism of action is the same against E. histolytica or Schistosoma mansoni has not been determined so far. A tumorigenic effect was observed mainly in those di-nitrobenzenes which are classed as alkylating compounds. Because of the small chemotherapeutic index the trials were not continued with the most effective compounds mentioned.


[2,2-Hydrazinopyrimidines with branched substituents as potential antitumor agents. Condensation with hydrazine-N,N-dicarboxamidine]. With a view to the cytostatic effect exhibited by certain representatives of the 2,2'-hydrazopyrimidines on the one hand, and by various drugs carrying branched substituents on the other hand, 4,4',6,6'-tetra-tert.-butyl-2,2'-hydrazopyrimidine (III) has been prepared by condensation of 1,2-hydrazine-dicarboxamidine (I) with 2,2,6,6-tetramethyl-3,5-heptanedione (II). Structure III has been confirmed by IR and NMR data and by its N,N'-diacetyl derivative IV.


Neuroleptic piperazinyl-dibenzo-azepines. Chemistry and structure-activity relationships. The chemistry and the molecular and physicochemical properties of the 11-piperazinyl derivatives of dibenz[b,f][1,4]-oxazepines and -thiazepines and of dibenzo[b,e][1,4]diazepines as well as those of the 6-piperazinyl-morphanthridines are reviewed. The physicochemical parameters sigma, pK, eta, RM and surface pressure are considered in relation to each other and in relation to two pharmacological effects, namely apomorphine antagonism and cataleptic activities. The influence of substituents, bridging moiety and basic side chain on structure-activity are discussed. Finally, the dibenzodiazepine derivative clozapine, which differs markedly from the classical neuroleptics in its biochemical, pharmacological and clinical properties and represents a new type of antipsychotic agent, is discussed.


A new series of benzodiazepines. 1-Hydroxyalkyl derivatives of 1,3-dihydro-2H-1,4-benzodiazepin-2-ones. A series of new 1-hydroxyalkyl derivatives of 1,3-dihydro-2H-1,4-benzodiazepin-2-ones bearing a 3-hydroxyl or a 4-N-oxide function together with some related compounds have been synthesized. Compound (22) [1-(2-hydroxyethyl)-3-hydroxy-7-chloro-1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one] has been selected for further studies both in animals and in humans as an antianxiety-sedative agent.


A few factors contributing to the mechanical strength of collagen fibres. A knowledge of the influence of several factors on the stability and properties of collagen and preparations thereof precedes their industrial application. The results of such a study are reported in this paper. The mechanical properties of skin samples vary significantly with location and direction of cutting. The properties of isolated fibres from these locations, however, did not differ significantly, in a single animal. Collagen fibres from tendons and skins of several mammalian and other species exhibited under identical conditions of testing differences in their physical properties. The influence of factors like composition, shrinkage temperature, non-collagenous components, fibril width and age, on the properties is discussed individually. A slight increase in strength was observed in deaminated and deguanidinated collagen fibres while all the other treatments studied, viz. modification of side chains, crosslinking, tanning and irradiation with gamma-rays decreased the strength. An inverse correlation was observed between shrinkage temperature and strength of treated collagen fibres. The strength was also found to be influenced by the morphological structure of collagen. Irradiation with gamma-rays caused a reduction of not only the strength and shrinkage temperature of collagen but also caused severe destruction of the fibrillar structure at the X-ray and electronmicroscopic levels. The degradation was progressive with dosage. Non-hydrolytic scission of the polypeptide chains seemed to be responsible for the changes observed, which were also species specific.


The potentiation of the activity of adenosine on coronary blood flow, blood pressure and heart rate by inosine in the dog. The activity of adenosine and inosine on coronary blood flow and arterial blood pressure was investigated in anaesthetized and thoracotomized dogs. The following results were obtained. 1. Individual adenosine administration caused an increase in coronary blood flow. However, this adenosine activity was significantly strengthened when the same dose of adenosine was applied simultaneously with inosine in doses of 3.2, 5.6 and 10.0 mg/kg body weight i.v. The duration of the effect of adenosine on the coronary blood flow was also potentiated by inosine. 2. The hypotensive effect resulting from 0.2 mg adenosine/kg i.v. was significantly strengthened by simultaneous inosine application (3.2, 5.6 and 10.0 mg/kg i.v.). The activities on the blood pressure of increments in the individual adenosine dosages (0.2, 0.4 and 0.6 mg/kg i.v.) were significantly potentiated by 10 mg inosine/kg body weight i.v. 3. The heart rate was not modified by 0.2 mg adenosine/kg i.v. However, the same adenosine dosage plus inosine (3.2, 5.6 and 10.0 mg/kg i.v.) applied simultaneously led to bradycardia. Increasing adenosine doses (0.2, 0.4 and 0.6 mg/kg i.v.) applied simultaneously with inosine (10.0 mg/kg body weight i.v.) led to a dose dependent retardation of the heart rate. 4. The possible reasons for the potentiation of the effect of adenosine by inosine were discussed.


[The effect of a combination of 1-(4'-hydroxyphenyl)-2-methyl-aminopropanol-(1)-hydrochloride with a nucleotide containing heart muscle extract on the heart and circulatory system of the dog]. The heamodynamic activity of Carnigen, which is a blood pressure stabilizer consisting of 1-(4'-hydroxyphenyl)-2-methylaminopropanol-(1)-hydrochloride (Suprifen) and a nucleotide containing heart muscle extract, was investigated in 15 anaesthetized dogs following intraduodenal application (0.3--1--3 mg/kg body weight). The following results were obtained: 1. The stroke volume and cardiac output were raised significantly exhibiting a dose dependent activity follwoing Carnigen application. 2. The cardiac work exhibited a dose dependent rise which was significant after 3 mg/kg. 3. The contractility of the left ventricle increased following each of the tested dosages. This was expressed by a significant rise in the dp/dt value as well as in the quotient (see article). 4. The mean femoral blood pressure exhibited a moderate rise in the test range from 0.3--3 mg/kg. 5. The heart rate increased by a few beats follwoing doses of 0.3--1 mg/kg. 6. The total peripheral resistance was reduced in a dose dependent manner. 7. The respiration volume was slightly increased following 0.3 and 1 mg/kg Carnigen, 3 mg/kg caused a quite moderate respiration stimulation.


[The effect of increased extracellular calcium concentration on the hypoxic and pharmacologic hyperemia of skeletal muscle]. The influence of an increased Ca concentration on reactive hyperemia, work induced vasodilation and pharmacologically induced dilation (adenosine, nifedipine, verapamil) was studied in the blood perfused gastrocnemius of dogs. Reactive hyperemia, work induced vasodilation and increased blood flow by administration of adenosine could not be influenced by increased extracellular Ca concentrations. A Ca antagonism was demonstrated for nifedipine and verapamil, especially with regard to a diminution of the drug eff.


Electrophysiological and behavioral effects of 1-methyl-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (ID-540) in cats and rabbits. Effects of ID-540 (1-methyl-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one) on the central nervous system were evaluated electrophysiologically and behaviorally in cats and rabbits. The reference compound used was diazepam. 1. ID-540 as well as diazepam produced muscle relaxation, grooming, facilitation of appetite and suppression of defensive behaviors. ID-540 made the animals lie on their side during sleep, but diazepam did not. 2. Though more effectively inducing an increase in fast activity and a decrease in frequency of hippocampal theta-waves than diazepam, ID-540 scarcely affected the amplitude of subcortical EEG (hippocampus, amygdala and hypothalamus), which diazepam decreased in cats. 3. ID-540 and diazepam increased the waking phase and decreased the paradoxical sleep phase. 4. ID-540 and diazepam at a dose of 1 mg/kg decreased the duration of amygdala after-discharge for 1 h in cats. Diazepam increased the duration of the after-discharge after it had been decreased, but ID-540 did not. ID-540 did not affect the duration of hippocampal after-discharge whereas diazepam prolonged it. 5. ID-540 depressed more effectively the hippocampal arousal response to stimulation of the ventro-medial hypothalamus than did diazepam in rabbits. 6. ID-540 depressed amygdalo-hippocampal evoked potential in cats. 7. ID-540 did not affect norepinephrine-induced pressor response but reduced hypothalamic pressor response in cats.


Influence of spider Latrodectus tredecimguttatus poison on progressive muscular dystrophy in rat. The therapeutic influence of the spider Latrodectus tredecimguttatus poison on the progressive muscular dystrophy in rats caused by the method of Mendell's et al., as well as on the genetic dystrophy in mice, was examined. It was shown that the poison produces a functional and histological improvement, wheras the weight of the dystrophic muscles was not affected.


[The pharmacokinetics of papaverine and its bioavailability from a sustained-action preparation]. The serum levels of intravenously and orally given papaverine were determined in healthy, fasting beagles. The bioavailability of the drug was assessed in the same animals following single administration of the sustained-action preparation Panergon (papaverine-hydrochloride). Based on a one-compartment model, the time of invasion, the half-life of elimination, the volume of distribution and the absorption rate of papaverine were calcualted. A comparison of the areas under the concentration curves shows the complete bioavailability of the papaverine contained in Panergon.


Suppression of heparine-induced increment of rat free fatty acids by oxprenolol. Injection of heparin i.v. into rats increased significantly free fatty acids (FFAs) plasma levels. When 20 min before the heparin injection 1-(o-allyloxy-phenoxy)-3-isopropylamino-propane-2-ol-hydrochloride (oxprenolol, Trasicor) was administered i.p., FFAs increment was prevented. Isoproterenol-induced plasma FFAs rise was also inhibited by the administration of this beta-adrenergic receptor blocking agent. Treatment by beta-adrenergic receptor blockade for prevention of heparine-induced FFAs increase, which possibly contributes to the appearance of heart arrhythmias, must be considered.


[Reduction of serum triglycerides with a combined application of butylbiguanide and clofibrate in animal experiments]. When given separately, neither butylbiguanide (N1-butylbiguanide-hydrochloride, the active principle of Silubin retard) (75 mg/kg) nor clofibrate (30 mg/kg) decreased the serum triglycerides in normolipaemic rats. In combined administration, however, the two drugs produced a statistically significant average decrease in serum triglycerides by 30%. Simultaneous administration of the two drugs also lowered triglycerides in rats with carbohydrate-induced hypertriglyceridaemia.


The effect of beta-phenylethylamine on temperature in mice and its possible mechanisms of action. Beta-phenylethylamine on injection into mice (100 mg/kg i.p.) produces a marked hyperthermia which is followed by a prolonged hypothermia. The hyperthermic response was studied in this report. The hyperthermic response was inhibited by p-chlorophenylalanine, methysergide, cyproheptadine, alpha-methyl-tyrosine, propranolol, practolol, phenoxybenzamine, phentolamine, haloperidol, pimozide, protriptyline and desipramine. Lysergic acid diethylamide potentiated the response, while p-chloroamphetamine was without effect. While FLA-63 potentiated the response, disulfiram and reserpine were ineffective in preventing the hyperthermia. Nicotinic acid and prostaglandin E1 did not prevent PE induced hyperthermia. It was concluded from these results that PE induced hyperthermia in mice is blocked by agents that reduce the effective concentration of either DA or 5-HT in the central nervous system (by either synthesis inhibitors or receptor blockers). The involvement with catecholaminergic neurons at least was postulated to be a result of PE induced release of DA from DA neurons.


Blockade of the central effects of d-amphetamine by amantadine. II. 1-Adamantanamine (amantadine) pretreatment significantly reduced the motor hyperactivity and hyperthermia caused by d-amphetamine in reserpinized mice. In drug-naive mice, when amantadine was administered after d-amphetamine, the motor activity caused by the latter also was decreased. Since our earlier studies showed that amantadine pretreatment also antagonized the increases in both motor activity and homovanillic acid (HVA) in the caudate nucleus caused by d-amphetamine in mice, it is suggested that the antagonism is due to a competitive blockade at the pre-synaptic level in the brain.


Pharmacological study of a new substance, mecinarone. Mecinarone, a benzofuranic chalcone, shows considerable vasodilating activity on the peripheral and cerebral circulation. The intramuscular irrigation is thus improved and the cerebral blood supply increased. This vasodilating activity is accompanied by only a slight drop in the systemic arterial pressure and occurs without cardiac depression. Mecinarone has also antibradykinin, antiserotonin and antiaggregation properties which added to the vasodilating activity, greatly increase its pharmacological interest.


Relationship between activity and structure in derivatives of clonidine. 2-(2,6-Dichlorphenylamino)-(clonidine, Catapresan, Catapres), 2-(2,6-diethylphenylamino- (St 91), 2-(2-chloro-6-methylphenylamino)-, 2-(2-chloro-4-methylphenylamino)-, 2-(2-methyl-5-fluorophenylamino) -and 2-(2-chloro-3-methyl-phenylamino)-2-imidazoline were investigated in various pharmacological tests. 1. All substances increased blood pressure in spinal rats and initially in intact cats and dogs and increased the total peripheral resistance in the latter. As these compounds also showed mydriasis in conscious rats it has been concluded that these effects are due to stimulation of peripheral alpha-adrenoceptors. 2. With the exception of St 91 the substances lowered blood pressure following i.v. injection, they decreased heart rate in cats and dogs and the cardiac output in the latter. These four compounds also decreased heart rate in vagotomised and atropinised rats. It was concluded that these effects were due to a decrease in sympathetic activity of the CNS. 3. In anaesthetised rats with beta-adrenoceptor blockade by toliprolol, a blood pressure increase was elicited by i.v. injection of angiotensin and the resulting bradycardia was recorded as a measure of vagal reflex activity. Clonidine and three derivatives which have shown hypotensive activity facilitated the vagal cardiodepressor reflex; St 91 was inactive in this respect. It has been concluded that decrease in central sympathetic tone and increase in central vagal activity are linked together in these compounds. 4. St 91 did not lower blood pressure and did not facilitate vagal reflex bradycardia after i.v. injection in dogs, but was active after intracisternal injection. It has been concluded, therefore, that this compound is able to act on structures in the CNS like clonidine but these effects usually do not occur after systemic administration because of its poor ability to penetrate the blood-brain barrier. 5. All derivatives decreased gastric acid secretion. 6. All substances increased blood glucose levels and were sedative; St 91 was the least effective compound in both respects pointing to a central mediation of these effects. 7. The results show that clonidine and the derivatives tested have the same reaction pattern. 8. The relationship between the CNS mediated cardiovascular depression and the peripheral alpha-adrenergic stimulating potency in conjunction with the lipoid solubility have been discussed.


On the antitumor activity of gallium and lanthanides. When assayed on lymphatic leukemia BW5147 and lymphosarcoma 6C3HED bearing mice lanthanum shows a higher tumor inhibitory activity than does gallium. The mechanisms involved in the inhibition of the tumor growth appear related to effects of lanthanum and gallium on the tumor metabolism of calcium and magnesium.


The synthesis and pharmacology of a new analgesic, ID-1229. A new non-narcotic analgesic, 2-[3-(p-fluorobenzoyl)-n-propy]-5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan (ID-1229) has been prepared from 5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan. The analgesic activities of ID-1229 were several times more potent than those of pentazocine in the acetic acid writhing test in mice, bradykinin test in rats, Randall-Selitto's test in rats, and the electrical stimulation test in mice, while, ID-1229 showed little activity in both the tail pinch test and the hot plate test. ID-1229 did not show anti-narcotic activity in the morphine-combined test, and the Straub tail phenomenon was not observed in ID-1229. ID-1229 showed CNS activities in some tranquilizing tests, but did not show activity in several other CNS tests. The CNS potency is condiserably weaker as compared with haloperidol or diazepam, and the pattern of CNS activities in ID-1229 is quite different from those of both compounds. ID-1229 is a potent non-narcotic analgesic with tranquilizing activity, which is quite free from the undersirable side effects of morphine or morphine-like compounds including pentazocine.


Antinociceptive action and plasma levels of acetylsalicylic acid in the dog. 1. The analgesic potency of acetylsalicylic acid (ASA) is four times greater when administered intravenously than when administered orally. 2. The onset of the ASA analgesia after oral administration is significantly slower (30-60 min) than after intravenous (5-15 min) application. However, the duration of ASA-analgesia after oral administration is significantly longer (5 h) than after i.v. (2-4 h) application. 3. The onset and duration of ASA-analgesia in dogs after oral and i.v. administration cannot be correlated with plasma levels of ASA. During the period of analgesia, ASA can be detected only in extremely low concentrations, since it appears to be very rapidly hydrolysed to SA. 4. The development of an accurate and reproducible method for the separate determination of ASA and SA in plasma facilitated the direct correlation of plasma levels of these substances with ASA-induced analgesia.


Effects of topically instilled drugs on intraocular pressure in rabbits. The effect of the ocular instillation of some drugs on the intraocular pressure of non-anaesthetized rabbits was studied, using the Schiötz tonometer. The risk of systemic absorption of drugs follwoing ocular instillation was evaluated by 1. measuring the spreading of effects from the treated eye to the contralateral one and 2. studying the effects on blood pressure or on blood pressure responses to noradrenaline. The results showed that trazodone, epinephrine and acetazolamide produced hypotension on the treated eye; there was no spreading of effects to the contralateral one. These data could suggest that the primary site of action of these drugs is the eye. Naphazoline reduced the intraocular pressure both on the treated eye and, with a constant delay, on the contralateral one. This was interpreted as a combination of a local action and systemic absorption. The effects of chlorpromazien were more complex. This drug produced hypertension and a strong irritation on the treated eye as well as a hypotensive effect on the contralateral one. The rise in intraocular pressure was probably caused by irritation; the hypotensive effect by systemic absorption. The following drugs were inactive: amphetamine, chlorothiazide and pilocarpine.


[Animal experiments on the "dysionic genesis of intrauterine malformations"]. Pregnant rabbits were injected 12 mg 4-chloro-5-sulfamoyl-N-furfuryl-anthranilic acid (furosemide)/kg body weight from the first to the tenth day of pregnancy (o.p.). The serum concentrations of sodium, potassium and calcium were determined on the 1st, 9th and 14th day o.p. The mother rabbits were killed on the 29th day of o.p., their foetuses were removed and the mucous membrane of the uterus was inspected for resorption sites. The foetuses were examined, the skeletons were stained and studied under the microscope. The results of the treated rabbits were compared with those of the control rabbits. The sodium, potassium and calcium concentrations of the treated rabbits were not lowered significantly. The haematocrite did not change during or after the treatment. The mothers gained weight continuously. The rates of resorption and malformation of the treated group were slightly raised.


The occurrence of 3-hydroxy-phenprobamate, a new metabolite of phenprobamate, in dogs and humans. 3-Hydroxy-phenprobamate has been isolated from the urine of dogs and humans following oral administration of phenprobamate. The structure of this new metabolite was determined by analysis of its spectral data and corroborated by an unequivocal synthesis. The relative concentration of this substance, as well as other neutral metabolites occurring in the urine, either in the free form or as the glucuronide conjugates, is presented for both species. The presence of 3-hydroxy-phenprobamate in human plasma, and its interference with phenprobamate plasma level analysis by a previously described colorimetric method, is discussed


[Statistical evaluation of light protection factors]. The protection against erythema belongs to the cosmetic effects which lend themselves to mathematical treatment. It is demonstrated -- on the basis of the optimal definitions given by Ellinger and Schulze -- that the calculation of the mean value of the light-protection factor Q as hitherto in use, does not correspond to the real frequency-distribution. On the contrary there exists, independent of the radiation source having sunlike characteristics and of the distance from the radiator, a binary-logarithmic standard distribution. With reference to the gradation principles of the human skin a transformation of the pertinent differences of area is necessary first, i.e. a transformation responding to the Gaussian standard distribution principle. Tables are presented concerning the transformation and the practical evaluation of the light-protection factor Q.  By aid of these tables a standardization of the factors Q measured by different authors has been attained as well as a standardized statistical-mathematical analysis. The investigation of the threshold dose producing erythema on the unprotected human skin has revealed a superposition of three frequency-distribution types (showing logarithmic distribution, too) having different standard deviations. The results of this entirely statistical classification permit a safe forecast: the sunburn protection inherent in the human skin is compounded of several contributing factors which are interconnected multiplicatively, not additively.


[Pair differences-U-test. A distribution-free comparative study of two therapies]. Distribution-free comparison of the effects of two therapies The Wilcoxon-Mann-Whitney test forms the basis for the following common test-problem according to which the U-test should be performed. On two rows of independent -- connected in parallell -- matched paired samples a continuous variable is determined. Observations on a single pair are contributed to the identical individuum. The question that arises is formulated as follows. Can the differences of a pair of the two rows of samples -- connect in parallel -- be distinguished from each other with regard to their location? To answer this question a modified application of the U-test is proposed. This test can be used to compare the efficacy of two different treatments. Other uses of this test are also possible.


[Experimental psychological study of the effect of a hexobendine-etamivan-etofylline combination]. Instenon forte, a combination of hexobendine, etamivan and etofylline for treatment of cerebral vascular insufficiency, was tested in an experimental psychological study. Effects on performance, especially on functions related to driving, were investigated. The experimental group consisted of 15 male and 9 female, the control group of 15 male and 8 female students, aged between 17 and 25 years. All subjects were tested with the same series of psychological tests before and after long-term medication. The male subjects showed moderate increase of concentration performance and short-term memory under Instenon in various tests. Taking in complex traffic situations at a glance was significantly enhanced in the male experimental group, whereas reactive behavior under stress showed some impairment. In the female experimental group an increase of focal attention and an improvement of reactive behavior under stress was found, taking in complex traffic situations at a glance was impaired. The results of this study indicate that neither in female nor in male subjects a consistent positive or negative effect of Instenon on functions related to driving could be determined. Driving fitness in general is not influenced by Instenon in the dosage applied in young healthy volunteers.


[Preclinical research--toxicology].

[Preclinical research--toxicology]. The different steps of the toxicological testing of new drugs are shortly described. Furthermore it is discussed that only 60-70% of the drug induced adverse reactions in man can be predicted by the experimental methods being available at present. Special problems exist in evaluating the results of reproductive-toxicological, carcinogenicity and mutagenicity tests. These problems are illustrated by some experimental and clinical examples.


[Problem of the evaluation of experimental research for clinical testing of new drugs in man]. The differences in the implication of animal experimental results for the clinical investigation of drugs are pointed out. Interpretation of experimental data leaves a wide range to discretional decisions. These discretional decisions are tried to be defined as well as the terms "safety of drugs" and the "present state of science" used by legislative authorities. Pharmacological, pharmacokinetic and toxicological investigations are discussed which should be the basis for the first application to man. Moreover, further prerequisites for Phase I of Clinical Pharmacology are mentioned. The present experimental results, the limited number of patients and adaptation of dosage decrease the risk of serious complications to a minimum.


[Refinement of mensurational methods in human pharmacology]. In healthy persons the changes in heart rate and myocardial contractility induced by oxprenolol and phentolamine are more marked in the erect position and during physical exertion then in recumbency. Similarly, a dose-effect relation with regarded to the negatively inotropic activity of oxprenolol is more readily detectable in the upright position.


[Pharmacokinetics--questions of terminology and problems]. Pharmacokinetics have become one indispensable tool in drug evaluation, clinical pharmacology and diagnostics. Therefore the basic principles of pharmacokinetics are outlined and pertinent definitions are given. Some scientific terms in this field are explained in order to facilitate interdisciplinary communication. The theoretical background of some practicable algorithms for obtaining pharmacokinetical parameters is described with the attempt of relying solely on the understanding usually induced by basic courses in biology, medicine and chemistry. It is demonstrated that the evaluation of pharmacokinetical analyses may only be interpreted in a context of any or all of these disciplines. Without this context pharmacokinetical results may remain mere mathematical descriptions of unknown mechanisms.


[Analytical methods I].

[Analytical methods I]. The most frequently used methods such as spectrophotometry, fluorometry, etc., for the analysis of drugs in biological fluids are compiled. The usefulness of quantitative chromatographical procedures is also mentioned. Reliability criteria of these assays are extensively discussed and some results are compared to those found by other methods like labelling and microbiology.


[Use of spectroscopic methods in drug analysis]. The use of spectroscopic methods (IR, NMR, MS) for the investigation of drugs is demonstrated. Due to the high sensitivity mass spectrometry in combination with glass capillary gaschromatography seems to become in many cases the method of choice. The use of computers which are able to determine with the aid of key fragments partial structures of unknown metabolites will be a very promising technique in the the future.


[Practical evaluation of methods in pharmacokinetics]. A short discussion of the differences between kinetic processes of zero and first order is followed by an outline of evaluation methods used in pharmacokinetic practice, e.g. "paper and pencil methods" as well as the use of digital and analog computers. The increasing potency of new drugs requires not only more sophisticated methods of analysis and expensive facilities but also more complex models to generate pharmacokinetic information.


[The use of an EDP time sharing system]. Mathematical problems in pharmacokinetics can be solved in a simple and effective way by using a computer timesharing system. It is reasonable to make use of such a system because the capabilities of a large scale computer are available without the prerequisite of special knowledge in data processing. Besides the possibilities of individual and simple programming, there are predefined programs available to solve special problems: mathematical statistics, plotting of time series etc.


[Biological availability].

[Biological availability]. The term "bioavailability" is used to describe the actual percentage of a drug released from the dosage form, which reaches the receptor site in sufficient quantity to induce a biological effect. In this connection there are many problems arising in conjunction with the formulation of the preparation, as well as through the interaction of physiological and pathological factors. Prerequisite to the bioavailability of an orally administered preparation is, firstly, the quick disintegration of the dosage form, and secondly, the release and dissolution of the active substance. No in vitro methods for the examination of these factors have as yet been evolved which would allow a reliable prediction of bioavailability in man. Animal experiments only permit limited prognoses, since numerous influential factors, such as absorption from the intestine, metabolism and metabolic rates, influence of physical and mental stress, etc., strongly dependent upon the species. Bioavailability is determined using pharmacokinetical techniques on the area affected by the dose-response curve, or a combination of these methods.


[Pharmacopsychologic studies on normal subjects for the prediction of the therapeutic efficiency of psychotropic drugs]. The paper deals with some basic problems and possibilities of predicting the therapeutic efficiency of psychotropic drugs from studies in normal humans. Comparing drug studies with normal subjects and patients it seems evident that from a methodological and economical point of view studies with normal subjects have many advantages. However, the practical importance of drug studies with normal subjects is limited unless the therapeutic efficiency of a drug can be predicted. There are some arguments which deny the possibility of prediction, e.g. referring to the lack of comparability of dosages, administration regimens, situational parameters and psychosomatic states between normal subjects and patients. Discussing such arguments it is pointed out that perfect comparability of all these factors is not a necessary prerequisite of prediction. A number of theoretically possible models for predicting therapeutic efficiency is suggested. For some of them there already exists some empirical evidence. The first model takes into account the inter- and intra- individual variability of behavior. It is suggested that a state corresponding to the psychosomatic state of patients be approximated, or simulated, in the normal subjects by suitable selection procedures of subjects or by manipulation of the experimental conditions. The usefulness of such a model for predicting therapeutic efficiency has been shown in many studies with anti-anxiety agents. In another model the drug profiles of normal subjects and patients are compared and the prediction is based upon drug effects in normal subjects which can also be seen in patients and which have a high correlation to the patients' improvement. A further model assumes that improvement is partly the result of learning processes. The prediction of therapeutic efficiency is, therefore, based upon the properties of a drug to facilitate or inhibit learning processes. The final two models proposed, predict limitations of therapeutic efficiency. The one model takes into account side-effects; the other the variability of drug response due to situational and person-parameters.


[The role of clinical psychiatry in the development of new drugs]. A survey is given from a clinically working psychiatrist's point of view on principal aspects of the development of new psychotropic drugs. The comparison with the other medical branches shows, that clinico-pharmacological investigations and clinical trials play an important role in the development of new psychotropic drugs. 1. The importance of clinical screenings for the development of new psychotropic drugs is stated by means of a comparative analysis of the pre-clinical and clinical screening methods. In this connection, the importance of animal experiments, biochemical and pharmaco-psychological findings is reported. 2. The particular difficulties of characterizing the effectiveness of potential psychotropic drugs are explained based on the problems of placebo effects, of the unspecific influence on psychotropic drug effects and by means of the socalled "main and side" effects of these drugs. 3. The principles of psychiatric ratings and of data documentation are explained with the aid of different examples.


[Detection of side effects by systematic and programmed research]. The need for data on efficacy and rate of adverse reactions after the admission of drugs for common use has become obvious in recent years, in order to evaluate benefit and risk in the long run. Due to the lack of knowledge severe hazards were realized rather late in the past. To improve this unsatisfactory situation it will be useful to explore different ways to get a systematic registration of harmful reactions. None of the procedures known so far for this purpose have been proven to provide sufficient information when used single. In the future voluntary reporting, hospital monitoring and a drug surveillance program may be included in a cooperative system to discover the seldom and unforseen diasters by drugs as early as possible. Much effort will be necessary to reach this aim. One among other useful techniques is the procedure developed by the "Boston Collaborative Drug Surveillance Program", which is discussed in some detail. It is thought to improve chances for the detection of certain associations between drug usage and health dangers in short-term as well as long-term treatments. These would allow for preventive measures. It has to be stressed, however, that protection cannot be expected for every event but is limited at least to the drugs monitored and to the hazards recognised.


[Systematic collection of drug side effects]. An "Intensive Drug Monitoring" System has been established in collaboration of the Departments of Internal Medicine, Biometrics and Pharmacology of the Medical College Hannover. It is based on the hypothesis-free collection of therapy data as well as clinical symptoms and chemical parameters which may be side-effects of drugs. The procedure is described in detail. The advantages of "Intensive Drug Monitoring" are emphasized. Such systems especially should be used to answer specified questions. Besides "Intensive Drug Monitoring" the necessity of "Spontaneous Monitoring" of adverse drug effects is argued.


[Effectiveness and safety of drugs from the viewpoint of the Drug Commission]. Aims and duties of the Arzneimittelkommission from the very first in 1911 have served the efficacy and safety of drugs, so the 1961 started system to collect and evaluate adverse effects of drug therapy in the medical practice and hospital. Development and objects of this system are presented.


[Evaluation of side effects].

[Evaluation of side effects]. The calculation of the benefit-risk-ratio of drugs is discussed on the basis of examples of side effects of different grades of severity. The 4 categories of side effects which are more difficult to be evaluated. The "Stufenplan" is described, which is used for the coordination of necessary preventive measures when side effects of drugs are noticed.


Structure and action of saikosaponins isolated from Bupleurum falcatum L. II. Metabolic actions of saikosaponins, especially a plasma cholesterol-lowering action. Several metabolic actions of saikosaponins isolated from the root of Bupleurum falcatum L. were examined using albino rats. Hepatic protein synthesis from leucine-14C(U) was enhanced. Glycogen content in the liver was increased, but oxidation of glucose-14C(U) in the liver was not changed. Elevation of plasma levels of cholesterol, triglycerides and p-ospholipids by cholesterol feeding was reduced. Although hepatic lipogenesis and cholesterogenesis from acetate-1-14C of glucose-14C(U) were stimulated, the elimination of i.p. injected cholesterol-4-14C from plasma was acclerated. Fecal excretion of i.p. injected cholesterol-4-14C, expressed as total-14C including bile acids-14C and neutral sterols-14C, was increased. Among the saikosaponins isolated from Bupleurum falcatum L., saikosaponins a and d, but not c, had metabolic actions as well as anti-inflammatory action. These metabolic actions and anti-inflammatory action of saikosaponins may confirm the clinical application of Bupleurum falcatum L, which has been widely used in the prescriptions of the oriental medicine, and may suggest possible mechanisms for the actions of its active principles.


[The stability of amphetaminil. Syntheses with amphetaminil (author's transl)]. Amphetaminil (AN 1), chemically an alpha-phenyl-alpha-[(1-methyl-2-phenyl)-ethylamino]-acetonitrile (1), i.e. a derivative of alpha-aminonitrile, is stable under experimental conditions of preparation, reacting to neither acid nor alkali. It is a uniform substance, and it can be led to derivatives, such as derivatives of acryl (8-13) which are splittable into the corresponding alpha-amino-acid (7). It yields the corresponding hydantoin (4) and it is split up by oxidation with hydrogenperoxide in alkaline medium into an amide (14). These changes and the occurrence of amphetaminil--both under soft and energetic conditions of preparation--make it most improbable to split up easily amphetamine in the organism. Therefore, the existence of amphetamine under chromatographical conditions proves trace elements which are conditioned by use of disproportionately high quantities of solvents. These small quantities are practically irrelevant in case of preparation. They cannot be registered by preparations.


New tricyclic enamine derivatives with CNS depressant properties. 63 tricyclic enamine derivatives were synthetized and pharmacologically tested. Many of the screened compounds showed remarkable CNS depressant chlorpromazine-like activities. The compounds no. 9 (substituents CH3, Cl, H), 18 (substituents CH3, F, H) and 27 substituents CH3, OCH3, H) resulted the most interesting and were studied in comparison with chlorpromazine and chlordiazepoxide. They were submitted to further studies in view of trials in humans.


[Demonstration of the long term action of an oral retard preparation of verapamil in the conscious dog]. 1. In the conscious dog the duration of action of verapamil, usual galenic preparation (Isoptin, Cordilox), and of verapamil retard (Isoptin retard: verapamil mixed and pressed with the swelling agent sodium alginate) was tested by measuring the blood pressure decrease occurring with higher dosage. Furthermore lead II of the ECG was recorded. 2. Already 2 h after oral application of verapamil retard a significant action is observed. As had been expected verapamil retard shows a slightly protracted onset of action compared to verapamil. 3. At the end of the test period, 12 h after administration, the effect of verapamil retard is still significant. In equipotent dosage its duration of action is clearly superior to that of conventional verapamil dragées. 4. During the period of 2 h to 12 h the intensity of action of verapamil retard shows only slight variations; significant differences could not be detected. 5. Verapamil mixed and pressed with sodium alginate, used as swelling substance and food additive, is an adequate preparation which allows the oral administration of verapamil with very long duration and almost constant intensity of action.


Preliminary toxicological investigations of 3-hydroxy-3-methylglutaric acid (HMG). I: Study of acute toxicity and of teratogenic activity in rats and mice. The acute toxicity of 3-hydroxy-3-methylglutaric acid (HMG) was studied in mice. The LD50 was shown to be 7.33 g/kg p.o. and 3.23 g/kg i.p. Subtoxic and pharmacological doses applied to mice and rats during gestation did not induce malformation of the foetuses and offspring and did not affect the reproductive performances of the dams. This compound is being investigated for its hypolipidemic activity.


Clopimozide (R 29 764), a new highly potent and orally long-acting neuroleptic of the diphenylbutylpiperidine series. Clopimozide (R 29 764), 5-chloro-1-(4-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl)-2-benzimidazolinone, is a new member of the potent and long-acting series of diphenylbutylpiperidine neuroleptics of which pimozide is the prototype, In animals the pharmacological profile of R 29 764 resembles that of typical neuroleptic compounds. R29 764 is very potent by oral route and has an extremely long duration of action. The onset of action of clopimozide is relatively fast, it is already very potent after 4 h and, in the procedures described, reaches its peak effect 24 h after administration. In spite of the high potency and long duration of action clopimozide is relatively atoxic. The safety margin, calculated as the ratio between the acute LD50 value and the lowest ED50 value is larger than or equal to 15.000 in rats and greater than 7.250 in dogs. Qualitatively, R 29 764 is more closely related to haloperidol, pimozide and penfluridol than to chlorpromazine. The side effect liability is expected to be very low, when hypotensive, autonomic and undesirable neurological side effects are concerned.


Bone marrow involvement in the non-Hodgkin's lymphomata. The frequency, clinical settings and histopathological correlations of bone marrow involvement in the non-Hodgkin's group of malignant lymphomata is presented. The importance of formal bone marrow biopsy is stressed. The overall frequency of involvement in a prospectively studied group of 109 patients is 41%. In one subgroup, those with nodular lymphocytic poorly differentiated lymphoma, the incidence is 85% in previously untreated patients.


Management of generalized malignant lymphomata with "systemic" radiotherapy. The natural history of lymphocytic lymphomata is such that anatomical generalization of disease is usually present at the time of diagnosis. Tumour infiltration of extralymphatic sites such as the liver and bone marrow is identifiable with particular frequency in those cases presenting with lymph node manifestations of disease. Even in the absence of detectable extralymphatic dissemination, the lymphatic involvement is often sufficiently diffuse to mitigate against extensive lymph node irradiation "à la Hodgkin's disease" as appropriate or technically feasible form of treatment. Rather, systemic treatment must be recognized as imperative for the majority of newly diagnosed patients and we have investigated "systemic" radiotherapy as an alternative to chemotherapy during the past decade. Our experience with 57 consecutive patients with lymphocytic lymphoma has been reviewed. Total body irradiation (TBI) has been found to yield high remission rates despite a lack of serious toxicity or constitutional reactions. Rigorous diagnostic staging was not employed but despite the advanced stage of disease which was clinically obvious in most cases, survival rates have been strikingly high. Actuarially calculated 5-year survival rates for the well differentiated (diffuse and nodular combined), nodular poorly differentiated and diffuse poorly differentiated subtypes are 85%, 69% and 51% respectively. Furthermore, initial management with radio-therapy as described has not negated with effective use of subsequent chemotherapy when selectively required.


Interaction between hydroxystilbamidine and DNA. I. Binding isotherms and thermodynamics of the association. Isotherms describing the binding of hydroxystilbamidine to DNA and polydeoxyribonucleotides were obtained by means of sedimentation or dialysis experiments and fluorescence measurements, over a large range of ionic strengths, temperatures and base compositions. Two different sets of binding sites are necessary to explain the shapes of the isotherms. The first one is characterized by a higher binding constant, a topological specificity for the A-T pair, exclusion of four base pairs per bound dye molecule, the involvement of two ion-pairs, an almost purely entropic free energy of binding and a large enhancement of the blue fluorescence (450 nm) when the site corresponds to three adjacent A-T pairs. The latter does not present any specificity nor enhancement of fluorescence and only one ion-pair is formed. From the geometry of the dye and its selective binding to a double stranded structure, the hydroxystilbamidine molecule in the first set of sites is likely to be situated in the small groove astride the two complementary strands and slightly distorting the helical structure. The angle of the dye axis with the helix axis has a value close to 47 degrees. No definite explanation could be given for the specific binding of hydroxystilbamidine but the phenolic hydroxyl group is likely to play a major role. The hydroxystilbamidine molecule can be considered as a useful tool for checking the accessibility of the small groove.


Interaction between hydroxystilbamidine and DNA. II. Temperature jump relaxation study. Dynamics of nucleic acids and polynucleotides. A temperature-jump relaxation study of the interaction of hydroxystilbamidine with DNA and synthetic polynucleotides has been performed. Two concentration dependent relaxation times tau1 and tau2 have been observed in the submillisecond range when detecting relaxation effects by means of light absorption. The longer of these two times (tau1) is also observed when using "blue" or "red" fluorescence detection. In the longer time scale the "red" fluorescence shows no other relaxation but the blue fluorescence shows two additional relaxation processes (tau3 and tau4) which correspond to an increase of fluorescence with temperature and which are independent of concentration. The experimental results clearly indicate that tau1 and tau2 are associated with the binding of the dye to strong and weak binding sites, respectively. A kinetic model is given to explain the results. It allows the determination of the four rate constants for the two binding reactions and yields equilibrium association constants in good agreement with those obtained from stoichiometric studies. The study of the effect of temperature, nature of the polymer, ionic strength and fraction of bound dye on tau3 and tau4 indicates that the dye acts only as a "blue" fluorescence probe of some processes involving the DNA or polynucleotide alone. These processes appear to be related with the dynamic structure of the polymers.


Benzo (a) pyrene uptake by normal and by tumour cells in vitro. A method for determining the quantitative uptake of benzo(a)pyrene/B(a)P/by cells in culture is described. B(a)P uptake is very rapid and increases with concentration. The amount of B(a)P taken up by normal or by tumour cells depends on the cell type, and also, on the species from which they were derived.


Behavioral and biochemical interactions of 5,7-dihydroxytryptamine with various drugs when administered intracisternally to adult and developing rats. Intracisternal administration of 200 mug of 5,7-dihydroxytryptamine (5,7-DHT) caused a prolonged reduction of brain serotonin which was accompanied by a depletion of brain norepinephrine. The depletion of norepinephrine was found to be antagonized by agents that inhibit uptake of norepinephrine as well as by several monoamine oxidase inhibitors. Intracisternal injections of 5,7-DHT (75 or 100 mug) to 7-day-old neonatal rats reduced brain serotonin and norepinephrine and produced a significant reduction of adult body weight. As in adults, pretreatment of neonatal rats with pargyline or desipramine prevented 5,7-DHT induced depletion of norepinephrine without affecting depletion of serotonin. Behaviorally, treatment of adult rats with 5,7-DHT facilitated acquisition of an active avoidance task and enhanced muricidal behavior. 5,7-DHT treatment was also found to enhance the depressant effects of 5-hydroxytryptophan on a fixed-ratio barpress response, suggesting that 5,7-DHT treated rats are supersensitive to serotonin in the central nervous system.


The dependence of annulate lamellae formation on the nucleus in parthenogenetic rabbit eggs. Previously it has been shown that, in the rabbit, although annulate lamellae (AL) are absent in the follicular oocytes, they appear in the fertilized eggs after the formation of the pronuclei. Furthermore, neither pronuclei nor AL appear when unfertilized eggs are aged in vivo or in vitro. This study was undertaken to determine whether AL formation requires presence of an intact nucleus, or whether the sperm alone contains the stimulatory factors essential to AL synthesis. Rabbit eggs were exposed to 10 degrees C, then incubated for 24 hours. Control eggs were incubated without cold-treatment. Electron microscopic observations indicated that two-thirds of the eggs formed one to two 'pronuclei', or subnuclei. The remainder one-third of the cold-treated eggs and the control eggs failed to form 'pronuclei'. AL were present in large amounts only in those activated eggs (parthenogenones) which formed 'pronuceli.' AL were absent in the control and the non-activated experimental eggs, both of which failed to form a 'pronucleus.' A few small AL were observed in eggs with subnuclei. Condensed fine textured nucleoli appeared precociously during cold-treatment in some eggs and they were present in the 'pronuclei' of activated eggs. It was concluded that the sperm is not necessary for AL formation, but the presence of an intact nucleus is mandatory.


[Endoscopic-radiological demonstration of the gastrointestinal lymph nodes and lymph vessels]. Using an intragastric contrast medium (Lipiodol) the paragastric lymph nodes of 23 patients were lymphangiographed prior to laparotomy. The patients suffered from gastric or duodenal ulcers (15 cases), postresectional ulcers (3 cases), or gastric carcinoma (5 cases). The surgically resected material was examined by radiological and histological techniques. The following results were obtained: 1. After application of the contrast medium the paragastric lymph nodes could firstly be seen 5 hours later and even after 7 days and more. 2. The radiographs presented typical storage phenomena with granular or clod-like structures as an equivalent of the inflammatory lymph node alterations. Histologically a marked sinus catarrh with lipid laden reticulum cells and multinuclear giant cells of the foreign body types was observed. 3. In gastric carcinoma characteristic storage defects up to complete destruction of the lymph nodes were found as a roentgenological equivalent of lymph nodes metastases. In addition there were occasionally abnormal courses of the lymphatic vessels with variations in diameter and bizarre storage formations. 4. The described method provides a helpful tool in the diagnosis of gastric lesions. No side effects have been observed.


Inhibition of DNA synthesis in mouse lymphosarcoma LS/BL cells by fluorocitrate. Fluorocitrate is a specific inhibitor of aconitase activity (EC 4.2.1.3). It causes an inhibition of citric acid cycle reactions and consequently reduces the oxygen consumption, as well as the total volume of oxidative phosphorylations. Experiments using 3H-thymidine incorporation into mouse lymphosarcoma LS/BL cells proved that the in vitro blocking of citric acid cycle by fluorocitrate (3.6 and 7.2 mM) was accompanied by a decrease in DNA synthesis by 40 to 60 percent, as compared to control cells. A similar inhibitory effect upon DNA synthesis was also found in cells cultured in the abdominal cavity of host mice injected intraperitoneally with 5 mg./kg. of sodium fluoroacetate. Following the injection, fluorocitrate is formed in vivo by way of Peters' lethal synthesis.


Antimuscarinic action of an alkane-bis-ammonium compound alone and in combination with (+)-benzetimide. Heptane-1,7-bis-(dimethyl-3'-phthalimidopropylammonium bromide) ('C7/3-phthalimido-propyl') in concentrations of 10(-7) to 0.5 X 10(-3) inhibited negative inotropic responses to carbachol or acetylcholine to a similar extent in the electrically stimulated isolated guinea-pig left atrium. However, the degree of antagonism of responses to carbachol was less than expected for a competitive antagonist when the higher concentrations of 'C7/3-phthalimido-propyl' were employed. When 'C7/3-phthalimido-propyl' was combined with competitive antagonists such as (+)-benzetimide, atropine or homatropine the degree of antagonism was greater than expected for combination of 2 competitive antagonists. Qualitatively similar results were obtained in the presence of practolol (1.5 X 10(-5) M). The results obtained with 'C7/3-phthalimido-propyl' are shown to agree with theoretical predictions for a metaffinoid antagonist which influences the affinities of both agonists and competitive antagonists by combining with a regulatory site distinct from, but interdependent with the binding sites for agonists and competitive antagonists. Further, it is shown that the alkane-bis-ammonium compound produces a much greater reduction in the affinity of carbachol than that of the competitive antagonists and as a consequence causes 'supra-additive' effects when combined with a competitive antagonist. The reduction in the affinity of (+)-benzetimide produced by 'C7/3-phthalimido-propyl' did not differ significantly from the reduction in the affinities of atropine or homatropine.


Comparative effects of (+)- and (-)-isomers of propranolol and INPEA on (+)-tubocurarine- and succinylcholine-induced neuromuscular blockade. The effects of the (+)- and (-)-isomers of propranolol and INPEA on the neuromuscular blocking action of (+)-tubocurarine and succinylcholine were studied in the tibialis anterior-peroneal nerve preparation of the rabbit and the isolated phrenic nerve-diaphragm preparation of the rat. (+)-Tubocurarine-induced neuromuscular blockade was intensified by (+)- and (-)-isomers of INPEA whereas it was unaffected by isomers of propranolol in both preparations. In the rabbit tibialis anterior-peroneal nerve preparation, only the (-)-isomers of propranolol and INPEA increased the duration of succinylcholine-induced neuromuscular blockade without affecting its magnitude. Higher doses of both (+)- and (-)-isomers of propranolol and INPEA potentiated succinylcholine-induced blockade in the rat phrenic nerve-diaphragm preparation. The results obtained indicate that only the increase in duration of succinylcholine-induced blockade with beta-adrenoceptor blockers can be related to beta-blocking property of these compounds.


Convulsion following intrathecal cephaloridine. Following therapeutic intrathecal administration of cephaloridine to an 11-day-old premature infant with suspected meningitis, a generalized tonic convulsion was observed. Symptoms continued to subside over the next six hours, followed by postictal sleep. That convulsion and other symptoms were due to cephaloridine was confirmed when the second intrathecal administration produced the same symptom. Because of its possible damaging effect on CNS, it is strongly suggested that cephaloridine should not be administered directly into the cerebrospinal fluid space.


HL-A antigens in Graves' disease and Hashimoto's thyroiditis. An increased frequency of HL-A 1 and HL-A 8 was found in patients with Graves' disease and Hashimoto's thyroiditis, whem compared to a control group from the same geographic area, and drawn from a pool of subjects attending one diagnostic centre. Furthermore, an increased incidence of W15 and W17 was found in Hashimoto's thyroiditis; however, these were not detected in any patient with Graves' disease.


Oil coating of dietary protein for the ruminant. Diets containing expeller-extracted linseed meal treated with corn oil, lard or coconut oil were fed to lambs to determine the effectiveness of coating the protein in reducing its ruminal degradation. Three common indicators of nitrogen metabolism in the ruminant were used in evaluation: ruminal ammonia, blood plasma ammonia and plasma urea. Eight crossbred lambs, averaging 27 kg in weight, were allotted to the four diets which were fed at a rate of 350 g at 12-hour intervals. Ruminal ammonia, plasma ammonia and plasma urea were monitored at 0, 2, 4, 6 and 8 hr after feeding. Lambs consuming coconut oil-treated linseed meal produced less rumen ammonia (average of .5 mg/100 ml across all collection times) than those fed normal linseed meal (10.3 mg/100 ml). Lambs fed corn oil-treated and lard-treated linseed meal had ruminal ammonia levels intermediate to those fed normal and coconut oil-treated linseed meal. Levels of plasma ammonia and plasma urea nitrogen of normal linseed meal were significantly higher than the same measures with the oil-treated linseed meals. Differences in plasma ammonia and urea nitrogen were not significant among the three oil-treated diets.


Chronic intussusception associated with ileocecal lymphosarcoma. A 1011/12-year-old boy with chronic ileocolic intussusception associated with ileocecal lymphosarcoma was decribed. The patient had abdominal pain of 3 months' duration, vomiting, and a firm mass with smooth surface in the right lower abdomen. Barium enema showed intussusception at the distal part of the ascending colon, which was irreducible by hydrostatic pressure. Barium by mouth revealed markedly distended small intestines, which were displaced to the left abdomen. The tumor was inoperable, and the boy died.


Appearance of paoproteins of pulmonary surfactant in human amniotic fluid. We have isolated and partially characterized the protein found in surface-active material from adult human lungs, and have determined the time of appearance of this protein in amniotic fluid. Fluids were drawn at gestational ages from 12 to 44 wk, and were assayed for their concentration of apoprotein by an agglutination immunoassay. Surfactant apoprotein ((defined as that protein which is reproducibly found in purified preparations of surface active material) was usually first detected from 30 to 32 wk gestation, and its concentration increased almost fivefold to a maximum at 37 wk. The change in apoprotein concentration was approximately paralleled by the change in phospholipid concentration. At all gestational ages there was wide variability in both phospholipid and apoprotein concentrations, and the time of appearance of the apoprotein in amniotic fluid differed among fetuses. The results suggest that the presence of surfactant apoprotein in amniotic fluid is coincident with the biochemical and morphological maturation of the fetal lung, and are additional evidence that this apoprotein is cosecreted with the lipids of surface-active material.


Oxygen-induced changes in pulmonary phospholipids in the rat. The composition and synthesis of alveolar and lung tissue phospholipids were investigated in normal and oxygen-poisoned rat lungs. Sixty-hour exposure to oxygen increased the total amount of phospholipids in the endobronchial extracts and lung tissue. Phosphatidyl glycerol was identified in both endobronchial extracts and lung tissue. The amount of unsaturated fatty acids in surfactant lecithin and phosphatidyl glycerol was slightly increased in oxygen-poisoned lungs whereas the composition of phospholipids in the endobronchial extracts was not affected by oxygen. After intraperitoneal administration of [32P]phosphate the specific activities of surfactant lecithin and phosphatidyl glycerol were clearly lower in oxygen-treated animals whereas the specific activities of lung tissue lecithin and phosphatidyl glycerol remained unaffected. The synthesis of lecithin from [14C]methionine through N-methyltransferase pathway was markedly depressed in lung slices but increased in liver tissue taken from oxygen-poisoned rats and incubated under oxygen indicating a difference between lung and liver methyltransferase enzymes. In conclusion, the present work suggests impaired synthesis and removal of alveolar phospholipids in oxygen-poisoned rats.