Severe mental retardation in a Swedish county. II. Etiologic and pathogenetic aspects of children born 1959--1970. In an unselected series of 122 children born in 1959--1970 with severe mental retardation (SMR), the magnitude and distribution of the different etiologic and pathogenetic factors were analysed. Prenatal causes were considered relevant in 73 per cent, perinatal in 10 and postnatal in 3. In 12 per cent no traceable cause whatsoever was found. Infantile primary psychoses constituted 2 per cent. Within the prenatal group, no less than 43 per cent presented firm evidence favouring a genetic etiology, chromosomal syndromes together constituting 36 per cent and mutant gene disorders 7 per cent. Etiologically unclassifiable cases with prenatal stigmata and congenital defects amounted to 18 per cent. A condition of fetal deprivation of supply was considered to have been of major importance in 8 per cent. Almost half of the cases had one or more associated CNS handicaps. Cerebral palsy syndromes were evident in 18 per cent and epilepsies in 30 per cent. The relative risk of having cerebral palsy in addition to SMR was strongly correlated to cases classified as prenatally or perinatally acquired CNS syndromes. It is concluded that prenatal prevention is of special importance for reducing the occurrence of SMR. As chromosomal aberrations are the cause in more than 1/3 of cases with SMR, the desirability of developing effective cytogenetic screening methods and programs applicable to all pregnant women is particularly emphasized.


Renovascular hypertension as a cause of cerebrovascular accident in childhood: a case report. Report on a 10 year-old boy with acute hemiplegia after an ischemic cerebrovascular accident, provoked by an unilateral renovascular disease with malignant hypertension, for which nephrectomy was carried out. The few publications pertinent to cerebrovascular complications in children with hypertension and the value of comprehensive diagnostic operations, are the basic motives for this report.


On the mechanism of accumulation of 67Ga by tumors. There is strong experimental evidence indicating that a competitive binding of 67Ga3+ to Ca2+- and Mg2+-binding sites rather than a metabolic process is involved in the accumulation of this radioisotope. These observations suggest that in tumors, as well as in other inflammatory and infectious processes, the most important role in 67Ga accumulation is played by a higher availability of those binding sites than in normal tissue.


The use of metronidazole in the preparation of the bowel for surgery. The preliminary results of this study have shown that a combination of oral phthalylsulphathiazole and metronidazole for preparation of the bowel for surgery reduces the incidence of postoperative infection compared with phthalylsulphathiazole alone.


Mycotic aortic aneurysm in premature infants. Three cases of aortic aneurysm adjacent to the tip of the umbilical artery catheter are described. The clinical presentation, radiographic findings, and proposed pathogenesis are discussed. Mycotic aneurysms in childhood are infrequent but serious threats to life, requiring early recognition and prompt therapy. The appearance of a progressively enlarging middle or posterior mediastinal mass in a child with a history of septicemia should suggest a mycotic aneurysm.


[Experimental studies on clinical application of 13N-ammonia; a metabolic model and functional image based on animal experiment]. Ammonia has been known to be an inducing agent of hepatic coma associated with liver cirrhosis. In order to establish a non-invasive method of investigating the portal circulation and the metabolism of ammonia at liver the following studies were performed, by using cyclotron produced 13N-labeled ammonia and delayed line-camera interphased with on-line computer system. 1) Animal experiment. Dynamic scintigraphy of thoraco-abdominal region of a rabbit after intrasigmoidal as well as intravenous administration of 13N-ammonia were performed. 2) Theoretical consideration on the functional image of liver: According to the results of the animal experiments, a model of ammonia metabolism having the minimal complexity necessary to represent data in the case of intrasigmoidal administration was proposed. Starting from the solution to the differential equation describing the model, relevant parameters characterizing the dynamic curve of liver were duded.


[Experimental studies on clinical application of 13N-ammonia; clinical application of the functional image]. 1) Clinical application: Dynamic scintigraphy of liver and heart of a patient having liver cirrhosis after intrasigmoidal administration of 13N-ammonia (pH 8.1) were performed. Simultaneously, continuous measurments of radioactivity at the left side abdomen and the left temporal region were done by using a scintillation detector for renography. Successive measurement of radioactivity of blood was also carried out. 2) Comstruction of functional images of liver and heart: By using digital radioisotope image of liver and heart of the patient after intrasigmoidal administration of 13N-ammonia, the maps with respect to parameters described in the pervious paper were constructed.


[Anatomic localization of scintillation colour image by means of simultaneous colour polaroid film photographing of emission scintiphoto and transmission scintiphoto]. A study has been made of a simple and practical method to add the information of anatomical localization upon the emission scintiphoto of the generally used polaroid film. Our experients were a follows: first, the polaroid film of transmission scintiphoto, according to the Anger method, was made, and then, that of emission scintiphoto was made. Next, by double-exposing these two photos to the same polaroid film with the Mamiya-made duplicator, these photos were made into a composite photo. In that case, in order to distinguish the images of these scintiphotos on this composite photo. In that case, in order to distinguish the images of these scintiphotos on this composite photo, a colour polaroid film was used in the double exposure, and here, when each of the two scintiphotos was given its own colour-filter, it was found that the images could be sharply sorted by colour. This method does not require any highly expensive apparatuses and according to this method a disc source and a polaroid duplicator are enough for the exact anatomical localization of scintiphoto-images by the polaroid film.


Metabolic fate of timepidium bromide (SA-504)--Unstable metabolities in the rats. The colored substances excreted in bile or urine have bee investigated after adminstration of a high dose of SQ-504 to rats. A reddish-violet colored substance and a bluish-violet colored substance were dominant. Their chemical structures were not assigned because of their small quantity and instability. It was recognized that the colored substances were metabolites of SA-504 from the studies with 3H and 14C labelled SA-504 and the derivatives of SA-504.


Effect of acute hypobaric hypoxia on fatty acid metabolism in rat lung. Exposure of male albino rats in the weight range of 70-200 g to 25,000 ft of simulated altitude for 6 h at 32 degrees C caused an increase in plasma free fatty acids with decreased oxidation of palmitic acid-1-14C in lung slices of hypoxic rats. The in vivo esterification of palmitic acid-1-14C to form truglycerides, phosphatidylcholine and phosphatidylethanolamine was also low indicating decreased utilization of fatty acids by hypoxic lungs. De novo lipogenesis was observed to decreased to decrease because of decreased fatty acid biosynthesis as judged from acetate---14C incorporation. The specific activities of triglycerides, phosphatidylcholine and free cholesterol were also decreased. The decreased incorporation into phosphatidylcholine affected the incorporation into phosphatidylcholine of alveolar surfactant (2,000 g sediment fraction). The results are discussed in view of possible decreased energy status of hypoxic lungs.


[Intramuscular injections and activity of serum creatine phosphokinase. Histopathological study in animal experiments]. In healthy Labrador dogs a single intramuscular injection of benzoctamin, diazepam and pethidin leads to a distinct increase in serum-creatine-phosphokinase (SCK) activity, whilst a single intramuscular injection of physiologic saline has no effect whatsoever. Intravenous injection of an identical dose of the above-mentioned drugs leaves SCK activity unchanged. Muscle specimens of the injection site, excised 5 days after intramuscular injection of the same drugs, display muscle cell necrosis, macrophage proliferation and reparative changes. The impressive histological alterations point to the striated muscle cell as a probable source of the increase in SCK activity (MM fraction).


Bone marrow involvement in malignant lymphoma without peripheral lymphadenopathy. Twelve cases of non-Hodgkin's lymphoma and a single case of Hodgkin's disease were first diagnosed on bone marrow biopsy. None of the patients had superficially enlarged lymph nodes, and in 3 patients the histological examination of the biopsy specimen showed normal reactive nodes. Eight patients were over the age of 60. The differential diagnosis from benign nodular lymphoid hyperplasia is discussed, with emphasis on the cytology and the paratrabecular position of the lymphoid infiltrate. Ten patients had focal involvement of the bone marrow and 1 of the 3 patients with diffuse involvement had Hodgkin's disease. Lymphoid nodules occur normally in the bone marrow and we conclude that non-Hodgkin's lymphoma and Hodgkins's disease can arise primarily in the bone marrow.


[Intercellular transmission of information in the process of immunogenesis. V. Study of the role of low-molecular "immune" nuclear RNA in the synthesis of antibodies by rat transplantable lymphosarcoma cells]. The karyotype of the Ararat cochineal has been studied. The cochineal chromosomes are holokinetic, i.e. they have a diffuse centromeric activity; however, in some of them constrictions are detected. The constrictions are seen only in early stages of spiralization and are not detected in late metaphase. Sex determination in the cochineal takes place according to formula XX-X0. The female have two sex chromosomes being the longest pair in the set. The males are heterogametic having the X0-constitution. The meiosis is of a chiasmatic type. In the diakinesis bivalents are detected in the form of crosses or rings. Of different types of meiosis, the coccids possess a so called the Puto type, which s, according to preliminary evidences, very similar to the cochineal meiosis.


[Gunshot injuries of chest and abdomen (author's transl)]. A total of 51 patients with gunshot injuries of the chest and the abdominal cavity were treated at the Emergency Aid Institute "Pirogov" in Sofia from 1967 to 1976. The series included 45 men and 6 women, with a letality rate amounting to 21.5 per cent (11 patients). In 41 per cent it was a matter of abdominal injury where the letality was the highest (33 per cent). Chest injuries included 33 per cent with 12 per cent letality, while combined chest-abdominal injuries included 26 per cent with 14 per cent letality. Involvement of the small and large intestine showed the highest incidence of all abdominal organs (37 per cent). Traumatic-hemorrhagic shock and acute respiraotyr insufficiency prevailed. The operative tacties resorted to was strictly individual. In combined lesions of treatment of respiratory insufficiency, parenchymatous organs and major blood vessels has priority over the treatment of hollow organs.


[The effect of toxoplasma antibodies after reinfection with T. gondii. II. Communication: investigations over the incidence of toxoplasma in peripheral blood after primary and secondary infection (author's transl)]. After reinfection, parasites could be detected through transfusion of tail blood to healthy mice between 24 and 100 to 352 hours. A time point beyond this was not examined. Parasitaemia could be frequently established between 68 and 76 hours post reinfection. Infection immunity in mice does not protect against reinfection by Toxoplasma. It occurs after oral infection inspite of the presence of humoral antibodies. The parasites spread by blood circulation and increase the titer by one or two titer steps in the SABIN FELDMAN test.


[Micronucleus and cytogenetic disorders in mouse embryos before implantation]. Studies of mice embryos of different genotypes revealed 4.1% of polyploids, 8.5% of aneuploids and 7.9% of embryos with structural chromosome aberrations. Embryos of lines BAIB and CBA were reliably different in micronuclei occurrence (9.8 and 4.6%). A relation is shown to exist between the presence of micronuclei and structural aberrations. Normalization of the embryo genotype at early stages of embryogeny might occur by means of elimination of cells with disturbances or due to the death of anomalous embryos in the period of implantation.


Allergy to grass juice.

Allergy to grass juice. Crushed, fresh grass did not produce positive skin reactions in 149 patients with grass pollen allergy, six of whom suffered from rhinitis and conjunctival discharge while cutting grass. An additional patient without an allergy to grass pollens but with clear-cut symptoms from newly cut grass showed a negative result in the scratch-chamber test and in the scrubbing test.


Immunoglobulins in serum and nasal secretion. A comparison between patients with aspirin hypersensitivity and allergic rhinitis. Immunoglobulins A, E and G were studied in serum and nasal secretion from patients with allergic rhinitis, chronic rhinitis and aspirin hypersensitivity, and normal controls. The allergic patients differed from the other groups in having higher IgE values, both in serum and in nasal secretion. The patients with aspirin hypersensitivity did not differ from the control group regarding the IgE values. No difference between the groups was found with respect to IgA and IgG. The results indicate that reaginic antibodies are not involved in causing aspirin hypersensitivity.


Hypothesis-determinant factors in the manifestations of atopic disease. It is postulated that both the initiation and the perpetuation of atopic disease occur as a result of a complex interaction of a genetically determined IgE response, increased permeability of the gastrointestinal and respiratory tracts, and an inherent metabolic instability that may be either localized or generalized. These three factors vary as a function of age and serve to explain the complicated natural history of allergic manifestations in atopic persons.


A study of dust-induced lymphocyte blastogenesis. The in vitro measurement of dust allergen-stimulated lymphocyte blastogenesis by the incorporation of H3-thymidine can be a useful measurement for the evaluation of the cellular immune function in dust allergy patients. Dust allergy patients receiving immunotherapy had lower lymphocyte responses than those not receiving immunotherapy. Additionally, dust allergy patients as a whole showed higher lymphocyte stimulation indices than normal control.


Long-term transfer factor treatment in severe atopic dermatitis. Transfer factor therapy was applied in three patients with severe atopic dermatitis and given at regular intervals for 1 1/2 years. Clinically, slight improvements were seen, attacks of impetigo ceased and admissions to hospital were not necessary. However, IgE concentrations in serum remained constantly high in all cases and the absolute number of T and B lymphocytes was continuously subnormal despite treatment. The in vitro cellular reactivity to PPD as assayed by a leucocyte migration test was not significantly altered in the patients, although a slight increase was found early on in the therapy. Finally, a serum factor inhibiting leucocyte migration and appearing simultaneously with attacks of impetigo disappeared during treatment. In conclusion, no convincing effect of transfer factor therapy was encountered in immune parameters and no major alterations were found in the status of the patients' atopic dermatitis.


Hyposensitization of patients with allergic rhinitis by intranasal administration of chemically modified grass pollen allergen. A pilot study. In a pilot study, five adult patients with allergic rhinitis due to grass pollen underwent local intranasal hyposensitization with a chemically modified grass pollen extract--a so-called allergoid. Local hyposensitization during a pre-seasonal period resulted in an increased serum level of timothy-specific IgE antibodies in all patients, indicating that the allergoid had immunogenic properties. In four of the patients the clinical effect during the grass pollen season was judged satisfactory. Pre- and post-seasonal provocation test in these four patients also showed a reduction of the nasal sensitivity during this period. All patients tolerated the treatment well without any marked side effects. These promising preliminary results motivate further investigation into this form of therapy.


Lymphoma and other lymphoid lesions of the orbit (II). The incidence, survival rate and causes of death of patients with orbital lymphomas and other lymphoid lesions of the orbit in Denmark, during the period 1943-62 inclusive, were studied by means of a clinico-pathological analysis. In the period examined, the incidence of histologically verified primary orbital tumours was 0.06%. The incidence of primary orbital lymphomas and lymphoid lesions was at least 0.012%. These can be histologically divided into 3 categories: benign, indeterminate (intermediary) and malignant. The present study confirms the relevance of this classification, as there is a definite relationship between the histological diagnosis and the clinical survival rate. For the patients in question, the chances of dying of a universal malignant disease were approximately 10(3) times greater than in the normal Danish population.


The influence of stimulus duration on the human d.c. registered c-wave. A quantitative study. The c-wave of the human ERG was studied at different stimulus durations with a d.c. technique which permitted stable and reproducible recordings. With increasing stimulus lengths the implicit time increased up to a maximum of about 5.5 s. Also the amplitude of the c-wave rose. However, it was influenced by positive and negative off-effects, seen in most volunteers, and at several stimulus lengths superimposed upon the peak of the c-wave. This fact must be considered when developing a standardized method for measuring the c-wave amplitude proper.


Atypical rubeosis iridis in congenital cyanotic heart disease. Report of a case with microhaemangiomas at the pupillary margin causing spontaneous hyphaemas. Neovascularisation of the iris developed in a woman with congenital cyanotic heart disease. This neovascularisation was predominately in the form of microhaemangiomas at the pupillary margin causing spontaneous hyphaemas. Proliferative vascular alterations did not develop in the retina and secondary glaucoma did not occur.


The influence of the nictitating membrane on steroid inhibition of limbal wound healing. In a study involving 34 rabbits, it was found that local corticosteroids inhibit limbal wound healing in normal rabbit eyes, and do not inhibit similar wounds if the nictitating membrane has been removed. It was further found that the contact time of fluorescein labelled corticosteroids is almost 3 times longer in rabbit eyes with nictitating membranes than those in which the membranes have been removed.


Reinforced episcleral cerclage in retinal detachment. A note on surgical technique. Episcleral silicone rods are used as encircling elements in retinal detachment surgery. In order to reinforce the encircling effect and form a stable effective buckle, the episcleral silicone rod is combined with an Arruga suture or a fairly rigid teflon band. The Arruga string (a 2-0 supramid suture) is sewn, in a longitudinal direction, into a solid silicone rod (2 mm in diameter) or into a silicone half-cylinder (diameter 3 or 4 mm). Soft sponge-like rods can also be reinforced with a 2 mm broad teflon band placed on the flat surface of the half-cylindrical silicone element. Drainage of subretinal fluid is usually performed in order to make room for the high circumferential buckle. Experience has shown that this modified encircling procedure is very useful in complicated cases of retinal detachment.


In vitro investigations on the effect of pilocarpine on the metabolism in pig lenses illustrated with some intermediate metabolites. 22 pairs of pig lenses were incubated in TCM 199 5 g, with pilocarpine 5 X 10(-4) M and 10(-2) M. 5 X 10(-4) M is the probable concentration in the aqueous during ordinary pilocarpine medication. The concentration of 1-lactate, pyruvate, RTP, RDP and AMP was determined in the lenses and the assimilation of glucose and the production of 1-lactate and pyruvate were measured. As far as pilocarpine 5 X 10(-4) M was concerned no significant differences were found, but pilocarpine 10(-2) M gave a significantly higher 1-lactate concentration in the lenses (118%) and increased the assimilation of glucose to 120% and also augmented the production of 1-lactate to 168% and the pyruvate to 184%, tending to show that pilocarpine 10(-2) M increased the glycolytic activity in the lenses. The concentrations of RTP, RDP and AMP were unchanged.


The value of fluorescein fundus angiography in evaluating optic disc oedema. 43 patients with blurred disc margins were studied by means of fluorescein fundus angiography. The differentiation between very early disc oedema and a normal disc was possible, due to an increased capillary network, some microaneurysms and the late fluorescence located in a special circular manner at disc margin. It was not possible to differentiate between optic neuritis and papilloedema, although minor differences may exist. Ischaemic optic neuropathy is a type of optic disc oedema which clearly differs from other causes of oedema when studied by fluorescein fundus angiography. The method is especially suitable in differentiating pseudopapilloedema from genuine oedema of the optic disc.


Traumatic hyphaema treated with the antifibrinolytic drug tranexamic acid II. During the year 1976 (January 1st to December 31st) 75 patients, consecutively admitted to the eye department of Arhus Kommunehospital with traumatic hyphaema, were treated with the antifibrinolytic drug tranexamic acid. No secondary haemorrhage occurred. The patients were not confined to bed. The eyes were not patched and the activities of the patients were not restricted. In a previous series from 1975 where the patients were confined to bed but otherwise treated identically with tranexamic acid one out of 72 patients had a secondary haemorrhage. When the two materials are combined one out of 147 patients had a secondary haemorrhage corresponding to 0.68%.


A method of isolating and collecting pseudo-exfoliation material from extracted cataractous lenses. It has been observed that the pseudo-exfoliation (PE) material on the surface of extracted lenses was not dissolved by a papain solution, while the underlying lens capsule was digested. This forms the basis of a method for isolating and collecting PE material. The anterior lens surface was swept with a cilium after the lens had been suspended in a 5% papain solution for 1/2-1 hour. The PE material was loosened in flakes which adhered to the tip of the cilium and could be collected as a lump. By light and scanning and transmission electron microscopy no contaminants could be seen, and no damage to the PE material was disclosed.


Dacryocystography with amipaque (metrizamide). Amipaque is found to be very suitable for dacryocystography because it has a low osmolality and high viscosity, and is in addition the only aqueous contrast medium currently available which in higher concentrations does not cause pain when applied to the conjunctival sac.


The effect of experimental uveitis on the uptake of prostaglandin E1 in the rabbit iris-ciliary body. Disruption of the blood-aqueous barrier in rabbits was elicited by infrared irradiation of the iris or by alpha-melanocyte stimulating hormone (alpha-MSH) given subcutaneously. One group of animals was pretreated with topical imidazole before the injection of alpha-MSH. The aqueous flare response was followed and the rabbits were killed at the expected height of the uveitis. The uptake of 3H-prostaglandin E1 in the iris with the ciliary body was then determined and found to be significantly decreased in the rabbits in which alpha-MSH had caused a severe damage of the blood-aqueous barrier. When alpha-MSH caused a more moderate aqueous flare response the prostaglandin uptake was on the contrary significantly increased. Pretreatment of the animals with topical imidazole enhanced parallelly the prostaglandin uptake and the aqueous flare response to alpha-MSH. Topical imidazole per se was found to increase the accumulation of prostaglandin. The prostaglandin uptake values were, however, unchanged in eyes in which infrared irradiation of the iris induced a moderate flare response.


Time changes of contrast thresholds during automatic perimetry. Contrast thresholds were continuously recorded in six points of the visual field through a repetitive up-and-down staircase method using the automatic perimeter developed by Heijl & Krakau (1975b). The uninterrupted sessions lasted about 30 min. Nineteen patients with a verified diagnosis of glaucoma, or in whom glaucoma was suspected, and twelve healthy normal subjects were tested. With increasing test time, a decreased contrast sensitivity was found. In most subjects the mean threshold increment was small (less than 1.5 dB). The threshold increments were larger in the patient group than in the normal subjects--many test points showing increments of 6-10 dB during the test session. Such a large deterioration of sensitivity was most common in eyes with visual field defects. Test points which showed large threshold increments were often situated in the vicinity of documented visual field defects. In eyes with pathological visual fields, the short-term variation increased with increasing test time. An impairment of fixation with increasing test time was found in the patient group.


T3 toxicosis in children.

T3 toxicosis in children. Triiodothyronine (T3) toxicity has been well documented in adults, but only isolated cases have been reported in children. Two girls presented with firm goitres and overt hyperthyroidism. In each patient, total serum thyroxine (T4) values by competitive protein binding were normal, however total T3 values by radioimmunoassay were elevated. One patient had Graves' disease, the second patient had Hashimoto's disease which has been only infrequently associated with T3 toxicity in adults. Both patients responded to therapy with propylthiouracil. The mechanisms by which T3 is preferentially secreted in thyrotoxic states in man are poorly understood, but iodine deficiency and poor iodination of thyroglobulin may be important factors.


Disposition of the hypoglycaemic sulphonylurea CS 476. The disposition of radioactivity was studied after administration of a new oral hypoglycaemic agent, 14C-labelled CS 476, to rats, rabbits and dogs at a pharmacologically active dose level of 0.2 mg/kg and to human subjects at a therapeutic dose level of 5 mg. After oral doses, most of the drug was excreted in the faeces by rats and dogs and faecal radioactivity was obtained from biliary excretion. Rabbits and humans excreted most of the dose in urine. Unchanged CS 476 was the major radioactive component in the plasma of all the species during 6 hours after dosing, and was extensively bound to the plasma proteins. The half-life of CS 476 in plasma was 2 hours in dogs and humans, and 16 hours in rabbits. Drug accumulation did not occur in dog and rabbit plasma during a period of consecutive daily doses and the half-lives after the last of the repeated doses were similar to those found after single doses. In rats, plasma concentrations were relatively low, and did not reach the peak level found in female rats until 24 hours after dosing. CS 476 was extensively biotransformed. The apparent species-dependent disposition of CS 476 may explain differences in tolerance to chronic doses.


Penetration of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood-brain barrier. The relative brain uptake (extraction into brain) of delta-9-tetrahydrocannabinol (delta-9-THC) and the primary metabolite 11-OH-delta-9-tetrahydrocannabinol (11-OH-delta-9-THC) was measured after close intracarotid injection in rats of radiolabelled moities using labelled antipyrine as reference. The extraction percentage was of the same magnitude when injections were given in saline, 66 +/- 11% and 70 +/- 9% respectively after 5 sec., 59 +/- 4 and 67 +/- 8 respectively after 15 sec. While the extraction of 11-OH-delta-9-THC was the same when injected into plasma, the extraction of delta-9-THC was only about half of the extraction from saline, and also half the extraction of the metabolite from plasma. The higher uptake quantity of the metabolite into the brain may account for the relatively greater effect on the central nervous system of the metabolite than of the parent compound at equal concentrations in plasma. Moreover our experiments demonstrate that 11-OH-delta-THC formed in the liver after cannabis (delta-9-THC) administration may exert significant brain effects.


Evidence for two catalytically different binding sites of liver microsomal cytochrome P-450: importance for species and sex differences in oxidation pattern of lidocaine. When the local anaesthetic drug lidocaine is added to liver microsomes biphasic type I spectral change titration curves can be observed. A high-affinity and a low-affinity phase is observed. In the present study we have found that microsomes from female rats have a dominant high-affinity phase, which can hardly be observed within microsomes from female guinea pigs. Male rats showed an intermediate phase. On incubation of lidocaine at concentrations of 1 micron or less with female rat liver microsomes a larger fraction of the drug was aromatically hydroxylated than deethylated. The opposite was true for guinea pig liver microsomes, and microsomes from male rats were intermediate. The ratio between the formation of deethylated and hydroxylated metabolites increased with the lidocaine concentration and at a lidocaine concentration of 10(-4)M deethylation was the dominant oxidation type in all microsomes. The data suggest that the two spectral phases represent two binding sites of cytochrome P-450 each having a certain "catalytic specificity" - the high affinity catalyzing aromatic hydroxylation and the "low-affinity site" deethylation. This hypothesis is further supported by the observed differential effects of pH and MgCl2 concentration on the two types of oxidation.


Chronic administration of cyanide: urinary excretion of thiocyanate in male and female rats. The urinary elimination of thiocyanate was investigated in male and female rats following the chronic administration of potassium cyanide. Female rats dosed at the level of 5 mg KCN/kg once a week and twice a week respectively, displayed no significant difference in the excretion of thiocyanate in urine after periods of up to eight weeks of study. Similarly, male rats that were administered 5 mg/KCN/kg twice weekly showed no significant difference in the amount of thiocyanate excreted. The elimination patterns of thiocyanate in male and female rats showed no significant differences. The results suggest that a substrate saturation phenomenon is not operative with cyanide metabolism at the dosage level of potassium cyanide employed in this study. This is contrary to a previously published study which reported that the urinary excretion of thiocyanate decreased after chronic potassium cyanide administration.


Cerebrospinal-fluid concentrations of nitrazepam in man. The concentrations of nitrazepam in the plasma and cerebrospinal-fluid (CSF) of 38 neurological patients were determined by gas chromatography 2-36 hours after a single 5 mg oral dose. The percentage ratio between the mean CSF and the plasma concentrations increased from 8.0% at 2 hours to 15.6% at 36 hours. This percentage rise was significant (P less than 0.001). The maximum concentration of nitrazepam in the plasma was 36.7 +/- 5.7 ng/ml (at 2 hours) and CSF 3.0 +/- 0.3 ng/ml (at 4 hours). During the beta-phase the half-life of nitrazepam in plasma was about 27 hours and in the CSF markedly longer about 68 hours, indicating a very slow elimination of nitrazepam from the CSF.


Evaluation of a modified method for arthrography of the knee. A modified method for knee arthrography based on the technique introduced by Lindblom has been applied in 1 200 patients. The arthrographic reports on 132 patients submitted to arthrotomy are compared with the findings at surgery. The modified technique is easy to perform and offers a fairly reliable all-round method for diagnosis of both meniscus and crucial ligament lesions.


The gay bowel syndrome. A review of colonic and rectal conditions in 200 male homosexuals. Our experience in the management of 260 male homosexuals with colorectal problems is described. The increased incidence of amebiasis, shigellosis and hepatitis, specific and nonspecific protocolitides, venereal disease and anal warts, is emphasized. It is important to recognize homosexual patients and the conditions to which they are predisposed.


Determining fetal lung maturity: a sensitive surfactant method. The presence of fetal lung surfactant in amniotic fluid is indicative that fetal lungs are sufficiently mature for delivery without subsequent respiratory distress. However, current methods for detecting surfactant fail to positively distinguish saturated phosphatidylcholine (primarily dipalmitoyl phosphatidlycholine) from the many similar phosphatidylcholines also present in amniotic fluid. As a result small amounts of this lipid are obscured by the presence of the other lipids and delivery of many patients is delayed unnecessarily. A  sensitive method is here described in which extraneous phosphatidylcholines are oxidized while the saturated phosphatidylcholines remain intact for positive determination by thin-layer chromatography. The method is insensitive to contaminating lipids from blood or meconium and provides an unequivocal test for the presence of disaturated phosphatidylcholine in a relatively short time. About one half of the patients tested in whom lecithin/sphingomyelin ratios were 1.4 to 1.7 had this surfactant lipid present in their fluids and presumably could have been delivered immediately.


Isoxsuprine-induced release of pulmonary surfactant in the rabbit fetus. Rabbit fetuses were injected intramuscularly with 0.5 mg. of isoxsuprine on the twenty-eighth day of gestation. They were killed in utero four hours after the injection, and fetal pulmonary fluid (FPF) was collected through a tracheal catheter. The quantity of FPF and the lung weight/body weight ratio were both significantly less in the isoxsuprine-treated fetuses than in control fetuses. Surface activity, evaluated with pulsating bubble, and the lecithin/sphingomyelin (L/S) ratio were greater in FPF from isoxsuprine-treated animals than in control samples. We concluded that isoxsuprine is able to dehydrate the fetal lung and cause a release of surfactant stored in type II pneumocytes. This latter conclusion was supported by a significant decrease in the number of lamellar inclusions observed in these cells.


Results of vitrectomy for rare proliferative and hemorrhagic diseases. We compiled the results of pars plana vitrectomy in rare proliferative and hemorrhagic diseases. In retinal vasculitis of unknown origin (perhaps Eales' disease), six out of seven eyes had visual improvement; in sickle cell disease, two out of three eyes improved. Three eyes with presumed toxocariasis were successfully treated. In retrolental fibroplasia (RLF), only lighter degrees of the cicatricial stage with traction detachments can be treated. Some cases may simulate Coats' disease. There are also cases which simulate the typical picture of RLF, where there is no history of prematurity or oxygen usage. Five patients with RLF were treated, three of these successfully. Cryoglobulinemia (one case) and hereditary hemorrhagic telangiectasia (one case) were successfully treated. Senile macular degeneration can also be an indication for vitrectomy (two out of three eyes were successfully treated).


Case report: circulating anticoagulant, autoimmune hemolytic anemia and malignant lymphoma. A circulating anticoagulant of the type often seen in systemic lupus erythematosus, an autoagglutinin and a Coombs-reactive autoantibody were identified in a patient who had the subsequent diagnosis of poorly differentiated diffuse lymphocytic lymphoma. Evidence indicated that the red cell autoantibodies did not possess anticoagulant properties. The red cell autoantibodies as well as the anticoagulant disappeared following corticosteroid therapy. It is probable that the anticoagulant is a manifestation of autoimmunity. The coexistent autoimmune and lymphoproliferative abnormalities in this patient resemble certain animal models in which evidence exists for a viral etiology of the autoimmune and lymphoproliferative disorders.


Gastric complications after radiotherapy for Hodgkin's disease and other lymphomas. Six patients who originally received radiotherapy for Hodgkin's disease or primary gastric lymphoma developed radiation injury of the stomach requiring surgical management. Only two of these patients had evidence of gastric neoplastic involvement at the time of treatment. Experience with these patients leads us to draw the following conclusions: (1) Symptoms of radiation injury mimic those of recurrent neoplastic disease. (2) The effects of radiation are progressive and may be resistant to medical management. (3) The indications for surgical management include perforation, hemorrhage, obstruction, intractable pain, fistula formation, and inability to rule out recurrence. (4) Parenteral hyperalimentation can be an important adjunct in preparing debilitated patients for operation. (5) Gastric resection with gastrojejunostomy is the preferred operation. (6) Frozen section examination can be useful in determining the proper level of resection.


Clotrimazole vs haloprogin treatment of tinea cruris. A study to compare the efficacy of clotrimazole 1% solution with that of haloprogin 1% solution for the treatment of tinea cruris was conducted among military personnel on active duty in a hot, humid climate. Eighty patients with documented dermatophyte infections were treated with the topical antifungal agents. Analysis of the response to treatment for 14 days demonstrated that clotrimazole was significantly more effective clinically and mycologically than haloprogin. With no further treatment, significantly more patients treated with clotrimazole remained free of the disease four weeks later.


[Plasmatic thyroid hormones during treatment of hyperthyroidism by carbimazol (author's transl)]. Plasmatic concentrations of thyroxine (T4-D-) and triiodothyronine (T3 RI) were evaluated in 32 Graves' diseases on treatment by carbimazol. Among 131 measures, T4 and T3 were dissociated in 56%, with T3 more elevated than T4 in 89%. Compensated hypothyroidism was frequently seen (35%).


[Long term effects of the treatment of the Graves' disease by 4 different therapeutics (author's transl)]. 166 patients suffering of Graves' disease have been treated between 1967 and 1971 with 4 different methods (Carbimazole alone, Carbimazole + Surgery, 131 I, 131 I + Carbimazole between 10th and 50th days). The choice was conducted by the volume of the gland and the age of the patient. Isotope was calculated to deliver 7 000 rads in 76 cases and 10 000 rads in 17 more severe cases (cardiothyreosis). 129 patients were submitted to a long term follow up. Medical treatment gave euthyroidism in 34/47 after a mean duration of 8 months. 1/3 to 1/2 of the patients relapsed between 1 to 9 years. Surgical treatment was successful in 25/26 after a total period of 5,5 months. 8 relapsed and 3 became hypothyroid. Relapses were more frequent after bilateral subtotal thyroidectomy than after total lobectomy + subtotal contralateral lobectomy. Isotope gave a complete cure in 14 patients (delay 4,1 months) and in 34, a complementary treatment was necessary (delay 13,5 months). Relapses (12/94) were detected in general after 2 years. The results were the same after 7 000 ans 10 000 rads doses and in the patient receiving, or not, systematically carbimazole. The treatment of Graves' disease is long and difficult. An excellent result is obtained only in half of the cases. 1/3 of these good results needs less than 6 months and 2/3 12 months. A thyroid of less than 40 g include after surgical treatment or after isotopic irradiation an increasing risk of hypothyroidism.


Induction of unscheduled DNA synthesis by chemical mutagens in testicular cells of the mouse in vitro. Testicular cells of male mice were isolated, and the incorporation of tritium labeled thymidine into the DNA of the cells was estimated after exposure to various chemical mutagens. The normal semiconservative DNA synthesis was suppressed by the addition of hydroxyurea. Thirteen compounds were tested. Unscheduled DNA synthesis (UDS) was stimulated by ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and triaziquone, and, to a lesser extent, by 4-nitroquinoline 1-oxide (4-NQO), mitomycin C, ICR-191 and nitrogen mustard (HN-2). No thymidine incorporation could be estimated after incubation of the cells with 9-aminoacridine, hydroxyurethane, alpha-naphthylamine, 2-acetylaminofluorene (AAF) nor with N-hydroxy-2-acetylaminofluorene (N-OH-AAF).


The effect of mercuric chloride on the excretion of two urinary enzymes in the rat. The effect of intravenous injections of HgCl2 on the renal excretion of alkaline phosphatase (AP) and leucine aminopeptidase (LAP) was investigated in rats. On the first day after Hg enzyme excretion showed a linear rise with the Hg dose from a threshold value of 0.44 mg Hg/kg. On the second day a statistically significant effect was seen already after 0.25 mg HgKG. After doses of 0.75 mg/kg or more a decrease of enzyme activity below control values occurred which persisted for more than 4 days. Treatment with 2,3-dimercaptopropansulfonate (DMPS) brought about a normalization of AP excretion. An effect on LAP excretion was observed only with early treatment. The same holds for the effect of DMPS on Hg-induced lethality. The usefulness of a measurement of LAP excretion for estimating the exposure to inorganic mercury is discussed.


Cardiac sensitization induced by phenobarbitone and prolonged by CS2. The arrhythmogenic effect of 8 microgram/kg noradrenaline given i.v. was increased in male rats pretreated 1-2 days earlier with phenobarbitone and starved from the time  of the first phenobarbitone injection (80 mg/kg followed by 50 mg/kg 6 h later). Daily exposure to 4.0 mg/l CS2 (first exposure 24 h after the first phenobarbitone injection) for 4 h prevented the decline in susceptibility on the 3rd and 4th days after phenobarbitone, when the reaction of unexposed rats to noradrenaline returned to normal.


[Acute fatal ioxynil intoxication (author's transl)]. An occasional fatal intoxication of Ioxynil is reported. Relevant autopsy findings are given and an extraction procedure for the determination of Ixoynil in the taken in fluid and in autopsy material is described. In the unknown fluid Ioxynil has been identified by using IR and NMR spectroscopy and determined by UV spectrophotometry. In biological material Ioxynil has been identified by TLC and IR spectroscopy. For the determination of blood serum, TLC-densitometry in situ has been carried out.


Receptor maturation and synaptogenesis in the golden hamster cochlea. Maturation of hamster cochlea was studied using light and electron microscopy. Critical stages of receptor and neural structure development have been determined. At birth the hamster cochlea shows a pronounced immaturity, but innervation can already be found. 2 or 3 days later, characteristic afferent synapses can be recognized beginning at the inner hair cell level. Similarly, efferent endings first appear on the inner side at the end of the first week. The onset of auditory function must be related to structures depicted at around 10 days, and cochlear maturation is achieved at about 25 days. The sequence of synaptic development in the cochlea is discussed regarding the general morphogenesis of synapses within the nervous system. Some determinations of the timing of peripheral myelination are given. This process begins almost a week before the presumable date of the onset of function.


[Problems of otorhinolaryngologists in perinatology (author's transl)]. Some of demonstrable pathological changes which are already present during the perinatal period are described in this work. Since nasal septal deviations due to trauma at birth can be straightened out immediately and often no special set of instruments are required, the importance of routine E-N-T-examinations is stressed. Such otorhinolaryngologic examinations were performed by the author in 1030 nearly born babys. Out of this number 19 birth traumatic nasal septal deviations were corrected without surgery.


[The influence of uni- or bilateral recurrent paresis on physical capacity (author's transl]. Patients suffering from uni- or bilateral recurrent laryngeal paresis were tested by means of spirometric and complex functional capacity tests. The results obtained from patients with unilateral paresis (spirometry, spiroergometry, acid-base equilibrium, oxygen tension) did not differ from those of the control group. A restriction of the functional capacity due to disorders of breathing was not found. In patients with bilateral paresis, physiologic parameters were always influenced by the respiratory tract stenosis. Functional tests resulted in alveolar hypoventilation up to total respiratory failure connected with decreased ergometric values. The results also gave an insight into the pathophysiologic mechanisms of the respiratory obstruction as a result of the stenosis under conditions of physical strain. Suggestions for evaluating the physical functional capacity of patients are given.


Comparative study between the normally hearing child and the hard of hearing child, by acoustic impedance measurements of the ear. In the first part, the author makes a comparative study of the tympanometric results obtained from the normally hearing child and the hard of hearing child. The frequency of serous otitis media is statistically higher in the deaf child. The author compares such results of tympanometry as obtained from the child, considers the contribution of this technique to the field of pediatric audiology and suggests a classification of tympanograms in terms of the probe-tone frequency of the impedancemeter. The second part concerns the acoustico-facial reflex. This study compares the recording of the stapedius reflex obtained by pure tone and Narrow-Band noise acoustic stimulation, thanks to Madsen electro-acoustic bridge, in two groups of children, the one consisting of normal hearing children and the other of children suffering from severe perception hearing loss. The study of the stapedius reflex threshold makes it possible to analyse the dynamics of the field of perception in both groups. After an analysis of the results, the author outlines the importance attributable to the study of the stapedius reflex in the child as a means of objectively examining the auditive function and a means of differential diagnosis in cases of sensorineural impairment of the hearing function.


[The implantation of lyophilized and gamma-sterilized allogenetic incus and of lyophilized and gamma-sterilized xenogenetic malleus (calf) in rabbits and humans (author's transl)]. The histological reactions to the implantation of allogenetic and xenogenetic lyophilized and gamma-sterilized material into the middle ear of rabbits and men is described. In contrary to the behaviour of allogenetic material the xenogenetic shows a clear minor tendency of revitalisation. The reason is the antigen-antibody-reaction which takes place at the capillary network of the donor and leads to a hylinosis with following obliteration of the vascular rete. Therefore the angiogenetic osteogenesis cannot develop. The clinical usuability of such material is discussed.


[Scanning electron microscopy studies concerning the epiglottis epithelia of rats (author's transl)]. The epithelial surface of the epiglottis in adult male and female albino rats is studied by scanning electron microscopy. Prominent differences exist between the surface morphology as observed in the males and that observed in the females sacrificed in the estrus phase of the ovarial cycle. The differences are most pronounced in respect to the amount of secretory vesicles, microvilli- and microridge-cells and in respect to the observable number of desquamating cells. The existence and the importance of the microridge-cells are discussed. Special attention is also paid to the results indicating that at least some parts of the extrapulmonary airway epithelia act as possible target organs for sex hormones. Finally the importance of the observed differences is discussed for the correct interpretation of pathomorphological alterations in the extrapulmonary airway epithelia that have been observed under experimental conditions and during infections.


[The "stimulatory proteodyschylia" in the amitriptylin (Laroxyl) treated rat parotid gland. Experiments on the effect of antidepressive pharmacotherapy on the parotid glands of the rat (author's transl)]. The activity of total amylase and isoamylases in the rat parotid gland is reduced by treatment with Amitriptylin (Laroxyl) for 3 and 7 days while the protein content of the glands remains constant. These changes are no longer visible after treatment for 21 days and following a period without drug application. To differentiate the disturbances of protein secretion (proteodyschylia) prominent in the clinical picture of sialadenosis, the following classification is proposed. We suggest the term "stimulatory proteodyschylia" for a decrease of acinar amylolytic activity, here caused by Amitriptylin application, as opposed to the "inhibitory proteodyschylia" characterized by an acinar amylase congestion.


Coagulant fractions of snake venom and the control of capillary bleeding during microsurgery of the ear in vivo demonstration. In 398 cases of observed capillary bleeding out of total of 968 otological microsurgeries, the i.v. use of Bothrops Jararaca enzyme proved to be highly useful in controlling the bleeding in 79% of those, namely in 318 cases. We may assume that if capillary bleeding is indeed the consequence of some haemostatic deficiency, not always detectable with the routine laboratory preoperative tests, Bothrops Jararaca enzyme is extremely valuable in controlling this bleeding. If however oozing or capillary bleeding is the result of other circumstances, such as insufficient analgesia and neurolepsia, inadequate anaesthetic technique, wrong positioning of the head resulting in venous congestion of the operative region, or local fibrinolysis due to protracted microsurgery, other measures should be taken to correct these conditions which are not due to coagulation defects. Bothrops Jararaca enzyme, given by i.v. route, even in single dose of 2-6 units = 2-6 ampoules, was perfectly tolerated by all the patients without any side effect or allergic manifestations.


Osteoma of the mastoid.

Osteoma of the mastoid. We present herein a rare case of osteoma mixtum of the mastoid. The main features of the osteoma were demonstrated clearly by preoperative tangential X-ray projection. Histological studies revealed the osteoma to be composed of multiple small foci of ossification on the outer layer with a large single inner mass. Subsequent examinations revealed that the osteoma had arisen from the parietosquamosal suture.


The growth of acoustic neurinomas.

The growth of acoustic neurinomas. Through analysis of 20 case histories of patients with confirmed acoustic neurinomas, the weights of the tumors in correlation with the symptoms and findings were used, and a system of estimating the growth of this tumor was advocated. Factors, affecting the rate of growth as observed from these cases were underlined.


[Bacteriological study on the chemotherapeutic combination sulfametrole-trimethoprim/comparison with co-trimoxazole (author's transl)]. The synergism of the compounds Nd-(4-methoxy-1,2,5-thiadiazol-3-yl)-sulfanilamide (sulfametrole; SOL) and 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine (trimethoprim; TMP) contained in the preparation Lidaprim was proved in vitro in the agar dilution test, the disc agar diffusion method as well as a crossover test against various grampositive and gramnegative bacteria. Sulfametrole enhanced the activity of trimethoprim or its activity was intensified by trimethoprim, respectively. The increase in efficiency depends on the primary sensitivity or resistance of the bacteria against trimethoprim and/or the sulfonamide. The combination of trimethoprim + sulfametrole (1 + 20) had the same antibacterial activity as the combination co-trimoxazole = trimethoprim + Nd-(5-methyl-3-isoxazolyl)-sulfanilamide (sulfamethoxazole; SMZ). The bactericidal efficiency was shown against a strain of E. coli. Using the combination experimental development of resistance against various bacteria could not be obtained (10 times repeated contact with subbacteriostatic concentrations). Chemotherapeutical experiments in the mouse have confirmed the enhancement indicated in vitro of the combination trimethoprim-sulfonamide, irrespective of the sulfonamides chosen. Determinations of the intestinal flora before, during and after oral administration of 2 X 2 tablets SOL-TMP (Lidaprim) over a period of 10 days showed that the absolute number of bacteria in samples of faeces had not been reduced. Enterobacteria and anaerobic lactobacilli (L. bifidus), which could not be identified during the period of administration, reappeared after the end of therapy.


[Effects of gentamicin and lincomycin on the ultrastructure of mitochondria and plastids of Chlamydomonas reinhardii (author's transl)]. It is known that antibiotics which have an effect on 70 S ribosomes inhibit both the bacterial and the mitochondrial protein synthesis of plants and animals. This also applies to the plastid protein synthesis of plants. On this basis the present study has examined whether the inhibition of the mitochondrial protein synthesis caused by such antibiotics, may also be recognized by structural changes in the mitochondria. The effects on the ultrastructure of plastids have been investigated comparatively. The mixotroph flagellate Chlamydomonas reinhardii was used in our study. It was found that gentamycin (0.3 to 0.6 microgram/ml) and lincomycin (200 and 300 microgram/ml) cause structural anomalies in the mitochondria and in the plastids as well. Depending on the concentrations and the periods of exposure the mitochondria exhibited the following alterations: disorientation of the cristae within the organelles, reduction in the number of cristae and considerable differences of their length. In addition, vesicles and bodies which are surrounded by circular single or doubled membranes appeared in the mitochondria under the influence of gentamycin. We were able to detect mitochondria of unusual sizes and shapes in the cross sections. We also noticed changes in the arrangement of the thylakoids in the plastids under the influence of both gentamycin and lincomycin. In addition, electron-dense thylakoids, the so-called compact membranes, appeared under the influence of gentamycin. We suspect that mitochondrial alterations under the influence of such antibiotics could be one of the causes of side-effects, which frequently occur in medical use.


A gas chromatography-mass fragmentographic method for the assay of ajmaline and its monochloroacetyl ester. A gas chromatograph-mass fragmentography method for simultaneous assay of 17-monochloroacetyl-ajmaline (MCAA) and its hydrolysis product, ajmaline, is described. Recovery of both compounds from whole blood averaged 71%. About 5% of MCAA was hydrolyzed during the assay procedure. The method was accurate and precise to within a few percent. It was suitable for assays of blood levels in the dog after an i.v. dose of 2 mg/kg or an oral dose of 5 mg/kg.


1-Methyl-2-nitroimidazol-5-yl derivatives. IIIrd communication. A series of 1-methyl-2-nitroimidazole-5-carboxaldehyde derivatives (substituted hydrazones, oximes and Schiff bases) have been prepared and tested for their antimicrobial activity.


An integration of the modes of action of coumarin. An explanation of its effectiveness as a therapy for thermally injured tissue. The mode of action of coumarin is well suited to the relief of high-protein oedemas. It binds rapidly to the serum albumins, and the protein binding capacity of a substance provides insight into its interaction with sites of biological activity. Together with proteins, inflowing through the damaged capillary endothelium after thermal injury, it is taken up by the monocytes in the inflamed tissues and by the resident macrophages. Coumarin can stimulate these cells to enhanced proteolysis of the engulfed protein which is digested to debris of molecular weight less than 1000. This is on the other hand readily utilisable protein for the large number of monocytes to mature and differentiate into macrophages. Coumarin may dissociate from protein in the tissue and cause local site activation or even activate all cell sites increasing cell numbers or rejuvenate older phagocytic cells and stimulate the reticulo-endothelial system (RES). A passing histamine-like effect of coumarin and other benzopyrones is an indirect stimulant for the RES. The released injurious amines open additional numbers of endothelial intercellular junctions, allowing extra protein and fluid into the interstitial tissues. A reinforced phagocytosis follows and results in more rapid and complete digestion. The action of the drug in causing the opening of intercellular junction is very beneficial. The extra protein is of little consequence, since its inflow is more than compensated for by the other actions of the drug which results in its lysis. Coumarin has also a number of other important actions on the vascular system. It causes constriction of the precapillary sphincters and a dilatation of the arterio-venous anastomosis. The result is an increased blood pressure and flow, and a better oxygen supply of the area. It is able to restore the deformability of the red blood cell to near normal levels and to protect the thrombocyte by membrane stabilizing. The result is a reduced likelihood of thrombosis and embolism. By increasing the glucose uptake and transport the benzopyrones can improve the chance of survival of those cells in stagnant areas of the circulation.


Benzopyrone treatment of mild thermal oedema: determination of the most effective doses. Mild thermal oedema is a very common injury, yet most forms of treatment are cumbersome and painful. Treatment with benzopyrones is certainly very effective in rats. All the drugs tested reduced the swelling volumes of the limbs and increased the rates of oedema resolution. The optimum doses for various benzopyrones were determined. To date, only very low doses of benzopyrones have been used in clinical trials. Based on the results of experimental dose-reaction assessment it is suggested that higher doses should be used, i.e. in regard to the different metabolism of benzopyrones in man compared with rodents; they might then produce similarly dramatic results to those obtained in animal experiments.


Differentiation of in vitro and in vivo effects of a flavonoid on endothelial cell counts. Parenterally administered flavonoids decrease endothelaemia in rats as determined by a new method in two ways: in vivo and in vitro. The in vitro effect caused by flavonoids present in blood might interfere with the cell counting and can be eliminated by neutralization of flavonoids with cobaltous ions. The resulting endothelial counts represent the "true" in vivo effect. Using this method it has been shown that the in vitro interference did not modify significantly the previously demonstrated marked effect of a flavonoid (mono-7-hydroxyethylrutoside) on increased endothelial counts after provocation with citrate.


Advantages of a combination of proteolytic enzymes, flavonoids and ascorbic acid in comparison with non-steroid anti-inflammatory agents. The action of a combination of chymotrypsin-trypsin + flavonoids + ascorbic acid (zymolean) has been compared with that of 7 non-steroid anti-inflammatory substances in 4 tests: a histamine induced wheal, dextran and carrageenin induced edemas, and permeability to Evans blue in the peritoneal cavity. 1. The non-steroid anti-inflammatory substances, which reduce markedly the carrageenin induced edema, are active against peritoneal permeability, but bring about almost no decrease in the effects of histamine and dextran. 2. The combination studied is effective in all of the techniques. 3. The reduction of capillary permeability induced by histamine is due to the action of flavonoids and ascorbic acid. 4. The action of the proteolytic enzymes, administered by duodenal route, on the one hand, and that of hesperidin-methylchalcone + methyl-4-esculetol + ascorbic acid on the other, accumulate to reduce the two types of edema. 5. The effect against permeability in the peritoneum seems to exerted by the combination of the flavonoids + ascorbic acid. 6. The combination studied, therefore, shows a more complete spectrum of action than the non-steroid anti-inflammatory substances against initial symptoms of inflammation.


[Mechanism of action of catecholamines on the electrically-stimulated, isolated guinea-pig gallbladder]. Effects of catecholamines on the contraction of isolated guinea-pig gallbladder induced by transmural stimulation (TM) were investigated. Tetrodotoxin and atropine prevented the TM-induced contraction. Atropine, but not tetrodotoxin, blocked the acetylcholine-induced contraction. Furthermore, the TM-induced contraction was sharply reduced during a cold storage for 1 to 4 days and then abolished 4 to 7 days later. Norepinephrine (5 X 10(-6) M) and epinephrine (4.5 X 10(-6) M) did not affect acetylcholine-induced contraction, but reduced the contractile response to TM by about 40% and 60%, respectively. Phentolamine, but not propranolol, abolished the inhibitory effects of norepinephrine and epinephrine on the contraction induced by TM. Isoproterenol and phenylephrine did not significantly modify the TM-induced contraction. These observations suggest that TM-induced contraction is produced by the release of acetylcholine from the ending of postganglionic cholinergic fibers. The possibility that norepinephrine and epinephrine act on the inhibitory alpha-adrenoreceptors in the ending of cholinergic neuron is discussed.


[Pharmacokinetic studies following administration of 14 C-D-penicillamine to rats]. 14C-Labelled D-penicillamine [D-(--)-alpha-amino-beta-mercapto-isovaleric acid; Trolovol] was administered to rats in doses of 10 to 50 mg/kg body weight orally or i.v. A dose of 0.25 mg per rat was used for intra-articular injection (knee joint). 4 h after a single i.v. administration about 30% of the given amount were detected in the animal. This amount of activity was located predominantly in skin and connective tissues and was eliminated very slowly. 2 days after administration 20 (i.v.) or 10 (p.o.)%, resp., of the radioactivity administered were found in the animal, in any case half of it in the skin. In comparison to the skin and the connective tissues, the parenchymatous organs and the central nervous system showed distinctly lower concentrations. The activity is eliminated mainly with the urine: 80 (i.v.) or 50 (p.o.)%, resp., of the administered activity were eliminated renally within 48 h. 90% of it were excreted within 6 (i.v.) or 7 (p.o.) h, resp., after administration. Less than 2 (i.v.) and approx. 40 (p.o.)%, resp., of the given activity were found in the faeces collected for 2 days. The extent of gastrointestinal absorption was about 2/3 of the dose administered. Up to 24 h after the three modes of administration distinctly detectable concentrations were to be located in the lig. patellae of the knee joints, somewhat lower values in the ligaments between the articular cartilages. Studies carried out on rats in parallel with an arthritis experimentally induced (secondary phase, after injection of Freund's adjuvant) demonstrated the same activity distribution compared with the pattern which was obtained on healthy rats.


Excretion and distribution studies in rats with two forms of 14carbon-labelled polyvinylpyrrolidone with a relatively low mean molecular weight after intravenous administration. Excretion and autoradiographic distribution studies were performed in rats with two 14C-labelled polyvinylpyrrolidone preparations, both of relatively low mean molecular weight but different in molecular weight distribution. At different time intervals after i.v. administration, elimination of radioactivity was found to be more complete for the preparation with the smallest fraction of molecules having a weight of over 25000, which is approximately the weight limit for rapid glomerular filtration in the rat. Our study demonstrates that the retention of PVP in organs, which in the literature are mentioned as target organs for PVP-toxicity, can be largely prevented by decreasing the fraction of molecules with a weight of more than 25000.


[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradien-9(11),16-oic acid-18] / 2nd communication (author's transl)]. 6 metabolites are formed by incubation of grandiflorenic acid (GFA) with rat liver microsomes. 79% of GFA are metabolized after i.p. application to rats; 11 biotransformation products are found in faeces, the main excretion way. They are conjugated to glucuronic acid. Gut microflora is involved in these metabolic reactions. The structure of three metabolites is proved by IR-, MS- and NMR-spectroscopies.


[Investigation of the absorption properties of two synthetic emulsifiers by means of radioactively labelled iodine / Short communication (author's transl)]. The absorption properties of the two non-ionic synthetic emulsifiers polyoxyethylene-glycerin-monooleate (PGMO) and polyoxyethylene-glycerin-monostearate (PGMS) were studied experimentally on male Wistar rats using radioactive iodine (Na131I) solution. The two emulsifiers were compared with a combination of equal parts of lanoline and vaseline. PGMO showed better absorption properties than did GPMS and the lanoline-vaseline combination.


Stimulatory effect of Panax ginseng principles on DNA, RNA, protein and lipid synthesis in rat bone marrow. Effects of extract fraction 3 and 4 from the root of Panax ginseng on bone marrow cells of the rat were investigated. Oral administration of fraction 3 and addition of fraction 4 in vitro stimulated DNA, protein and lipid synthesis in bone marrow cells. The stimulatory effect was reduced by pretreatment of cycloheximide. Single i.p. injection of fraction 4 also increased DNA and RNA synthesis. Numbers of mitosis were increased by oral administration of fraction 3. Extent of the increase was almost equal in both myeloid and erythoid. Numbers of total nucleated cells in bone marrow and reticulocytes in peripheral blood were significantly increased. The hematopoiesis-stimulating action of Panax ginseng and its mechanism of the action were discussed.


1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (ML 1024), a new hypolipemic agent. 1-(Theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (ML 1024) was tested on acute and chronic toxicity, on teratogenesis and fetotoxicity, on blood pressure and blood flow behaviour, on hypolipemic activity and general pharmacological behaviour in a screening test using 54 parameters. Results warrant further investigation of the potential therapeutic application of ML 1024 in humans based on its superiority to the well-known antilipemic clofibrate (CPIB).


Ca2+-transport inhibition by the antitumor agents adriamycin and daunomycin. The antitumor agents adriamycin and daunomycin inhibit Ca2+-transport in mitochondria from Ehrlich ascites carcinoma cells as well as in a biphasic model system. The experimental results indicate that both antibiotics interact with phospholipids. The significance of these observations in the pharmacological behavior of these anticancer compounds is discussed.


[Findings following antidote therapy in rats intoxicated with phosphoracetic acid. / Histochemical and biochemical lipid demonstration in liver and kidneys (author's transl)]. The fatty degeneration of the liver and kidney of Sprague-Dawley rats was observed by histochemical and biochemical means after intoxication with LD50 and 8 X LD50 O,O-diethyl-O-p-nitro-phenylphosphate (paraoxon). The degree of fatty degeneration in these organs was demonstrated alternately after antidote-treatment with bis(pyridinium-4-aldoxim-1-methyl) ether (Toxogonin) and after injection of a combination of Toxogonin, atropine and a protein-free extract from calf blood containing low-molecular substances (Actihaemyl, Solcoseryl). Under the influence of Actihaemyl the degree of fatty degeneration induced by the toxin was, in respect to both triglycerides and phospholipids, near control levels. The mode of action of Actihaemyl is discussed with regard to the activation of fatty acids.


Investigation of the liver glycogen level in rats treated with anticonceptives. The results of our experiments with carbohydrate metabolism confirmed that 1. the gestagen component of norethynodrel (Infecundin) causes a more explicit increase of the liver glycogen level than that of ethynodioldiacetate (Bisecurin); 2. among oestrogens mestranol (Infecundin) gives a higher glycogen production in the liver than ethinyloestradiol (Bisecurin); 3. the greatest increase of liver glycogen level is in the course of the acute (14 days') treatment period; 4. the active substances of Infecundin (first of all mestranol) produce a longer lasting effect on the quantity of liver glycogen than those of Bisecurin; 5. to this action of the drug molecules of both anticonceptives (Infecundin, Bisecurin) there is a tendency to habituation. After a treatment lasting 48 days, the liver glycogen level in comparison with the control did but slightly increase; 6. evaluable changes occur sooner in the glycogen level of rats treated with hormonal contraceptives prior to the generally used so-called liver function test becoming positive.


Some aspects of the neuropharmacology of phenylurea. The neuropharmacology of phenylurea was studied. The compound is a potent sedative hypnotic agent with a fairly good margin of safety. It produced significant motor incoordination and behavioral changes in sub-sedative doses, thus suggesting that it acts on the areas of the brain which control motor coordination (neurological deficit) and spontaneous motor movements (awareness of environment). The activity pattern of phenylurea as measured on the rotarod treadmill was identical with that of an ataractic drug, meprobamate, and different from that of the sedative drug, 2-ethylcrotonylurea (ectylurea). It exhibited significant meprobamate-like antistrychnine (myorelaxant) activity, and at high doses only, anticonvulsant activity (pentetrazole antagonism). Phenylurea also protected mice against tremorine-induced tremors. A sub-sedative dose of phenylurea significantly prolonged pentobarbital sleeping time.


Modifications of platelet retention in patients treated with pyridinolcarbamate. A preliminary report. Pyridinolcarbamate (1 g daily for 30 days) was used for treating 9 patients with peripheral arteriopathies; 8 subjects had also diabetes mellitus in good metabolic control. A statistically significant decrease of platelet retention as measured by Salzman's method could be demonstrated.


The effect of cyproheptadine on the chromosomes of human lymphocytes in vitro. The effect of 4-[5-dibenzo(alpha,alpha)-cyclohepten-5-ylidene]-1-methylpiperidine (cyproheptadine, Periactinol) on the chromosomes of human lymphocytes in vitro was investigated. Cell cultures that had been established for 48 h from lymphocytes obtained from the peripheral blood of four volunteers were exposed for an additional 24 h to drug concentrations of 2.54 X 10(-5), 5.09 X 10(-5), 1.02 X 10(-4), or 2.03 X 10(-4) Mol/l. No variations or aberrations were seen in the chromosomes of human lymphocytes that could be definitely related to treatment with cyproheptadine.


[The influence of drugs on the purine salvage metabolism in human blood cells (author's transl)]. The influence of 1-phenyl-2-(p-hydroxyphenyl)-3,5-dioxo-4n-butylpyrazolidine-monohydrate (oxyphenbutazone) and N-(alpha,alpha,alpha-trifluoro-m-tolyl)-anthranilic acid (flufenamic acid) on the purine salvage pathway of erythrocytes and lymphocytes following incubation of heparinized whole blood with the drugs was investigated. As described in earlier experiments in vitro with enzymes derived from cell homogenates, the enzyme activities of whole cells were also decreased. Lymphocytes exhibited a reduction of purine-phosphoribosyltransferase (purine-PRT) activities (adenine-, guanine- and hypoxanthine-PRT) of about 20%. The effect on the enzyme activities in red blood cells was different. The A-PRT-activity was decreased to about 33%, the GH-PRT on the other hand, to about 10%. The possible significance of these results in vivo is discussed.


[On the dose-effect relation of allopurinol (author's transl)]. The hypuricemic action(y) of 1H-pyrazolo(3,4-d)pyrimidin-4-ol (allopurinol) is dependent on the serum concentration of uric acid (x). After treatment with allopurinol at doses of 300 mg daily for 8 days there exists a highly significant correlation corresponding the equation y = 0.875x + 3.950. At a level of 8 mg/dl without any therapy serum uric acid concentration is expected to decrease by an average of 3 mg/dl if allopurinol is applied at daily doses of 300 mg in a preparation with or without any retarding effect. Following a dose reduction to 150 mg allopurinol daily over a period of 8 days, too, the mean diminution of the hypuricemic action amounts only to 0.43 +/- 0.26 mg/dl (S.D.). In some cases, however, long-term therapy with allopurinol at daily doses of 150 mg is insufficient to guarantee a normuricemic state.


[On the pharmacokinetics of gentamycin. / Clinico-pharmacological study on the course of gentamycin concentrations in serum during large-volume infusions (author's transl)]. Infusions of large volumes have a remarkable influence on the blood levels of gentamycin insofar that with normal dosages no effective concentrations can be found in the serum of the patient. The present investigation was planned as a pharmacokinetic model with the aim of finding out the possible reasons for this phenomenon. The results show that the infusions enhance the total clearance tremendously. Furthermore the elimination half-life of gentamycin is much shorter under infusion conditions. This explains the subtherapeutic blood levels.


Papaverine blood levels after administration of a sustained-release preparation. Short communication. The authors report the papaverine blood levels obtained after administration to a group of volunteers of a sustained-release preparation in comparison with a conventional form. The new preparation shows bioavailability equivalent to a normal papaverine but substantially more prolonged papaverine blood levels.


Serum and urine concentrations of rifampicin administered by intravenous infusion in man. Two studies were carried out in man with the aim of assessing the serum and urine concentrations of rifampicin administered by i.v. infusion. In patients suffering from various diseases, a dose of 600 mg i.v. proved to be equieffective with a 600 mg oral dose. Repeated administration of a 600 mg dose by i.v. infusion for a week produced serum levels corresponding to those achieved by oral administration. With the i.v. preparation the drop in serum rifampicin levels during continuous administration was less marked than with the oral administration. The recovery of antibiotic in the urine seems to be lower with i.v. than with the oral preparation. The i.v. preparation was very well tolerated by all the patients.


[The behaviour of visually evoked potentials (VEP) in schizophrenia under gradually rising doses of fluphenazine dihydrochloride (author's transl)]. The paper describes a study of visually evoked potentials (VEP) during 50 days in a schizophrenic female patient to whom we administered increasing dosages (from 150 mg up to 600 mg) and afterwards progressively decreasing ones (from 600 mg to 20 mg) of 10-(3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl)-2-trifluoromethylphenothiazine (fluphenazine-dihydrochloride). We tried to establish a relation between the aspect of latencies and form of curves and the dosages. We also discussed a possible correspondence between VEP and psychopathological changes.


[Plasma concentrations and renal excretion of vincamine after oral administration in man (author's transl)]. Plasma concentrations and renal excretion of 14,15-dihydro-14beta-hydroxy-(3alpha,16alpha)-eburnamenine-14-carbonic acid methylester (vincamine, Vincapront) were studied in 5 healthy volunteers following the oral intake of 30 or 60 mg vincamine, respectively. After the higher dose (60 mg vincamine), the treatment was continued by the daily intake of 3 X 20 mg vincamine for 5 days. Plasma vincamine levels were determined in the morning prior to the ingestion of the first 20-mg dose and in the evening 2 h after the intake of the third 20-mg dose. Our results prove that vincamine is rapidly liberated and absorbed from the tablet formulation used, the maximum plasma levels being reached 90 min after ingestion and amounting to a mean value of 139 ng/ml after 30 mg and to a mean of 252 ng/ml after 60 mg of vincamine. There was a biphasic elimination of vincamine after both doses indicating a process of distribution influencing also the elimination phase. In the 24-h urine, unchanged vincamine amounted to 5.8% of the applied dose after 30 mg and to 7.3% after 60 mg vincamine. Vincamine did not accumulate during the daily intake of 60 mg for 6 days. Side-effects were not observed in any volunteer during the period of observation.


[Vincamine concentrations in plasma and cerebrospinal fluid in patients following intravenous infusion (author's transl)]. The pharmacokinetic characteristics of 14,15-dihydro-14beta-hydroxy-(3alpha,16alpha)-eburnamenine-14-carbonic acid methylester (vincamine; Vincapront) were studied after i.v. infusion (30 or 40 mg vincamine-hydrochloride within 28--40 min, respectively) in 6 patients with cerebrovascular diseases. At the end of the infusion, maximum plasma levels ranged between 607 and 999 ng/ml. The decline of the plasma concentrations after the end of the infusion could be described using a two-compartment open model. After a phase of distribution lasting 1--2 h there was a linear elimination of vincamine in the semilogarithmic plot. The mean half-life for the beta-slope was 2 h. In four patients we measured the vincamine concentration in the cerebrospinal fluid 2 h after the end of the infusion. It amounted to only 5--24% of the simultaneously estimated plasma concentration.


[The influence of vincamine on global and regional cerebral blood flow in acute and subchronic human cerebral ischimia (author's transl)]. The alterations in global and regional cerebral blood flow (CBF) following i.v. application of 14,15-dihydro-14beta-hydroxy-[13alpha,16alpha]-eburnamenine-14-carbonic acid methylester (vincamine) were studied in 18 patients suffering from acute or subchronic cerebral ischemia. CBF measurements were made after intra-arterial injection of 133Xe using a multi-detector measuring instrument. 30 sec after a single i.v. application of 30 mg/20 min vincamine a statistically significant increase of CBF by 1.5 ml/100 g/min was found, corresponding to 6.1% (p less than 0.01). The regional CBF was influenced to a varying degree, the areas marked by an insufficient blood supply showing a mean increase by 13.4% and the areas marked by normal basic values showing a mean increase by 5.3%. This difference in alteration is statistically significant (p less than 0.02) comparing the differences as percent. The duration of the action of vincamine on the CBF, after a single dose of 30 mg/20 min i.v., was determined for a maximum of 15 min. The CBF values measured within 15 min after the completed i.v. application of vincamine showed a mean decline in blood flow values by --2.5 ml +/- 7.4%, which is statistically insignificant.


[The effect of vincamine on cerebral blood flow as a function of application rate (author's transl)]. The effect of infusions of 14,15-dihydro-14beta-hydroxy-(3alpha, 16alpha)-eburamenine-14-carbonic acid methylester (vincamine; Vincopront) on cerebral blood flow (CBF) was investigated by the xenon clearance method. In 12 patients receiving 30 mg vincamine within 35--40 min no significant changes in hemispheric or regional CBF were observed. 14 patients received 40 mg vincamine within 35--40 min: in this group hemispheric CBF was significantly increased (p less than 0.01) when compared to the spontaneous changes observed in a control group. The increase was particularly prominent in poorly supplied brain regions. This effect was proved statistically by regression analysis. In a patient with astrocytoma the tumor-hyperperfusion was diminished by vincamine while the flow to the surrounding brain improved. The results indicate the dependency of the vincamine effect on the rate of application and thereby on the plasma concentration of the drug.


Effects of caffeine on mitotic index, mitotic aberrations and bimitosis with and without aeration. The effects of 1 to 3 h 0.2% caffeine treatment on mitosis in lateral roots of Vicia faba with and without aeration have been investigated. During the treatment a marked decrease of the mitotic index followed by strong deviations and changing phase indices can be stated. By means of aeration the number of mitotic aberrations increases with time of treatment, while it decreases without aeration until 3 h treatment. Tetraploid cells are supposed to be formed by spindle aberrations at early anaphase. The number of binucleate and tetraploid cells is affected by aeration during caffeine treatment. During division of the binucleate cells tetraploid nuclei are formed by fusions, so the population of binucleate cells may become smaller.


Evaluation of methods to determine protein-binding of drugs. Equilibrium dialysis, ultrafiltration, ultracentrifugation, gel filtration. The reliability of the most important methods to determine protein-binding of drugs was compared. Applying these methods to different drugs solved in bovine plasma or in protein-free solutions the incidence of errors specific for each method was examined. Certain limits are found for the applicability of each method. If these limitations are observed reproducibility differs only slightly within the four methods. Considering all the results, however, the values achieved by equilibrium dialysis appear to come closest to the real extent of binding.


[Biotransformation and pharmacokinetics of grandiflorenic acid [kauradien-9(11),16-oic acid-18]. 3rd communication (author's transl)]. Absorption, metabolism and excretion of 14C-GFA following i.v., i.p. and oral application are investigated in rats. After i.p. administration GFA is completely absorbed, after oral dosage about 83% are absorbed. GFA is excreted by 100% via bile and undergoes extensive enterohepatic circulation. After administration of 20 mg/kg 14C-GFA nearly all radioactivity is eliminated after 96 h, more than 80% via the faeces.


Biological properties and clinical application of propolis. III. Investigation of the sensitivity of Staphylococci isolated from pathological cases to ethanol extract of propolis (EEP). Attempts on inducing resistance in laboratory Staphylococcus strain to EEP. Staphylococci isolated from pathological material exhibited a reduced sensitivity to ethanol extract of propolis (EEP) in 90% of cases. No cross-resistance of the staphylococci to EEP and to any commonly used antibiotics was found. The induction of resistance to EEP in laboratory strain of Staphylococcus aureus (Oxford 209 P) can be achieved already after serial passages on nutrient media containing EEP. Culturing Staphylococcus resistant to EEP in an environment devoid of this compound caused a remission to sensitivity of the strain investigated.


Derivatives of N,N-bis(alpha, alpha, alpha-trifluoro-m-tolyl)amine. Amongst a series of novel derivatives of N,N-bis-(alpha, alpha, alpha-trifluoro-m-tolyl)amine, several were found to possess antiinflammatory, hypotensive, antibacterial and antifungal activity. The synthesis of these compounds is described and their biological properties are discussed.


Stimulatory effect of Panax ginseng principles on DNA and protein synthesis in rat testes. The effect of fraction 4 of the extract from the roots of Panax ginseng, Oura, on DNA and protein syntheses was investigated. Addition of fraction 4 in vitro stimulated DNA and protein syntheses in testes. The stimulating effect was reduced by pretreatment with cycloheximide. This might give some evidence about the stimulatory effect of ginseng on spermatogenesis.


[Inhibitory effect of the calcium antagonist fendiline on digitalis glykosides induced contractions in the guinea pig terminal ileum (author's transl)]. The 10 mm muscle-strips from the guinea pig terminal ileum digitalis glycosides (0.4 microgram/ml beta-acetyl-digoxin or 0.5 microgram/ml k-strophanthin) induce contractions which are dose-dependently and reversibly prevented by the calcium antagonist N-(2-benzyl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride (fendiline, Sensit) (0.01--1 microgram/ml). Therapeutic use of calcium antagonists for manifest symptoms of digitalis intoxication (diarrhoea, intestinal infarctions) is discussed as these symptoms may be caused by digitalis-induced increase of intracellular calcium ions.


[Reaction of local myocardial blood flow in non-anesthetized dogs and anesthetized cats to the oral and parenteral administration of a Crateagus fraction (oligomere procyanidines)]. Local blood flow in the myocardium of the left ventricle in unanesthetized dogs was measured by chronically implanted heat-conduction probes. Oral administration of a fraction of Crataegus (oligomere procyanidines) led to a significant rise in blood flow for several hours depending on the dose, the highest increase reaching an average value of about + 70% of the resting flow. In dogs regularly fed with this substance for a longer period of time, a rising tendency of the matutinal resting values of myocardial blood flow towards a maximum was seen. Intravenous application of oligomere procyanidines in anesthetized cats led to a dose-dependent increase in myocardial blood flow for several minutes and a slight decrease in arterial blood pressure.


Action of bencyclane-hydrogen-fumarate on the carbohydrate metabolism of bovine lens homogenates. 1-Benzyl-1-(3-dimethylaminopropoxy)cycloheptane (bencyclane-hydrogen-fumarate; Fludilat) in a concentration of 10-2 M effects an increase in the O2 consumption and the formation of CO2 in a 10% bovine lens homogenate. This effect is even increased if the glucose-substrate supply is raised from 25 mM to 37 mM. Investigations on the concentrations at ATP, ADP and AMP show that bencyclane is able to stabilize the physiologic distribution pattern of the three free adenine nucleotides. Further, the observed changes in the distribution pattern indicated that the fumaric acid rest of bencyclane may serve as a substrate for this reaction in the same way as fumarate.


Hypolipemic activity of clofibrate-related compounds. 2nd Communication. Clofibrate-related compounds were synthesized from substituted phenoxyacetic acids by esterification with salicylic acid derivatives, by amidation of thiazolidines or by reaction with cinnarizine. Lipid lowering effect was investigated in normolipemic and hyperlipemic rats. The long-term hyperlipemic model used permits differentiation of hypolipemic efficacy, i.e., from clofibrate or compounds of similar activity.


Pharmacokinetics and bioavailability of diltiazem (CRD-401) in dog. Pharmacokinetic behaviour of a new coronary vasodilator, the d-cis-isomer of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride (diltiazem, CRD-401), as well as the bioavailability study of the release controlled tablet Herbesser have been described by using the proposed specific assay method of unchanged diltiazem in plasma. Quantitive analysis after its oral administration evidenced that diltiazem was absorbed through the gastrointestinal tract in the intact form. In the kinetical experiment, where diltiazem was administered i.v., a rapid and large distribution of diltiazem into tissue compartment were suggested. In the bioavailability study, a comparison of plasma concentrations of diltiazem between the two different crystals and the micronized powder resulted in no difference in their bioavailability, when they were administered in the form of capsules. In the single and multiple administration of the release controlled tablet, a slow and continuous absorption of diltiazem was observed. Elimination rate after the multiple dose regimen was in good agreement with that in a single dose, thereby indicating no accumulation in the body.


[On the spasmolytic action of 3-butoxy-1-phenoxy-propanol-(2) (febuprol) on the biliary tract (author's transl)]. The spasmolytic activity of 3-butoxy-1-phenoxy-propanol-(2) (febuprol) on the biliary tract is demonstrated in two different experimental arrangements in anesthetized dogs. This effect on the spasm provoked by morphine or prostigmine is illustrated by measuring the alteration of pressure in the choledochal duct. The spasmolytic efficacy of febuprol is significant and indicates a favourable secondary therapeutic effect of this substance.


Pharmacological studies of o-chloro-alpha-[(tert.-butylamino)methyl]benzylalcohol hydrochloride (C-78), a new bronchodilator. III. Actions on the nervous systems and miscellaneous organs. Pharmacological effects of o-chloro-alpha-[(tert.-butylamino)methyl]benzylalcohol hydrochloride (C-78) on the nervous systems and miscellaneous organs were studied. 1. Through a low dosage of C-78 had little influence on the central nervous system, a high dosage of C-78 had a little slow-waving effect on the spontaneous EEG in rabbits, inhibitory action of the convulsion caused by pentetrazol or electroshock in mice and anti-pyrogenic action in rabbits. C-78 also dose-dependently inhibited the increase of motility caused by amphetamine in mice. 2. Only high concentrations of C78 had a local anesthetic action on the cornea and the skin of the back in guinea pigs. 3. C-78 significantly increased non-esterified fatty acids (NEFA) and glucose contents of blood in rabbits, but these actions were inhibited by propranolol. Another, high dosage of C-78 had anti-ulcer and anti-inflammatory action. From the results of the previous experiments and this study, it was concluded that C-78 is a new beta 2-receptor stimulating drug where beta 2-receptor selectivity is greater than that of isoproterenol, salbutamol and clorprenaline.


Potentiation of antitussive effect of codeine by some 1-dimethoxyphenyl-3-alkylaminobutanols in guinea pigs. Newly synthesized 1-(2',5'-dimethoxyphenyl)-1-n-butyl-3-diethylaminobutanol (compd. 4) and its analogs enhanced the antitussive effect of codeine and morphine as tested on the cough induced by mechanical stimulation of the trachea in guinea pigs. This effect was illustrated to be a potentiation on the Gaddum's diagram. The following parameters were affected little or to a small extent: 1. analgesic effect of codeine and morphine in guinea pigs and mice, 2. duration of anesthesia induced by hexobarbital in mice, 3. respiratory depression caused by codeine in guinea pigs, and 4. LD50 of codeine in guinea pigs and mice. Explorations of the mechanism of potentiating action suggested some peripheral mechanism, but the exact one remained to be elucidated.


Comparison of the anti-inflammatory activity of Commiphora mukul (an indigenous drug) with those of phenylbutazone and ibuprofen in experimental arthritis induced by mycobacterial adjuvant. In the present investigation a method of induction of experimental arthritis in animals was modified to provide a better model replica of human arthritis. Inflammatory syndrome, resembling rheumatoid arthritis in man, was induced in the right hock joint of albino rabbits by intra-articular injection of the killed mycobacterial adjuvant in liquid paraffin. Development of this arthritic syndrome was studied from a period of five months with and without drugs. Anti-inflammatory agents such as phenylbutazone, ibuprofen and fraction "A" of gum-guggual from Commiphora mukkul were administered orally at a daily dose of 100, 100 and 500 mg/kg, respectively, for a period of five months. All three drugs decreased the thickness of the joint swelling during the course of drug treatment. These results indicate the beneficial role of phenylbutazone, ibuprofen and fraction "A" of gum-guggul in experimental arthritis.


Anomalous Ullman additions with 2-chloronicotinic acid and pharmacological properties of isonixine, a new anti-inflammatory drug. An anomalous Ullman reaction with 2-chloronicotinic acid is described. The resulting product 2',6'-di-methyl-anilide of 2-pyridone-3-carboxylic acid (isonixine) presents very interesting pharmacological properties as a potential analgesic-anti-inflammatory agent. Chemical and pharmacological data are given.


Toxicological investigations of isonixine. The subacute and chronic toxicity of 2,6-xylidide of 2-pyridone-3-carboxylic acid (isonixine), a non-steroidal analgesic-anti-inflammatory agent, was investigated in male rabbits and in rats of both sexes, respectively, after oral administration. Isonixine was very well tolerated by the two species studied and only at the dose of 2000 mg/kg presented some mild toxic effects after 6 months of daily treatment. It is worthwhile to note that isonixine did not induce any gastro-intestinal lesion even after repeated oral administration for periods up to 6 months at 2000 mg/kg.


[Studies on toxicity and fertility of escin in the rat (author's transl)]. The DL50 of escin was determined after i.p. application. Juvenile male rats were treated with 2X5 mg/kg escin at age 32 days. After they had reached fertility, kidneys, testes and sperm were examined. The high dose of escin used did not affect fertility and a nephrotoxic activity could not be detected either.


[On the effect of iodine containing opaque media on erythrocyte acetylcholinesterase (author's transl)]. Clinical symptoms of side effects by iodinated opaque media are approximately similar to those caused by inhibition of acetylcholinesterase. The inhibition of acetylcholinesterase of human erythrocytes was tested with the following opaque media in vivo and in vitro: adipiodonmeglumine, meglumine-iothalamate and sodium-iothalamate. Apparently there is no connection between opaque media induced incompatibility and the inhibition of acetylcholinesterase because 1. by the time maximal inhibition is reached most of the renally excreted opaque media has been eliminated, and because 2. a fairly rapid reversibility of the inhibition follows. For patients with congenital variants of acetylcholinesterase it could be of clinical consequence under succinyldicholinanaesthesia.


Effects of 1,3-dimethyl-5-aminoadamantane hydrochloride (DMAA) on the stretch-induced reflex tension of flexor muscles and the excitability of the gamma-loop in decerebrate and spinal cats. The effects of 10 mg/kg i.v. 1,3-dimethyl-5-aminoadamantane hydrochloride (memantine, DMAA) on the stretch-induced reflex tension of flexor muscles extensor digitorum longus and tibialis anterior (EDL/TA) and on the excitability of the neurons relaying transmission in the gamma-loop have been investigated in decerebrate and spinal cats. DMAA essentially reduced the relfex excitability of flexors EDL/TA induced by fusimotor activity in the decerebrate preparation. The drug did not stimulate the reflex activity in acute spinal cats. In the concentration used, DMAA suppressed largely the transmission of the fusimotor reflex in the decerebrate as well as in the spinal preparation, although in spinal cats DMAA increased the average firing rate of muscle spindle primaries originating from EDL/TA muscles. The possible mechanism of action of the compound on dopaminergic and serotonergic systems as well as its basic effects on neuronal membranes is discussed.


[The action of 1-aminoadamantane. Comparative studies with isolated nerve endings and thrombocytes on the release of serotonin and dopamine]. Nerve endings isolated from rat brain accumulate exogenous serotonin and dopamine. Both biogenic amines are released from nerve endings as well by means of electrical stimulation with rectangular pulses of alternating polarity as by incubation with 5 X 10(-4) to 5 X 10(-5) M solutions of the adamantane derivatives 1-aminoadamantane hydrochloride (D 1) and 1-amino-3,5-dimethyladamantane hydrochloride (memantine, D 145). The electrically stimulated liberation is small but is significantly increased after simultaneous incubation of the nerve endings with subthreshold concentrations of 1-aminoadamantanes (5X10(-6) to 5X10(-5) M). The reuptake of released serotonin is noncompetitively inhibited by 1-aminoadamantanes. Also in blood platelets frequently used as model cells of the nerve endings the serotonin uptake is inhibited by small concentrations of D 145, 10(-5) to 2X10(-4) M. High concentrations of D 145- greater than 2X10(-3) M, induce the "release-reaction", the simultaneous liberation of serotonin, ATP, and ADP. In the concentration range of 2X10(-4) to 2X10(-3) M D 145 only serotonin is set free.