Effects of ergocryptine on prolactin secretion druing concurrent pregnancy and lactation in the rat.

Ergocryptine (2 mg/kg) caused short- and long-term reduction of prolactin secretion in rats experiencing concurrent lactation and pregnancy. The long-term effects of the drug lasted at least 60 days and resulted in reduced milk secretion and termination of pregnancy. Prolactin replacement therapy at a low dose (5 i.u./day) was unsuccessful in overcoming these effects but a higher dose (up to 60 i.u./day) increased milk production and maintained pregnancy. One possible explanation of these results is that prolactin, rather than the suckling stimulus, was responsible for the suppression of oestrous cycles, because ergocryptine brought about a resumption of oestrous vaginal smears in all treated rats in spite of continued suckling.


Human pulmonary pasteurellosis.

Pasteurella multocida causes hemorrhagic septicemia in many domestic and wild animals. The most common human infection with P multocida is a local cellulitis following animal-inflicted wounds, preponderantly cat bites and scractches. The typical clinical manifestations and complications have been well described previously. We present three cases of pulmonary pasteurellosis that were recently evaluated by the infectious diseases service at Barnes Hospital. In three additional cases, the technologists in the microbiology laboratory isolated P multocida from respiratory tract secretions.


[Tomodensitometry of the orbit. Possibilities of an approach to histopathological diagnosis (author's transl)].

The value of scanning lies above all in the determination of the site, size and shape of orbital lesions and, where applicable, their relations with neighbouring extra or intra cerebral structures. But certain conditions such as exophthalmos during hyperthyroïdosis have characteristic scan findings. Even intra-ocular tumors are visible on elarged scanfilms. It nevertheless remains difficult to attempt to predict a histological diagnosis on the only basis of scan findings. Particular emphasis must be placed upon the contribution of techniques of treatment of the films obtained (enlargement, contrast media, histograms, lateral views) as well as the complementary use of phlebography and ultrasonography.


[The diagnosis and therapy of endocrine ophthalmopathy (author's transl)].

Radio-iodide diagnosis of the thyroid is a simple method of high security in the diagnosis of endocrine ophthalmopathy. This procedure is valuable especially, in cases where neither clinically, nor in the sero-hormonal diagnosis a disturbance of the thyroid can be found. In many cases an accelerated intrathyroidal turnover of radio-iodide can identify an unclear ophthalmopathy as an endocrine ophthalmopathy. The therapy of choice for hyperthyreoidism with endocrine ophthalmopathy is 131-iodide resection. This statement has been proven by our own experiences in more than 1000 cases in the past 15 years and by the results indicated in early literature about the course of ophthalmopathy after surgical or medical treatment. For the therapy of a malign, or imminent malign endocrine ophthalmopathy, we use percutane irradiation of the orbit with sparing of the lens in a dose of 200 rad 5 times a week. In practically all cases, this therapy eliminates the consequence of visual disturbances and avoids surgical decompression.


Effects of preexercise feedings on endurance performance.

Eight male and female students were studied during exercise to exhaustion on a bicycle ergometer at 80 and 100% of Vo2max following the ingestion of water (W), 75 g of glucose (G) or a liquid meal (M) (10 g protein, 12.5 g fat, 15 g CHO). When compared to the endurance ride (80% Vo2max) in the W treatment, endurance performance time was reduced by 19%, (p less than .05) (53.2 to 43.2 min) as a result of the preexercise glucose feeding (Trial G). No difference in performance at 80% Vo2max was found between the W and M trials. The preexercise feedings had no effect on exercise time to exhaustion at 100% Vo2max. During the G and M trials at 80% Vo2max, most of the subjects demonstrated a transient decline in serum glucose (less than 3.5 mM). After 30-40 min. of exercise, however, serum glucose returned to normal and was seldom low at the time of exhaustion. Serum free fatty acids (FFA) were depressed throughout the G trial. The results of these experiments indicate impaired lipid mobilization following CHO ingestion. The present data support our earlier findings (11) which demonstrate that glucose feedings 30-45 minutes before endurance exercise increase the rate of CHO oxidation and impede the mobilization of FFA, thereby reducing exercise time to exhaustion.


Production of two recognins related to malignin: recognin M from mammary MCF-7 carcinoma cells and recognin L from lymphoma P3G cells.

From the first two non-brain cancer cell types examined, mammary cancer cells (MCF-7) and lymphoma cells (P3G), two new acidic polypeptides of approximately 10,000 M.W. each have been produced, called recognin M and recognin L, respectively. These are very closely related in amino acid composition and in immunological reactions to the first two cancer recognins, astrocytin from human gliomas in vivo and malignin from malignant glial cells grown in vivo. Together with earlier findings, these observations suggest that the cancer polypeptide recognins may be produced from members of a closely related family of substances characteristic of malignant cells.


Inhibition of surfactant production by insulin in fetal rabbit lung slices.

Incorporation of labeled glucose and fatty acid residues into saturated phosphatidylcholine was significantly reduced in lung slices from 27.5 days of gestation fetal rabbits during 90 min incubation in the presence of 100 microU/ml insulin. When 14C-glucose was used as substrate, incorporation into both phosphatidylcholine and saturated phosphatidylcholine was reduced by insulin. This occurred despite an increase in overall glucose utilization by the lung from 11.3 +/- 3.9 to 16.3 +/- 5.2 nmole/g tissue in the presence of insulin (P less than 0.05). A decrease in incorporation of fatty acid residues into saturated phosphatidylcholine was also observed when 14C-palmitate was used as substrate, from 102 +/- 4 to 90 +/- 5 nmole palmitate/g tissue (P less than 0.01). In the presence of insulin, there were significant reductions of both substrates appearing in lysophosphatidylcholine, a precursor of saturated phosphatidylcholine. There was no significant change in incorporation of glucose residues into glycogen or lactate under these conditions.


Inhibition of the activity of the respiratory and vasomotor centers by centrally administered 5-hydroxytryptamine in cats.

The influence of 5-hydroxytryptamine (5-HT) on the activity of the respiratory and vasomotor centers was studied by injecting 5-HT into the lateral and fourth ventricles of lightly anaesthetized cats. 50 and 500 mu g of 5-HT injected into the lateral ventricle induced a shortlasting increase in frequency and/or tidal volume followed by a prolonged and dose-dependent reduction of frequency, tidal volume and minute volume, concurrent with an increase in end expiratory CO2. The CO2 responsiveness of the respiratory center was depressed and the blood pressure levels were also lowered. All these effects were markedly enhanced by monoamine oxidase inhibition with i.v. tranylcypromine injected 75 min prior to 5-HT. 50 mu g of 5-HT injected into the fourth ventricle induced a depression of respiration similar to that observed in the lateral ventricle studies, with the exception that the early stimulation was abolished.


The effect of oral local anaesthetic and alkali on basal and food-stimulated serum gastrin levels in patients with duodenal ulcer.

Twelve patients with duodenal ulcers were each given on separate days and in random order an oral local anaesthetic (oxethazaine), an alkali (aluminium hydroxide and magnesium hydroxide), a combination of local anaesthetic and alkali (Mucaine), and a similar volume of water (control) followed one hour later by a solution of meat extract (Oxo). The effect of these treatments on serum gastrin levels was measured. None of the treatments altered the normal basal gastrin levels. The gastrin response to ingestion of protein extract was significantly lower in patients who had been pre-treated with local anaesthetic than those who had received alkali, with or without local anaesthetic, or water.


Inhibition of gastric acid secretion in dogs by a new sympathomimetic drug.

The effect of salmefamol, a new beta 2-agonist, on pentagastrin-induced gastric acid secretion was studied in conscious gastric fistula dogs. Salmefamol inhibited the acid secretion, an effect which was dose dependent. The volume as well as the acidity was inhibited. Salmefamol caused an increase in the pulse rate. Propranolol prevented the inhibition of acid output as well as the increase in pulse rate. Practolol, a beta 1-adrenoceptor blocker, had no effect on the inhibition of acid secretion but prevented the increase in pulse rate. Dose-response experiments with 6 doses of pentagastrin and 1 dose of salmefamol showed a decrease in calculated maximal response (CMR) and an unchanged D50. It is concluded that salmefamol strongly inhibits pentagastrin-induced acid output in the dog, and the inhibition follows a non-competitive kinetic. The mechanism of gastric secretion probably involves a beta 2-receptor.


On the central antiserotonin activity of benzoctamine and opipramol.

Benzoctamine inhibited the head twitch reaction induced by L-5-hydroxytryptophan (5-HTP) in mice and by 5-methoxytryptamine (5-MT) in rats pretreated with tranylcypromine. It also antagonized tryptamine (TRP)-induced clonic convulsions of forepaws in rats. Opipramol had no effect in the 5-MT test and appeared to be a weak antagonist in the 5-HTP and TRP tests. Both drugs, of which benzoctamine was a more potent antagonist, inhibited hyperthermia induced by LSD in rabbits. Benzoctamine abolished also LSD-or quipazine-induced stimulation of the flexor reflex in spinal rats; the above effect did not depend on noradrenolytic action of the drug. Opipramol was ineffective as an LSD or quipazine antagonist in this test. These results suggest that benzoctamine blocks the central postsynaptic serotonin receptors. This effect may contribute to the anxiolytic effect of the drug.


Machakos Project Studies: agents affecting health of mother and child in a rural area of Kenya. XII. Beliefs and practices concerning treatment of measles and acute diarrhoea among the Akamba.

This sociological investigation, carried out within the framework of a medical research project, aimed at finding out what mothers believe about measles and diarrhoea and what they do when their children contract these diseases. Perceived aetiological notions about measles and diarrhoea were found to influence beliefs held and this led to their being classified among 'God's diseases', a classification which influenced adherence to traditional practices as well as the acceptability to seek modern care. It was found that mothers used modern medical care exclusively in 50% of measles cases and 63% of diarrhoea cases. In 48% of measles cases and 28% of diarrhoea cases, mothers combined modern and indigenous care. Use of indigenous care only was relatively rare. Withholding of water and milk from children with measles was practice by 62% of the mothers in the total sample. Variables like age and education did not influence the type of medical care mothers selected, but did influence use of certain traditional practices. Younger and better educated mothers were found to follow these practices much less than older and less educated mothers.


[Therapy of malignant non-Hodgkin's lymphoma].

Up to now the results of the therapy of malignant non-Hodgkin lymphomas are not satisfactory. In order to improve these results decisively it is necessary to develop and to test therapeutic strategies on standardised diagnostic basis. On the basis of the histological classification after Kiel of the malignant non-Hodgkin lymphomas and the clinical stage subdivision of the lympho-granulomatosis after Rye (for the malignant non-Hodgkin lymphomas modified by Musshoff) in the present paper therapeutic recommendations are given which are based on proved therapeutic regimes.


[Induction of fetal lung-maturity. Part III: surfactant-parameters in amniotic-fluid and fetal lung].

In animal experiments we determined surfactant-specific parameters of premature fetal lungs and of samples of amniotic fluid taken fromthe same animal, and compared them with each other. These parameters were, among others: total phospholipids, lecithine and palmitic acid. In these experiments, 75 gravid Wistar rats were treated with NaCl (controls) or drugs in clinically relevant doses for stimulating the fetal synthesis of phospholipids like betamethasone, bromhexine metabolite VIII and D-L-carnitine hydrochloride. A relation between the amniotic fluid and the fetal lung with regard to the quantity of surfactant substances was found - with a security of 95% - with the controls only. The value of amniotic fluid analysis is discussed under this aspect.


A modified lecithin/sphingomyelin ratio test for fetal maturity.

Several desirable techniques (rapid chromatogram development, planimetry, acetone precipitation of lecithin, and copper molybdate staining) used in other published lecithin/sphingomyelin (L/S) ratio procedures were integrated into a single L/S ratio test. The resulting test requires only 2 ml of amniotic fluid, can be performed within 75 minutes, and is semiquantitative. Methodology tests showed a high degree of reproducibility without the need for a densitometer: Coefficients of variation for the standards and amniotic fluid samples were 11% and 4%, respectively. Also, a linear relationship was observed between the L/S weight ratios in synthetic mixtures and the corresponding area ratios up to the mature value of 2.5. Clinical evaluation on a normal and high-risk patient population showed excellent reliability: The accuracy in predicting fetal lung maturity and immaturity was 100% and 85%, respectively. Moreover, the numerical value of the L/S ratio in the immature range was found to be indicative of the severity of respiratory distress syndrome. Finally, the relationship between the L/S ratio and gestational age in a normal population was described mathematically by an approximating curve. We concluded from our methodologic and clinical data that the L/S ratio may be determined simply and reliably by means of the procedure described in this report.


The role of centrifugation in the measurement of surfactant in amniotic fluid.

Analysis of amniotic fluid fractions obtained by differential centrifugation has revealed the presence of intact globular-like structures of approximately 1 mu dimensions. These particles, which appear to be representative of fetal lung surfactant, begin precipitating at very low g forces and the extent of their removal by centrifugation was found to significantly alter L/S ratio measurements. This effect is particularly significant when moderate levels of these structures are present, which is usually between 34 and 37 weeks' gestation. False-negative L/S ratios could be attributed to this effect. Centrifugation can be employed to harvest these structures in reasonably pure form and measurement of their concentration, by phospholipid analysis, showed good correlation with fetal lung function in a trial study with 91 patients. These findings suggest that measurement of these surfactant particles harvested from amniotic fluid may provide a simple yet specific index of fetal pulmonary maturity.


An examination of the possibilities of preventive therapy in arteriolar retinopathies.

The identification of certain chronic vascular retinopathies has been marked by a search for their classification. Such proper classification has therapeutic implications. The similarities of these retinopathies are based on a shared pathogenic process, initiated by diminished arteriolar perfusion pressure, as the result of varied causes but leading to somewhat nonspecific capillary and reactive stages. On the basis of such a pathogenesis, various possible prophylactic and therapeutic measures and their organizational requirements are significant. These measures are directed to the correction of a blood perfusion pressure defect and to leaking capillaries and new vessels. Prophylactic and therapeutic exercises will be required for various chronic arteriolar capillaropathies, although the experience with one disease may be applicable to the others. Senile macular disciform degeneration provides the factors necessary for a therapeutic trial.


[Wolff-Parkinson-White during a basedowienne thyrotoxicose (author's transl)].

The case reported here consisted of an association of a Wolff-Parkinson-White syndrome (WPW) with thyrotoxicosis, with simultaneous recovery by thyroidectomy; this lead the authors to review 13 previous cases in the literature. The physiopathologic discussion emphasized several points: 1) the specific action of thyroid hormones, 2) the hypothesis of the possible existence of inapparent pathways of pre-exitation in most subjects and 3) a simple practical attitude to adopt in all Wolff-Parkinson-White cases especially when rapid.


[Pleuropericarditis: early systemic manifestation of an active chronic hepatitis (author's transl)].

A case of relapsing pleuropericarditis is reported in which no etiological factors were found initially, especially in relation to any possible collagen disease. A retrospective review of the clinical, biological, and histological findings, coupled with the nature of the progression of the disease, suggested to the authors that this was the first expression of a systemic disease which later developed signs of Gougerot-Sjögren's syndrome, Hashimoto's thyroiditis, and, three and a half years later, an active chronic hepatitis.


Absorption of lidocaine following subarachnoid and epidural administration.

The absorption of lidocaine into the vascular system from the epidural and subarachnoid spaces was determined in 20 patients. Seventy-five milligrams (1.5 ml of a 5% solution) of lidocaine was administered intrathecally to 10 patients for spinal anesthesia and 75 mg (3.75 ml of a 2% solution) was injected epidurally. Venous plasma levels of lidocaine were determined at 2, 5, 10, 15, and 30 minutes after subarachnoid or epidural injection. No significant differences existed between the maximum venous plasma concentrations of lidocaine following epidural injection (0.41 +/- 0.07 microgram/ml) and following subarachnoid injection (0.32 +/- 0.07 microgram/ml). However, the rate of vascular absorption of lidocaine from the subarachnoid space was significantly slower than from the epidural space. By 2, 5, and 10 minutes after injection, venous plasma concentrations of lidocaine were significantly higher following epidural injection than they were after subarachnoid injection. This variation was not attributable to differences in blood pressure folloiwng injection. The differential rate of absorption is probably related to the anatomical arrangement of the venous plexuses in the epidural and subarachnoid spaces.


Delayed hypocalcemia after thyroidectomy for Graves' disease is prevented by parathyroid autotransplantation.

Late hypocalcemia appears associated with thyroidectomy for Graves' disease more frequently than with thyroidectomy for other conditions. Of 62 total thyroidectomies done by a single surgeon, 28 were done for carcinoma, 18 for benign disease (primarily nontoxic nodules with a history of radiation therapy to the head and neck (RT)) and 16 for Graves' disease. Mean calcium concentrations measured two months or more after surgery were 9.38 +/- 0.07 (SEM)mg/% for patients with cancer, 8.79 +/- 0.31 mg/dl for patients with Graves' disease and 9.38 +/- 0.08 mg/dl for patients with other benign diseases. No patient without Graves' disease developed late hypocalcemia. In contrast, six of 16 patients with Graves' developed significant late hypocalcemia requiring calcium therapy. The incidence of hypocalcemia after total thyroidectomy for Graves' disease was significantly greater than that seen in other conditions (p < 0.01). Since no parathyroids were removed in the patients with Graves' disease, and since branches of the inferior thyroid artery were invariably ligated distal to the parathyroids, we hypothesized that the late hypocalcemia might be associated with a peculiarity in scar formation in the presence of this autoimmune disease. Accordingly, parathyroid autotransplantation was performed synchronously as a prophylactic measure in nine subsequent patients undergoing total thyroidectomy for Graves' disease; no instance of late hypocalcemia has occurred in this group. The decreased incidence of late hypocalcemia is highly significant (p < 0.01). Although the precise etiology of late hypocalcemia after thyroidectomy for Graves' disease remains undetermined, this experience indicates that synchronous parathyroid autotransplantation is beneficial in preventing this complication.


The basophil. Its morphology, biochemistry, motility, release reactions, recovery, and role in the inflammatory responses of IgE-mediated and cell-mediated origin.

The current state of our knowledge of basophils is reviewed. Much has recently been learned about these cells-their morphology, biochemical contents, interactions with homocytotropic antibodies, release of mediators in anaphylaxis, capacity for ingesting and releasing exogenous tracers, motility, participation in and progressive degranulation in cell-mediated hypersensitivity reactions, and their recovery from degranulation. It seems unlikely that basophils exist to destroy the organism by anaphylactic shock. Nonetheless, basophil function is probably closely related to the potent chemicals stored in their cytoplasmic granules. Perhaps small amounts of these chemicals are required for homeostasis and these cells function by releasing such substances as they are needed. This hypothesis requires that basophils be capable of releasing their contents slowly and piecemeal, which apparently occurs. This hypothesis also requires that physiological, rather than pharmacological, roles be found for histamine.


Midline malignant reticulosis and lymphomatoid granulomatosis. A case report.

A patient had lethal midline granuloma syndrome of the malignant midline reticulosis type. Lymphomatoid granulomatosis of the lung eventually developed that resulted in respiratory failure. There is a histology and biologic behavior associated with these two diseases, and they possibly represent different expressions of the same disease process.


Bromochlorophenol blue. A new stain for erythroblasts.

In erythroblasts of varying maturational stages, cytoplasm stained bright yellow with bromochlorophenol blue. Since this staining reaction appeared to be distinctive among various cytological types of marrow cells, it may constitute a rapid method for visualization of cells of erythroid origin.


Ultrastructure of hematoxylin bodies in systemic lupus erythematosus.

Two specimens, the first from a percutaneous renal biopsy and the second autopsy tissue of ovary, from two subjects with active systemic lupus erythematosus were found to contain many striking hematoxylin bodies in the walls of several small arteries. The specimens were reprocessed for electron microscopy; in one case, corresponding plastic embedded sections were also stained with hematoxylin-eosin and Feulgen stain. Hematoxylin bodies were easily identified on electron microscopy. They were found to be dense, homogeneous structures, approximately the size of a nucleus. They probably represent mainly altered nuclear material with occasional small chromatin remnants or minor cytoplasmic inclusions.


Retinal complications of gas myelography.

Bilateral retinal and preretinal hemorrhages with an acute and permanent partial loss of visual acuity developed in a 60-year-old man after an oxygen myelogram. In order to increase the contrast of the myelogram, a greater volume of oxygen was injected in the subarachnoid space than the volume of CSF that was removed. It is believed that the hemorrhages and visual loss were secondary to the sudden increase in CSF pressure caused by the excess volume of oxygen injected.


Dissociation constants of clonidine and structurally related imidazolidines.

The dissociation constants of clonidine and 27 structurally related imidazolidines have been determined by potentiometric titration of diluted aqueous solutions of the hydrochlorides with aqueous sodium hydroxide. Considerable differences in pKa' exist within this selection of congeneric substances. The pKa' is correlated with several electronic substituent parameters and the reaction constant has been calculated. The dissociation reaction of the present imidazolidine ions appears moderately sensitive to the electrical effects of the phenyl-attached substituents and is probably determined by one conformation of the molecules only. A major involvement can be attributed to inductive forces, whereas reasonance contribution seems of less importance, although it cannot be ignored. The dissociation constants are examined more closely with respect to their usefulness in biological systems. The influences of ionic strength and temperature on the dissociation of the compounds concerned are verified experimentally and compared with the values resulting from theoretical considerations. By making the corrections for ionic strength and temperature the acid/base equilibria as such present under physiological conditions have been calculated.


Chemotherapeutically active nitro-derivatives. 4. 5-Nitroimidazoles (Part IV).

16 novel 1-methyl-5-nitroimidazoles substituted at 2-position were examined for activity against various protozoa, in particular trichomonads in NMRI mice and amebae in golden hamsters. Six of the compounds proved to be superior to metronidazole and one superior to tinidazole against trichomonads. The compounds exhibited no marked effect against amebae and trypanosomes. The structure-activity relationships of the new compounds are discussed.


[Tumor-inhibiting agents. 8. 5-Aminomethylated barbituric acid derivatives].

In view of the tumor inhibitory activity of various pyrimidine derivatives, investigations aimed at the structure modification of barbituric acids were performed. In accordance with the aminomethinylation principle, barbituric acids (2) are converted into 5-formimidoylbarbituric acids (4) by s-triazine (1). Aside from the free barbituric acid (2a), both 1-substituted (2b,  d, and f) and 1,3-di-substituted (2c, e, and g) barbituric acids are amenable to this reaction. After introduction of the formimidoyl group into 5-position of the barbituric acid ring system, marked tumor inhibitory effects against lymphoma, lymphocytical leukemia, and luekemia L-1210, are ascertainable.


[A method for radio-immunological determination of g-strophanthin (author's transl)].

For the purpose of estimating g-strophanthin radio-immunologically the following steps are described: the preparation of g-strophanthin antigen, the production of antibodies in the rabbit, the presentation of calibration curves, and the possibility of a quantitative determination of heterogenous glycosides. According to Malaprades reaction, g-strophanthin adheres to human albumin. With this antigen thus obtained antibodies are produced in rabbits. For the presentation of calibration curves, the addition of antiserum and g-strophanthin have to be matched in quantity; the calibration curves correspond to mathematical data. An increased sensitivity of the method is possible to attain by reducing the amount of labelled antigen and antiserum. The slight cross-reactivity of antibodies can be used to determine other glycosides when these are incubated labelled with tritium instead of 3H-g-strophanthin.


[Methods for simultaneous recording of pharmacodynamic and toxic effects on interior sensitive receptors, respiration and cardiac-circulatory system of guinea pigs (author's transl)].

A method for simultaneous, continuous registration of pharmacodynamic and toxic effects, resp., on pulmonary-stretch receptors, on respiration and on hemodynamics in guinea pigs is described. The following parameters are recorded synchronously by a multi-track recorder: 1. The afferences in the cervical n. vagus; its electrical integration is employed for measuring the total intensity and the ex- and the inhalation intensity, resp., of the afferences; 2. the pneumatogram for measuring the maximum velocity of air flow, duration of the breath phase and parts thereof (in-, and exhalation and postexpiratory pause), and the respiration rate; 3. the diastolic and systolic blood pressure during in- and exhalation and postexpiratory pause; 4. the electrocardiogram (ECG). The normal distribution of the initial values is examined and discussed. Further the initial values measured in three series of experiments are discussed and compared: mono-vagotomy/spontaneous respiration, bivagotomy/spontaneous respiration and artificial respiration/monovagotomy. The results are compared with some experimental and clinical findings from literature.


Effects of creatinol-O-phosphate (COP) on haemodynamics and cardiac metabolism in conscious and anaesthetized dogs.

The effects of creatinol-O-phosphate (COP, Aplodan) have been studied on haemodynamics and cardiac metabolism of virtually normal heart (conscious dogs with electromagnetic probes chronically implanted) and progressively failing heart (open chest anaesthetized dogs). The results obtained show that COP in both series of experiments increased cardiac work and improved some myocardial metabolic parameters (delta redox potential across the heart, lactate/pyruvate ratio, excess lactate) probably by enhancing the myocardial O2 supply-consumption ratio, and consequently increasing the amount of O2 available for energetic reactions in the cardiac muscle and possibly in other tissues as well.


Hypolipidemic effects of S-methylmethionine (vitamin U) using various experimental procedures.

Hypolipidemic effects of S-methylmethionine (MMSC) were compared with clofibrate in 3 experimental procedures. In results, the characteristic effect of MMSC is discussed from therapeutic viewpoint.


Antagonistic effect of kallikrein against bradykinin.

The interaction of kallikrein with bradykinin, eledoisin and histamine was studied on the perfused hindquarters of the cat and isolated cat jejunum. The vasodilation induced by bradykinin, but not by eledoisin and histamine, was found to be inhibited by kallikrein. Kallikrein also inhibited the myotropic effect of bradykinin on the isolated cat jejunum. The possible mechanisms of the inhibitory action of kallikrein against bradykinin were discussed.


[Promoting and inhibitory influences of tribenoside and acetylsalicylic acid on spontaneous arthrosis in the mouse (author's transl)].

Tribenoside administered in moderate doses over periods of three or ten months, inhibited the development of spontaneous arthrosis in mice of the C 57 black strain. Acetylsalicylic acid administered once daily in oral doses of 50 and 150 mg/kg for five months, had a distinctly promoting effect on the development of the same arthrosis. Attention is drawn to certain common features in the activity spectra of the two drugs, but especially also to their opposite effects on mucopolysaccharide metabolism and on regenerative processes which are promoted by tribenoside but inhibited by acetylsalicylic acid.


The effect of acetylsalicylic acid/salicylic acid mixtures on acetylcholinesterase activity in vitro.

An attempt was made to inhibit acetylcholinesterase activity in homogenates of rat brain and in 2% solutions of hemolyzed human or rat erythrocytes, with concentrations of acetylsalicylic acid/salicylic acid (ASA/SA) equivalent to those evident in human plasma 0--2 h after ingestion of 0.65 g of ASA. None of the 5 different ASA/SA mixtures used produced inhibition in any of the enzyme preparations while the reference compound, eserine, inhibited all. These results suggest that ingestion of ASA, at least in recommended doses, should not significantly influence acetylcholinesterase activity in vivo.


Recent progress in teratology. A survey of methods for the study of drug actions during the preimplantation period.

To evaluate the effects of drug treatment during the first days of pregnancy new approaches have been developed which allow the study of teratogenic effects already before and around implantation, during organogenesis, and at term. The procedures used for the culture of preimplantation mouse embryos that were either pretreated in vivo or previously untreated and exposed to a toxic agent in vitro are presented in particular detail. In addition, an example is given which shows that it is possible to detect a DNA repair mechanism in preimplantation embryos maintained in vitro. The techniques of embryo transplantation and in vitro cultivation of embryos beyond implantation are outlined. The importance of the two methods in teratological research on embryos pretreated either in vivo or in vitro is discussed. Also presented are a survey of the literature and recent data obtained with rats and mice from our laboratory which prove that the action of drugs on the embryo and mother during the preimplantation period are more complex than is generally assumed.


The action of piracetam on the formation of ethanolamine-plasmalogen by neuronal microsomes of the developing rat brain.

In search of a common biochemical denominator of the action of the nootropic drug 2-oxo-pyrrolidine-1-acetamide (piracetam, Normabrain, Nootrop) the effects of the substance on the neuronal respiratory chain were investigated. The activity of the electron transport system of the respiratory chain was measured by the conversion of the ether to the enolether bond (plasmalogen) of ethanolamine containing glycerophosphatides. Piracetam enhances the formation of ethanolamine-plasmalogen from the corresponding ether lipid by neuronal microsomes and thus resembles the action of cytochrome b5. The addition of antibody against cytochrome b5 was able to inhibit the piracetam-dependent stimulation of the plasmalogen biosynthesis. Thus it appears that the stimulatory effect of piracetam on the formation of ethanolamine-plasmalogen is mediated by an increased synthesis or turnover of cytochrome b5.


[Estimation of pharmacokinetic constants in irregular repeated drug administration (author's transl)].

Least squares estimations for the fraction of the dose absorbed, volume of distribution, absorption and elimination rate based on drug measurements in blood and urine after aperiodical administration are described for a one-compartment model with first-order absorption. The non-linear regression analysis is carried out by means of a modified Gauss-Newton iteration procedure by Hartley. BASIC and FORTRAN functions are developed and applied in an example. The advantages of unbiased and consistent least-squares estimations in pharmacokinetics are pointed out.


[In vitro and in vivo investigations with different nitrofurantoin formulations (author's transl)].

In vitro dissolution tests and biopharmaceutical investigations on healthy test persons were carried out with 4 different galenic tablet formulations. Three of these formulations were prepared by a special galenic process, the fourth corresponded to the usual tablet formulations. It was shown that the dissolution behaviour of the formulations in vitro, in accordance with the specifications of the American Pharmacopoeia (USP XIX), does not correlate with the parameters found in vivo. However, if the formulations in vitro are checked with the Sartorius model according to Stricker, correlations can be found with the in vivo behaviour of nitrofurantoin. A linear relationship was achieved by the special galenic formulation directly regulating the pharmacokinetic behaviour of nitrofurantoin. The known biological scatter of nitrofurantoin was strongly reduced by this process. The amount of the substance still present and circulating in the body creating the side effects could be reduced to a minimum. All facts considered, the therapeutic safety is also ensured.


[Effect of sulfinpyrazone on enhanced platelet aggregation in vitro (author's transl)].

Adding sulfinpyrazone in a concentration of 500 and 250 microgram/ml to blood of patients with enhanced platelet stickiness a significant decrease (p less than 0.01) of the maximum amplitude and the aggregation velocity could be demonstrated with the spontaneous platelet aggregation test, PAT III, of Breddin, as well as with the collagen and the ristocetin induced aggregation. The lower concentration of 50 microgram/ml of sulfinpyrazone yielded the same results when aggregation was induced with the higher concentrations of 1.5 microgram/ml ristocetin and 5 microgram/ml collagen. Only the maximum aggregation velocity of the PAT III was significantly reduced after addition of 50 microgram sulfinpyrazone/ml blood. With sufficient concentrations of sulfinpyrazone the anti-aggregating action of this substance can very well be demonstrated with the aggregation induced by ristocetin or collagen and the PAT III. The effect is dose dependent.


[Therapy of sleeping disorders with l-tryptophane plus oxprenolol/a double-blind study (author's transl)].

38 psychiatric inpatients with various degrees of sleeping disorders were given L-tryptophane plus oxprenolol or placebo, each for two nights. Self-rating, rating of the nursing staff, tests of attention level and motor performance were the variables of the investigation. The statistical evaluation of the double-blind study shows no significant difference under these specific experimental conditions.


Vertigo, particularly of vascular origin, treated with flunarizine (R 14 950).

The antivertiginous properties of 1-[bis(p-fluorophenyl)-methyl]-4-cinnamylpiperazine (flunarizine, R 14 950) were evaluated in three consecutive studies -- two open and one double-blind -- in a total of 99 patients showing definite vertigo. Dosage was two tablets (= 20 mg) t.i.d. for three days in Study I (50 patients), 20 mg t.i.d. for two months in Study II (31 patients), and weekly decreasing doses of four, three, two and one (maintenance) tablets of flunarizine or placebo for three months in Study III (9/18 patients with vertigo of recent origin). Improvement of vertigo was significant both objectively and subjectively in Studies I and II. In Study III, objective tests were always clearly in favour of flunarizine, but subjectively, flunarizine was superior only by month two. Vertigo of vascular origin seemed to be a preferential indication for flunarizine treatment. No major side-effects were found in these studies.


[On the treatment of trichonocardiosis palmellina with econazol nitrate spray (author's transl)].

The effectiveness of econazol nitrate incorporated in spray was tested in trichonocardiosis palmellina. In all 5 cases an optimal therapeutic result was seen after a few days.


[The effect of acids on dianisyl-pyridyl- and dipyridyl-anisyl-methanoles (author's transl)].

Different dianisyl-pyridyl- and dipyridyl-anisyl-methanoles react with sulfuric acid, hydrogen iodide or formic acid. Depending on the position of the methoxy groups, pyridine nucleus and acid demethylation or reduction occurs and 10-aryl-pyridol[1,2-alpha]-indole or 9-pyridyl-xanthenole-9, respectively, are formed as main or byproduct. UV-, IR- and 1H-NMR-spectra of the pyridonindoles are discussed.


Physico-chemical properties of the active metabolites of the isoxazolylpenicillins as deduced from their chromatographic behaviour.

Reversed-phase chromatography of the active metabolites of the isoxazolylpenicillins revealed that the metabolites of oxacillin, cloxacillin, and dicloxacillin have the same fractional increase in hydrophilicity. The metabolite of flucloxacillin showed a much lesser decrease in lipid solubility. Regarding the relationship between the free-energy related hydrophobicity parameter pi and structure, it is concluded that the biotransformation of the isoxazolylpenicillins results in the same structural alteration of oxacillin, cloxacillin, and dicloxacillin. Flucloxacillin is handled differently by the drug metabolizing systems.


[The behaviour of codeine and codeine-6-glucuronide in hydrolysis with hydrochloric acid (author's transl)].

The behaviour of codeine and codeine-6-glucuronide with hydrochloric acid has been investigated. Three methods of hydrolysis were selected; they are often used in routine identification of drugs in urine. With method I (12--13% HCl; 30 min at 100 degrees C) about 53% of codeine-6-glucuronide were not hydrolized. The corresponding values: with method II (20% HCl; 6 min heated azeotrope in open vessel) about 8% and with method III (nearly 5% HCl; 30 min at 100 degrees C) about 83%.


Ganglionic action of some newly synthesized glutarimide compounds.

20 newly synthesized glutarimide compounds and their organic bases were investigated for their action on the autonomic ganglion in cats. Compounds 1 to 7 having piperidine moiety showed mainly ganglionic stimulant activity as evidenced by rise in blood pressure, contraction of nictitating membrane and rise in urinary bladder pressure of cats, which was completely blocked by C6 and partly by atropine. Compound 8 and 9 having diethylamine moiety showed initial stimulation--followed by blockade of the autonomic ganglia. Compounds 10 to 13 having morpholine moiety showed stimulation of both sympathetic and parasympathetic autonomic nervous system. The responses were due to effect partly on ganglia and partly on the receptors. Compounds 14 to 20, which have alkyl substitution chain at position 4 of beta-carbon atom, showed depressor action. The ganglionic activity of the glutarimide compounds in various groups was found to be in inverse ratio to the length of the alkyl side chain at position 4 of the beta-carbon atom.


Metabolic effects of clofibrate on experimental animals.

The effect of ethyl-alpha-(p-chlorophenoxy)-isobutyrate (clofibrate, Miscleron) on certain parameters of lipid and carbohydrate metabolism was studied in male and female white rats. The vitamin A content and the mixed function oxydase activity in the liver was also examined. 1. In short-term experiments over 10 to 30 days clofibrate significantly influenced the examined parameters. In a long-term experiment (9 months), however, these changes were no more observable. 2. Clofibrate exerted a protective effect against lipid mobilization following physical exercise (swimming). 3. No significant differences between male and female rats after clofibrate treatment could be observed.


[Acylaminoalkyl substituted benzoic and phenylalkane acids with hypoglycaemic properties (author's transl)].

Newly developed carbonic acids with hypoglycaemic properties are presented. Their activity is based on an insulin secretion with unusual biphasic dynamics which is seen both after enteral and parenteral administration. In vitro, the substances described have an inhibitory effect on gluconeogenesis in the liver and lipolysis in adipose tissue.


Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1 (H)-pyrazino(1,2-a) quinoline hydrochloride (compound 69/183). Part II: Effect on cardiac dynamics.

Effect of 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (centpyraquin, 69/183) on the cardiac function has been studied in situ in cat and dog and on isolated guinea pig heart. Centpyraquin (1.0 mg/kg i.v.) decreased cardiac output (20%) and total peripheral resistance (18%) along with blood pressure (40%). The decrease in dp/dt and PTI were secondary to hypotension. The contractility of the auricle as well as the ventricle was not decreased. In the heart-lung preparation of dog, centpyraquin (5 mg) had an inhibitory effect on the heart. The contractility of the isolated guinea pig heart was not changed up to 200 micrograms dose but higher doses had negative inotropic effect. The compound had no significant effect on ECG of cat. The effect of norepinephrine on dp/dt and PTI was potentiated. Isoproterenol induced hypotension was not changed but the cardiac effects were potentiated.


The pharmacology of clodanolene sodium, a new skeletal muscle contraction antagonist.

The pharmacology of hydrated 1 less than ([5-(3,4-dichlorophenyl)-2-furanyl]methylene) amino greater than-2,4,-imidazolidinedione sodium salt (clodanolene sodium), as skeletal-muscle contraction antagonist, is presented. Clodanolene sodium is remarkable in that it has no measurable direct effect on the peripheral or central nervous systmes. Skeletal muscle relaxation can be achieved with this drug at doses that do not affect motor coordination. Rats receiving clodanolene sodium for up to 30 days evidenced a downward trend in gross observation score of skeletal muscle relaxation, but the extent of twitch inhibition was the same on day 30 as on day 1. In an animal model of muscle spasticity (Straub-tail mouse), clodanolene sodium has been shown to be more efficacious for induction of skeletal muscle relaxation than neuromuscular blocking agents, local anesthetics, or centrally-acting muscle relaxants. Clodanolene sodium's mode of action has been identified as specific for skeletal muscle. It has no measurable effect on neuromuscular transmission or on the electrically excitable surface membrane. Indirect evidence indicates that the site of action of clodanolene sodium, like that of dantrolene sodium, is within the muscle cell and is related to caffeine-sensitive calcium stores. Its skeletal-muscle relaxant activity, we suggest results from a decrease in the release of calcium from the sarcoplasmic reticulum.


1,4-Dimorpholino-7-phenylpyrido[3,4-d]pyridazine (SD-511) as a new type of diuretic agent.

Diuretic features of 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) were studied in rats and mice. DS-511 was similar in diuretic effect to that of hydrochlorothiazide (HC) in both species, but was more water diuretic and less potassium-releasing than HC. After oral administration of DS-511 to rats the diuretic effect promptly appeared and lasted for 4 to 5 h. These patterns on onset and duration were similar to those of furosemide and acetazolamide (AZ). DS-511 was effective in experimentally induced acidotic and alkalotic rats. When DS-511 was used in combinations with other diuretics such as HC, AZ and triamterene at their maximum effective doses, urine volume and sodium excretion further increased, but potassium did not. Diuretic activity of DS-511 was not reduced by daily oral administration for 10 days to rats. In rats DS-511 reversed antidiuretic hormone (ADH)-induced antidiuresis. These findings suggest that DS-511 differs in mode and/or site of action from the known diuretics.


[Histochemical experiments on the action of clenbuterol on tracheal mucosa (author's transl)].

The effect of 4-amino-alpha-[(tert.-butylamino) methyl]-3,5-dichlorobenzyl alcohol hydrochloride (clenbuterol, Spiropent) on the tracheal mucosa was examined in 56 guinea pigs after i.p. administration during 5, 12 and 28 days, respectively. The alkaline phosphatases showed a minimum increase only in long-term tests. This increase concerned mainly the capillaries. It can be interpreted as a sign of enhanced transport processes. After administration of clenbuterol the total acid phosphatase in the mucosal epithelium rose. After a transient apical secretion of enzymes--together with consumption of enzymes at increased secretion--apparently more of new enzymes are produced. As a lysosomal enzyme the glucosaminidase showed also a similar reaction as did the acid phosphatase, while non-specific esterases increased only minimally or moderately. The effect of clenbuterol decreased the number of stainable goblet cells of the mucosa. It came to a secretory evacuation as a result of the secretolytic effect of the test substance in secretory evacuation. At the same time, the part of acid mucus components containing neuraminic acid rose so much that a qualitative change in the sense of the mucus components shifting in the direction to neuraminidasesensitive acid glycosaminoglycanes could be demonstrated.


Study of the antitumoral activity of S-carbamoyl-L-cysteine derivatives in animal experiments.

The antitumoral activity of three amino acid derivatives, S-carbamoyl-L-cysteine, S-ethyl-carbamoyl-L-cysteine, and S-chloroethyl-carbamoyl-L-cysteine, was studied. The ethyl and chloroethyl derivatives had a pronounced curative effect on certain animal tumors. It is interesting in the case of S-carbamoyl-L-cysteine that N-ethylization of the substance resulted in increased chemotherapeutic effectivity with no simultaneous change of the toxicity. According to various studies this effect is different in many respects from that of the known cytostatics, and a possibility of a specific selective or surface activity is raised.


The role of the responsiveness of animal stock to certain secretagogues in evaluating antisecretory drugs. Experiments in the lumen-perfused rat.

The gastric secretion pattern resulting from histamine, pentagastrin and carbachol infusion was studied in lumen-perfused anesthetised male Wistar rats. The differences between the results of this study and other published results and among the latter demonstrate the necessity of knowing the acid secretion patterns in given laboratory conditions before attempting to assess the antisecretory activity of any drug.


Influence of fasting period, ligation time, sex, age and bodyweight on the gastric secretory response of pylorus-ligated Wistar rats.

A study on variables influencing the gastric secretory response of pylorus-ligated Wistar rat, shows that: 1. 24 h is a sufficient fasting period for satisfactory emptying of the stomach, periods of up to 48 h yielding no advantage; 2. between 2 and 4 h is the most appropriate pyloric ligation time because in this range there are no variations in volume of gastric secretion, concentration and output of acid per unit of ligation time; 3. sex has no influence on any of the parameters; 4. animals should be age-selected because only above a given age threshold the gastric secretory response per unit of bodyweight is constant.


Rociverine, a new antispasmodic agent with balanced neurotropic and myotropic activity.

A systematic study in vitro and in vivo of the antispasmodic agent 2-(diethylamino)-1-methylethyl cis-1-hydroxy (bicyclohexyl)-2-carboxylate (rociverine) showed that its activity is both antimuscarinic and directly muscle-relaxant. The antimuscarinic activity is weaker than that of atropine, N-butylscopolammonium bromide and dicyclomine whilst the direct muscle-relaxant activity is equal to or greater than that of papaverine. The peculiarly balanced ratio of the neurotropic and myotropic components ensures that the antispasmodic effect is the outcome of both, without one prevailing over the other. This not only rules out major atropine-like side-effects but renders rociverine potentially effective on spasm of the different viscera, of particular interest in viscera in which there is only minor involvement of cholinergic structures. The muscle-relaxant activity of rociverine is achieved by inhibiting the availability of Ca2+ at contraction site and not through an antiphosphodiesterasic mechanism, which might explain the absence of muscle-relaxant effects on the smooth musculature of the blood vessels.


Correlation between the plasma concentration of free nicotinic acid and some of its pharmacological effects in the fasted rat after an oral dose of sorbinicate and of nicotinic acid.

D-Glucitol hexanicotinate (sorbinicate), when given orally to fasted rats, depresses the plasma free fatty acids (FFA) and triglycerides. The depression is about equal in intensity and duration to that induced by corresponding doses of nicotinic acid as such, but occurs in the presence of nicotinic acid plasma levels far lower than those obtained with nicotinic acid. In fact, sorbinicate is absorbed more slowly and more smoothly than is the case with nicotinic acid and the bioavailable nicotinic acid after oral sorbinicate administration is thought to be not more than 3--4% of the dose given. At the dose closest to that in clinical use sorbinicate exerts a more lasting effect than nicotinic acid both on FFA and on triglycerides, and at all the doses tested, contrary to nicotinic acid, sorbinicate did not induce plasma FFA rebound. This particular type of bioavailability, which differentiates sorbinicate from nicotinic acid, might explain the better effect on the plasma lipids as well as the absence of the side-effects that occur with nicotinic acid administration.


Polyvalent antiinflammatory activity of a polyanionic fraction of bovine pancreas. Potential value in the treatment of atherosclerosis.

A sulfomucopolysaccharide complex extracted from bovine pancreas displayed marked inhibitory activity against every one of a broad series of experimental inflammation models. No standard antiinflammatory drug has such all-inclusive action. The complex also exerts intense anticomplement activity in vitro. The potential antiatherosclerotic interest of this type of activity is suggested, in the light of recent hypotheses regarding the relevance of inflammatory and immune factors to the etiopathogenesis of atherosclerosis.


Syntheses and structure-activity relationships of 6-aryl-4H-s-triazolo[3,4-c]thieno[2,3-e] [1,4]diazepines.

A variety of 6-aryl-4H-s-triazolo[3,4-c]thieno-[2,3-e][1,4]diazepines was synthesized and tested for antipentylenetetrazole activity and inhibition of fighting episodes. The structure-activity relationships are discussed. Some compounds were more active than diazepam in the two assays. Among them, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine was found to have favourable properties as an anxiolytic drug with very low toxicity. Clinical studies of this compound (Y-7131) are under way.


3H-Cymarol in man. Excretion pathways and serum protein binding.

In 10 patients, 5 having received 3H-cymarol i.v., 5 orally, the radioactivity in plasma, urine and in the feces of some patients also was determined. After oral administration the plasma levels rose rapidly reaching maximum levels 1--2 h after administration. After i.v. injection about 30% of the given radioactivity were excreted in the urine. The remaining radioactivity was found in the feces suggesting a high biliary excretion. Only 10% of the radioactivity excreted in the first 24 h were chloroform-extractable. The radioactivity found in the urine after oral administration of the drug amounted to 17.6%. Between 51.1 and 58.5% of the drug were bound to serum proteins.


[Distribution and excretion of 14c-butylbiguanide in man (author's transl)].

Seven patients suffering from maturity on-set diabetes mellitus were given orally 100 mg of 14C-labelled butylbiguanide, specific activity 1.40 or 1.23 muCi/mg, resp. Three days before oral administration, two of the patients had received an i.v. injection of 50 mg butylbiguanide labelled with 120 muCi 14C. The radioactivity in the blood of the patients was followed up during the first 12-h period after administration of the drug. For determination of the radioactivity in the urine aliquots of three 24-h portions were measured. Furthermore, the radioactivity was checked of each individual sample of faeces for the first 72 h after administration. The radioactivity in the exhaled air was also measured. By comparison of the excretion after i.v. and oral application an absorption efficiency of 90% to 92% was calculated. Butylbiguanide is almost exclusively and fast excreted via the kidney. 86.5% of the i.v. administered material was eliminated within 24 h and 88.1% within 3 d in the urine of a person without kidney disease. Elimination through faeces was negligible, 0.2% in a person without kidney disease and 0.7% in a patient with renal insufficiency. The data obtained from the exhaled air show that there is only a negligible break-down of butylbiguanide, if any, to CO2 in man.


Domperidone, a novel and safe gastrokinetic anti-nauseant for the treatment of dyspepsia and vomiting.

The new potent anti-nauseant 5-chloro-1-(1p[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl)-1.3-dihydro-2H-benzimidazol-2-one (domperidone), which in contrast to available anti-emetics does not provoke extrapyramidal or adrenolytic adverse effects, also enhances gastric emptying motility. Controlled clinical trials have confirmed its prokinetic effects on the stomach and its lack of side-effects, even at high doses. This anti-nauseant appears to be a safe and effective treatment for patients, both adults and children, with dyspepsia or vomiting.


Effects of oral domperidone on gastric emptying and motility. A double-blind comparison with placebo and metoclopramide.

The effects of an oral treatment with domperidone on the gastric motor function were investigated in a double-blind study, including 129 patients, referred to the department of radiology for barium meal examination. None of them had an organic obstruction or had had previous gastrointestinal surgery. The patients received either domperidone (50, 20 or 10 mg), metoclopramide (20 mg) or a placebo. The medication was given 30 min before the intake of the barium meal in order to stimulate therapeutic conditions. During the barium meal examination, an assessment was made of the peristaltic activity of the antrum, the gastric emptying and the small bowel transit time. As to these parameters, 50 mg and 20 mg domperidone and 20 mg metoclopramide were significantly superior to the placebo.


[Indometacin glucosamide in the therapy of rheumatoid arthritis (author's transl)].

40 patients with classical or definite rheumatoid arthritis were included in a double blind trial to assess efficacy and side effects of indometacin (n = 20) versus glucametacin (n = 20). In a daily dose of 420 mg glucametacin proved to be equally potent to 150 mg indometacin daily in its anti-inflammatory activity but showed fewer side effects.


New 4-pyridonyl-acetamido-cephalosporins and related compounds.

A series of 4-pyridonyl-acetamido-cephalosporins of the following general formula and some compounds related to it have been prepared. Some new 4-pyridones and 4-pyridon-1-yl-acetic acids have been synthesized, and their conversion, by various methods, to give the compounds named in the title is described.


In vitro studies with cefazedone.

The minimum inhibitory concentrations of the new cephalosporin derivative (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,3]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) were tested in vitro against 358 bacterial strains. The antibacterial activity of cefazedone corresponds largely to that of cephalothin. Cefazedone is also active at a concentration of 16 micrograms/ml against 100% of enterococci, which can be classified as moderately effective, compared to cephalothin, which is completely ineffective. The MIC values from the dilution broth technique are in good correlation with the results determined by agar diffusion tests.


MIC determination, disc sensitivity testing, and analysis of regression in cefazedone and cefazolin.

Minimum inhibitory concentrations (MIC) of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl-a1-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen)), a new semisynthetic cephalosporin derivative were determined by a broth dilution technique. In comparison with cefazolin 130 gram-positive and gram-negative bacteria, recent clinical isolates, were tested. In parallel, inhibition zones for the same organisms were determined by a standardized disc technique using 30-micrograms discs. According to the calculated regression lines a good correlation was found for cefazedone and cefazolin between the MIC values and the diameters of the inhibition zones (correlation coefficients r = --0.90 and --0.92, respectively). Taking into account the dosages recommended for cefazedone and the mean serum concentrations to which they give rise, appropriate categories of sensitivity (break points) for susceptibility testing are recommended.


Blood levels and tissue concentrations of cefazedone in animals.

In mice, dogs, and rabbits blood and serum levels were evaluated after parenteral application of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), cephalothin and cefazolin. In all three animal species cefazedone produced higher and more prolonged serum levels than did cefazolin. Evaluation of serum protein binding in mouse, dog and rabbit serum revealed marked differences between the species. Cefazedone and cefazolin tissue concentrations were evaluated in rabbits. Both antibiotics did not penetrate the CSF or brain tissue. In all other tissues examined (except bone marrow) higher and more prolonged tissue levels were attained with cefazedone than with cefazolin.


Comparison of cefazedone with cefazolin and cephalothin in treatment of experimental infections in mice.

The chemotherapeutic efficacy of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) was assayed in comparison to cefazolin and cephalothin in experimental bacterial murine infections with 6 gram-positive and 8 gram-negative strains of the genera Staphylococcus, Streptococcus, Pneumococcus, Escherichia, Klebsiella, Proteus, Pasteurella and Salmonella. In 5 out of 14 strains (Staphylococci, Streptococci, E. coli, Klebsiella) cefazedone was markedly superior to cefazolin, whereas both compounds were of similar activity against the remaining 9 isolates. As compared to cephalothin, cefazedone exhibited highly superior effectiveness in all organisms tested.


Experimental investigations of the renal tolerance of cefazedone.

Renal tolerance tests in Wistar rats (n = 40) over 12 days showed that the tubulotoxic threshold dose of the cephalosporin antibiotic (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid acid (cefazedone, Refosporen) is 2000 mg/kg/day when the cell excretion rates in the urine are used as the parameter of toxicity. It is concluded that cefazedone and cefazolin are similar in respect of their nephrotoxicity.


Investigations on the action of cefazedone and gentamicin, alone and combined, on renal enzyme excretion in rats.

Administration of (6R, 7 R)-7-(2-[3,5-dichloro-4-oxo-1(4 H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) in a dose of 1000 mg/kg led to a statistically significant rise of the alkaline phosphatase activity in rat urine. The excretion of leucinaminopeptidase activity was not significantly affected. The enzyme activity in the animals' urine was raised by the administration of 100 mg/kg of gentamicin. Combined administration of the two antibiotics in the doses mentioned did not lead to any additive action. The established increases in activity were in the same range as after the administration of only one of the antibiotics.


Clinical pharmacology phase I of cefazedone, a new cephalosporin, in healthy volunteers. I. Tolerance in comparison with cefazolin.

In conjunction with pharmacokinetic investigations, the tolerance of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1 (4H)-pyridyl]-acetamido)-3-([(5-methyl-1,34-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), a new semisynthetic cephalosporin, was compared with that of cefazolin in two consecutive cross-over studies conducted on 10 healthy male volunteers each. The systemic tolerance of cefazedone after 1 X 500 mg and 1 X 1000 mg i.v., and 1 X 500 mg i.m. injections was very good and comparable with that of cefazolin. The same holds true for the local tolerance after i.v. administration. The local tolerance of i.m. administered cefazedone can also be classified as good when compared with that of cefazolin.


Clinical pharmacology phase I of cefazedone, a new cephalosporin, in healthy volunteers. II. Pharmacokinetics in comparison with cefazolin.

In two consecutive cross-over studies, each involving 10 healthy volunteers, the pharmacokinetics of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamindo)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) in comparison with cefazolin were investigated after single i.v. and i.m. administration. The doses were: i.v. cefazedone 500 mg and 1000 mg; cefazolin 1000 mg; i.m. cefazedone 500 mg, cefazolin 500 mg. The pharmacokinetic parameters were analysed by applying an open two-compartment model. The pharmacokinetics of cefazedone are nearly identical with those of cefazolin. In particular, it must be noted that cefazedone has a relatively long serum elimination half-life (1.64 +/- 0.23 h after i.v. and 1.85 +/- 0.51 h after i.m. administration) and that cefazedone exhibits, in comparison with cefazolin, a more favourable concentration ratio of central vs. peripheral (= tissue) compartment (1:2).


Investigations on the potential nephrotoxicity of cefazedone and gentamicin and of their combination, in comparison with the combination of cefazolin and cephalothin with gentamicin.

The nephrotoxicity of (6R,7R)-7-(2-[3,5-Dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), cephalothin, cefazolin and gentamicin was investigated by the determination of alanine-amino-peptidase (AAP) in urine of healthy volunteers. The results were compared with those obtained by application of the respective combination. The beta-lactam antibiotics showed no effect on the elimination of the characteristic tubule enzyme, while gentamicin, as is known, induced a marked increase of the enzyme elimination. The results with cefazedone + gentamicin show that the determining component on the extent of AAP elimination is the aminoglycoside exclusively, where high and low responders can be observed. When the experiments with gentamicin and with the combination gentamicin and cefazedone were carried out with the same volunteers, no additive effects could be observed.


Clinical study on the tolerance of cefazedone.

Tolerance of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) (3X1 g or 3X2 g/day; dosage interval 8 hours; duration of treatment 1 week) was examined in i.v. administration to 20 patients using numerous parameters. In 2 patients treatment was stopped sooner on account of the development of a morbilliform rash; a causal relation between this and the chemotherapy seemed probable in one case and possible in the other. 1 patient developed a transitory thrombocytosis without clinical symptoms, in 2 female patients yeasts were found in the mid-stream urine. Changes in the red or white blood count, in serum electrolytes, in bilirubin or increases in the activity of serum enzymes were not found. Indications of disturbances in renal function could be ruled out by examinations of endogenous creatinine clearance; repeat analyses of excretion of erythrocytes, nucleated cells and various urinary enzymes did not provide any indication of even slight renal lesions. Local tolerance of the substance was good.


Clinical evaluation of cefazedone.

The results of clinical trials with (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), a new cephalosporin derivative, are reported. Overall clinical assessment in a variety of indications, including urinary tract infections, respiratory tract infections, biliary tract and other abdominal infections, surgical and dermatological infections, gynaecological infections, on 699 patients showed very good and good results in 90.5% of patients. No difference in clinical effect was seen between twice daily and three times daily dosage. Local and general tolerance was very good. Changes in laboratory parameters attributable to the drug were infrequent and returned mostly from pathological to normal.


Investigations on group allergy reactions to cefazedone in patients with penicillin allergy of the anaphylactic type (type I) and of the delayed type (type IV).

Allergological investigations (scratch test, intracutaneous test, RAST test, patch test) on 19 patients displaying allergies of type I or IV, respectively, against penicillin G according to Coombs and Gell, in the skin test with (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) revealed in two cases group allergy against cefazedone. The studies demonstrate that group allergic reactions against cefazedone are quite possible in patients with primary allergy to penicillin derivatives or other beta-lactam antibiotics.


Potential antineoplastics. 4th communication: N-mustard derivatives of estrone).

The nitrogen mustards 5 and 9 are synthesized as potential mammatropic antineoplastic agents from estrone via 2--4 or 6--8, respectively. 5 and 9 show a binding affinity to the cytoplasmic estrogen receptor of the rat uterus of 1--10% compared to that of estrone. Both mustard compounds are irreversibly bound to the estrogen receptor.


Studies on some new thiosemicarbazones as potential antitubercular agents.

Twenty-one 4-aryl-3-thiosemicarbazides and their new vanillin-4-aryl-3-thiosemicarbazones have been prepared in good yield. Antitubercular activity of five of the vanillin-4-aryl-3-thiosemicarbazones was evaluated against mycobacterium tuberculosis strain H37 Ra in Löwenstein-Jensen medium. In addition to IR, biological activity and TLC studies for thiosemicarbazones were carried out.


Antiarrhythmic properties of carbocromen. Effects on depressed activity of sinoatrial and atrioventricular node.

1. In anaesthetized dogs and guinea pigs effects of carbocromen on the specific conduction system of the heart (SA- and AV-node) are demonstrated using a special experimental model. 2. Carbocromen stimulates and reestablishes to normal SA- and AV-node activity previously depressed by organic Ca2+-antagonistic drugs. 3. The results suggest an action of carbocromen on the "slow membrane currents" because it antagonizes negative effects of slow current inhibitors. There is no indication that the drug acts as an Ca2+-agonist. The basic mechanism of action is not clear, different possible effects are discussed. 4. Practical clinical consequences are reviewed: by improving a depressed AV-conduction carbocromen may prevent or interrupt different junctional re-entry arrhythmias.


The effect of diuretic drugs on lymph flow in experimental ascites.

The effect of several diuretic agents on thoracic duct and right lymph trunk lymph flow, and on some other parameters was examined in normal dogs and dogs with ascites produced by the constriction of inferior cava vein. In normal animals furosemide and etacrynic acid in diuretic doses did not influence thoracic duct lymph flow and reduced slightly arterial pressure and GFR (creatinine clearance). Hydrochlorothiazide increased slightly thoracic duct flow. Neither of the drugs had any significant influence on right trunk lymph flow. In dogs with ascites all drugs tested (furosemide, etacrynic acid and mercurophylline) reduced lymph flow in the thoracic duct but had no effect on the flow in the right trunk. The drugs reduced markedly arterial and inferior cava venous pressure. It is concluded that their effect on ascites is not based on enhanced lymphatic absorption and transport but mainly on the reduction of fluid and protein leakage from the liver sinusoids.


Studies on the effect of cyclophosphamide on Yoshida sarcoma ascites cells implanted into the colon wall of rats.

Yoshida ascites cells in doses of 10(3)X300, 500, 1500, and 3000 cells per animal were injected into the wall of the descending colon of 10 male Sprague-Dawley rats each. Doses of 10(3)X1500 cells and more per animal yielded a 100% rate of take-up of the graft. Whereas untreated control animals died medianly after 17 days, a single i.p. application of 70 mg/kg cyclophosphamide on days 8 or 10, respectively, after the tumor cell inoculation considerably prolonged the survival times. In both cases the median survival time amounted to more than 60 days. The application of the cytostatic drug 12 days after tumor cell implantation yielded only a slight increase in the median survival time (23 days). The introduction of this tumor model for screening new chemotherapeutics or combinations of chemotherapeutics to be used against colon tumors is discussed.


Teratogenic effect of cyclophosphamide and the preventive effects of pyrithinoldehydrochloride monohydrate.

Teratogenic effects were induced in outbred Swiss mice by treatment of 8-week-old pregnant females with one of five different doses (5, 10, 20, 30, 40 mg/kg b.w.) of cyclophosphamide. Because the 11.5th day of pregnancy was the most effective day to induce malformations in mice, animals treated on this day were used for prophylactic studies. A preliminary study had shown that 30 mg/kg b.w. cyclophosphamide was the ideal dose to produce 100% malformations on the 11.5th day of pregnancy. From day 7.5 to 9.5 all fetuses were resorbed with this dosage. Most malformations were induced with 20, 30 or 40 mg/kg b.w., whereas 5 and 10 mg/kg b.w. caused no alterations of the fetuses. The frequency distributions of the various induced malformations and combined malformations of a positive control group (30 mg/kg b.w. of cyclophosphamide on the 11.5th day of pregnancy) were compared to those found in groups receiving different doses of the prophylactic. This substance reduced significantly the rate of malformations; 1/160 LD50 pyrithinoldehydrochloride monohydrate administered 4 times prior to cyclophosphamide treatment was the most effective. However, a complete prevention of teratogenic effects could not be accomplished.


Pharmacokinetics and metabolism of i.m. injected polyenylphosphatidylcholine liposomes.

The pharmacokinetics of i.m. applied polyenylphosphatidylcholine liposomes has been investigated in rats with the aid of 3H- and 14C-labelled di-linoleoyl-sn-glycerophosphocholine. The experiments stated an efflux of polyenylphosphatidylcholine from muscle injection site with a half-life of 8.6 h. The analysis of remaining polyenylphosphatidylcholine at muscle injection site showed the great stability of this substance. After 24 h approximately 60% of remaining polyenylphosphatidylcholine are not disintegrated. Polyenylphosphatidylcholine was transported mainly to liver by high-density lipoproteins and other fractions with greater density. The rate constants were calculated. Approximately 50% of applied polyenylphosphatidylcholine were incorporated into liver as intact di-linoleoyl-sn-glycerophosphocholine. Hydrolyzed fatty acids form triglycerides and cholesterolesters whereas lyso-phosphatidylcholine is reesterified to phosphatidylcholine again.


[Expeimental studies in animals on a new lipid lowering compound: etiroxate hydrochloride (author's transl)].

D,L-alpha-Methyl-thyroxin-ethylester hydrochloride (etiroxate hydrochloride, CG 635, Skleronorm) has been proved to be highly effective in lowering serum lipids in rats. Even daily oral doses of 3.3 mumol etiroxate hydrochloride/kg (2.8 mg/kg) decrease serum cholesterol significantly in hypercholesterolemic rats. From a dose of 10 mg/kg upwards etiroxate hydrochloride also significantly reduces serum triglycerides. Etiroxate hydrochloride has much less effect on oxygen consumption, heart rate and heart weight of rats than have L-thyroxin and D-thyroxin, and its antigoitrogenic effect is also much slighter. As calculated from the ratio between relative effect on basal metabolism and relative effect on serum cholesterol, the relative therapeutic index of the compound is 10--35 in comparison to a relative therapeutic index of 1 for L-thyroxin and D-thyroxin.


The antithrombotic activity of viquidil, a cerebral vasodilator.

1-(6-Methoxy-4-quinolyl)-3-(3-vinyl-4-piperidyl)-1-propanone (viquidil, Desclidium) when administered parenterally was a potent inhibitor of thrombus formation in the microvasculature of the hamster cheek pouch. The drug was active at a minimum dose level of approximately 2.5 X 10(-4) mg/kg and appeared to be more potent than papaverine in the same test system. Papaverine was shown to be toxic at higher dose levels with intermittent vasodilatation and haemorrhage. Viquidil, however, appeared to be approximately twice as potent as papaverine and was apparently without toxic side-effects.


[Influence of 2-dimethylaminoethanol on the hepatotoxicity of paracetamol in rats and mice (author's transl)].

2-Dimethylaminoethanol (DMAE; 0.1--0.5 g/kg) significantly reduced the paracetamol-induced increments of serum-enzyme activities (GOT, GPT, SDH) in rats and mice. This hepatoprotective effect of DMAE depended on the applied dose in rats, but there was no complete protection following the highest dose. Paracetamol-induced depletion of hepatic glutathione (GSH) was not influenced by the simultaneous administration of DMAE in rats and mice. Metabolic disposition of paracetamol in the urine of rats showed an enhanced elimination of free paracetamol and the glucuronide in the DMAE-treated group, whereas the mercapturate excretion remained unchanged. Diminished p-hydroxylation of aniline in a 9000Xg supernatant of rat and mouse liver homogenates in the presence of DMAE indicated an inhibition of microsomal mixed-function oxidase activity, which is also involved in the metabolic activation of paracetamol.


Mice protection with 2,4-monofurfurylidene-tetra-O-methyl-sorbitol (MSF) against acute toxicity due to Amanita phalloides.

2,4-Monofurfurylidene-tetra-O-methyl-sorbitol (MSF), which protects rats against a number of hepatotoxins, also reduces the death rate in mice receiving a crude Amanita phalloides powder (APP) by i.p. route, this protective effect being dose- and time-dependent. MSF-pretreatment greatly reduces APP-induced liver damage and blood serum GOT and GPT increase. MSF antagonizes APP more effectively than do mercaptopropionylglycine (MPG) and silymarin. The results are briefly discussed.


A newly developed precise and sensitive radioimmunoassay for clonidine.

A new precise and sensitive radioimmunoassay for clonidine has been developed. Synthesis and analysis of the hapten (4-carboxy-clonidine; St 1984) as well as antibody production in rabbits are described in detail. At a final dilution of 1:1000 the resulting immune serum binds 50% of a tritiated clonidine standard containing 1 ng of clonidine. The detection limit of the presented radioimmunoassay for clonidine is 0.1 ng/ml. The coefficient of variation did not exceed 4.3% for any of 7 standard determinations with 5 replicates. There was no relevant cross-reactivity of inactive clonidine metabolites apart from 4-OH-clonidine. To avoid any errors from cross-reaction clonidine was selectively and quantitatively extracted into diethylether from unknown plasma samples. Following concentration of the extracts even such low concentrations as 20 pg of clonidine/ml plasma were detectable. With the radioimmunoassay applied in pharmacokinetic studies a maximal clonidine concentration in blood plasma of healthy human volunteers was determined to 0.6 ng/ml 1.5 h after oral administration of 150 micrograms.


Effects of dilazep (AS-05) on human blood platelet aggregation.

The effects of tetrahydro-1H-1,4-diazepine-1,4 (5H)-dipropanol-3,4,5-trimethoxybenzoate diester (dilazep) on platelet aggregation were studied by aggregometer-technique in vitro, using platelet-rich plasma obtained from healthy subjects. As agents for platelet aggregation, norepinephrine, at a concentration of 10 micrograms/ml, and ADP, at a concentration of 1 microgram/ml, were added. There was some inhibition when compared to controls with 200 micrograms/ml of dilazep, and complete inhibition on both norepinephrine and ADP-induced platelet aggregation with 500 micrograms/ml. The effects of dilazep on platelet aggregation before and after administration (75 mg) in vivo, using platelet-rich plasma obtained from healthy subjects, were studied in accordance with the screen filtration pressure method. In all cases the inhibitory tendency was first seen 30 min after administration. It reached a peak after 60--120 min and tended to return to the initial value after 180 min. The effects of dilazep (150 mg/day for 4 weeks) and verapamil hydrochloride (240 mg/day for 4 weeks) on platelet aggregation in vivo, using plasma obtained from sixteen patients with coronary insufficiency, were determined in each group before and after drug administration. A significant difference in the group receiving dilazep was found at tO = 3.2643 and  less than 0.01 in the Student's t-test (two dependent sample cases). In the experiments with verapamil hydrochloride there were no significant differences in the results before and after administration. However, there was a slight tendency towards a decrease of effects two weeks after administration.


[Binding of butocin to serum proteins (author's transl)].

The binding of N-[-5-(6-purinylthio)-valeryl]-glycin ethylester (butocin, PVG) to serum proteins and pure human albumin was studied using the method of equilibrium dialysis. Its binding to protein in sera diluted 1:1 of 10 patients with malignant disease averaged 48.4 +/- 7.07%. At the butocin concentration of 20 micrograms/ml an average of 36% of butocin were bound to pure albumin. Only a small portion was bound to globulin fractions. Measurements of the saturation curve showed butocin to be bound to albumin molecule by one binding centre with a microscopic association constant kappa = 1.7 . 10(3) mol/l.


Exocrine secretion of the pancreas and enzymes in the lymph after administration of a combination of courmarin and rutin sulphate.

The effect of Venalot, a combination of coumarin and rutin sulphate, on stimulated exocrine secretion of the pancreas and on changes of pancreatic enzymes in thoracic duct lymph was studied in 10 subjects with normal function of the pancreas. Venalot has no direct effect on the exocrine function of the pancreas. Following administration of the compound, the amylase and lipase activity in thoracic duct lymph increases temporarily, probably as a consequence of outflow from the interstitial liquid of the pancreas.


[Diuretic agents in urine extracts: clearance studies, tubular glucose absorption and blood pressure].

We previously described diuretic agents of human urine. The extracts cause a significant decrease in sodium and plasma albumin concentration in the medulla of the kidney. In the present study further investigations were performed to detect the site of action of these fractions. In the bio-assay of sodium depleted rats urine extracts of hydrated, healthy human volunteers cause a significant increase in water and sodium excretion. In a dose of 100 micrograms/kg b.w. the rise in water elimination exceeds that of sodium excretion. Compared with control the glomerular filtration rate (inulin clearance), the renal plasma flow (PAH-clearance), and the systemic blood pressure (Statham element) are not affected. There is no change in the tubular glucose absorption of glucose loaded rats. In contrast to the glucose induced increase of the renal water elimination the diuretic potency of the urine extracts is only modest. The data provide further evidence of the existence of a diuretic factor in human urine extracts. The results show that the diuretic activity is not caused by an enhanced glomerular filtration rate or by an augmented renal plasma flow. However, an effect on the renal medullary hemodynamics, that is not detected by the PAH-clearance, could play an important role.


[Dissolution rates and bioavailability of phenytoin preparations (author's transl)].

The dissolution rates of various commercially available oral phenytoin preparations were determined in vitro and compared with the in vivo data for the bioavailability obtained from volunteers in a subchronic study. There is a correlation between the described in vitro method and the classical parameters of a bioavailability study. There are significant differences between the preparations tested. It is shown that the results of the in vitro test give high information about the bioavailability of phenytoin even after chronic administration. Therefore a simple method for standardisation of phenytoin preparations for oral use is available in the field of quality control.


Treament of biguanide-induced lactic acidosis with dichloroacetate. 3 case histories.

The administration of dichloroacetate (DCA) in cases of biguanide-induced lactic acidosis (LA) improves pyruvate oxidation and therefore increases energy production from glucose. Preliminary results of treatment of LA in humans are reported. A continuous fall in pyruvate was observed in all 3 cases after administration of at least 20 g of DCA (4 g i.v. bolus, then continuously 12 g/h). In Case 1, in which no supplementary measures for controlling the acidosis were applied, the acidosis did not improve and the patient died. In Case 2, despite administration of tris-buffer and dialysis, pH-values could not be raised sufficiently. The production of hydrogen ions persisted and lactate continued to rise. This patient also died. Case 3 was admitted in the beginning stages of a phenformin-induced LA, and in this case therapy was successful. The decline in pyruvate was accompanied by a slow fall in lactate, and a further fall in pH was averted. The clinical condition of the patient improved markedly after i.v. administration of a total of 34 g of DCA.


[Double-blind study on the influence of difenoxin hydrochloride on intestinal passage time in healthy volunteers (author's transl)].

The effect on the intestinal passage of 3 X 1 mg difenoxin hydrochloride (Lyspafen) was tested in a randomised double-blind study; the trial included 10 healthy volunteers and lasted one week. The time until elimination of both the first and twentieth of the total of 30 applied radiopaque stool markers was measured. The total weekly weight and number of stools served as further test criteria. The treatment with difenoxin and that without placebo were compared with the standard treatment using placebo. The extensive statistical evaluation failed to reveal significant differences in the criteria observed.


Study of the antifungal capacity by means of the contact test.

The antifungal activity of econazole nitrate (Pevaryl) can be demonstrated by means of a new test -- called contact test -- developed by the authors. This method of assessing the fungicidal activity was tested in nine patients and found to be satisfactory.


[Voluntary description of drug effects as a method in clinical trials. Presented using the example of pentobarbital, promazine and their combination].

Free description of drug effects is suggested as a method in which subjects or patients describe spontaneously the effects of psychotropic drugs from their own experience with their own verbal concepts. The method is exposed in detail and examplified by examination of pentobarbitone, promazine and their combination (Norkotral). The results of the free description method have psychological as well as psychopharmacological plausibility. It is suggested to implement the method as a new means of clinical research in psychopharmacology.


A new easily accessible steric parameter for structure-activity relationships.

A simple steric parameter Sb is formulated on the basis of substituent branching. This parameter can be calculated for every conceivable substituent and gives an estimate of steric effects which is sufficient for most purposes in practical drug design. Sb may also be applied to quantitative structure-activity relationships.


Comparative study of the clinical effect of vincamine versus papaverine given parenterally in the acute phase of stroke.

The efficacy of the "oxygenator", vincamine was assessed in comparison to a classic vasodilator, papaverine, after parenteral administration during the first days of an acute thrombo-embolic stroke. All 263 patients admitted to this open trial had a thrombo-embolism of the A. carotis or one of its cerebral branches within the previous 24 h. Patients demonstrating minimal neurological deficit or requiring admission to an intensive care unit, or patients with a suspected hemorrhagic syndrome were excluded. Each patient received i.v. infusions (15 mg X 6) of 6 vials of vincamine per 24 h, or 6 vials of papaverine (40 mg X 6) per 24 h, occasionally in combination with acetylsalicylic acid (ASA), dipyridamol and hydrocortisone. An initial 3-h control was followed by regular surveillance for 5 days, paying special regard to consciousness and motricity. The administration of vincamine alone had a significantly more favourable effect than papaverine alone on consciousness (p less than 0.001). Furthermore, vincamine associated with other drugs was significantly superior (p less than 0.01) to papaverine given in association. A similar tendency was noted for motor recuperation after vincamine compared to papaverine (p less than 0.001). Vincamine and papaverine were well tolerated during the 5-days observation period, only one side effect after vincamine and four after papaverine being noted.


Chemical characterization of decomposition products of pyrazolidinedione-3,5 derivatives. Part 1: Identification of decomposition products and mechanism of degradation of 4-prenyl-1,2-diphenyl-3,5-pyrazolidine-dione in an aqueous solution.

From an aqueous solution of 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione sodium salt (Prenazone) subjected to accelerated ageing at 80 degrees C in anaerobic and in aerobic conditions the following decomposition products were isolated: N,N'-diphenylhydrazide-5-methyl-4-hexenoic acid,N,N'-diphenylhydrazide-2-carboxy-5-methyl-4-hexenoic acid, N,N'-diphenylhydrazide-2-carboxy-2-hydroxy-5-methyl-4-hexenoic acid, trans- and cis-azobenzene. The isolated compounds were identified by means of thin-layer chromatography, elemental analyses, UV, IR spectrophotometry and taking into consideration their chemical transformations. A decomposition mechanism of Prenazone Sodium in aqueous solutions maintained at 80 degrees C is proposed.


Physico-chemical and anlytical studies of penbutolol.

In the present paper physico-chemical and analytical studies on penbutolol sulfate (Hoe 893d) are reported. In addition to an interpretation of ultraviolet and fluorometric spectra, data are given regarding the dissociation constant, solubility, distribution, and protein binding. The substance and its major metabolte, as well as their glucuronides, are detectable by means of a selective fluormetric method. Moreover, mention is made of the results of a human pharmacokinetic study.


[Gas liquid chromatographic analysis for quantitative determination of mefruside and oxomefruside in blood plasma (author's transl)].

A specific and sensitive GLC-analytical method was developed for the determination of mefruside, its lactone and hydroxy acid metabolites in blood plasma. It requires the derivatization of the isolated compounds with dimethyl-formamide dimethylacetal and the quantization of the derivatives using a phosphorus nitrogen detector. The method has a sensitivity limit of 2 ng mefruside/ml, 10 ng lactone/ml and 10 ng hydroxy acid/ml, respectively, using 1 ml of blood plasma per assay. It was applied to the determination of plasma levels in a dog following a single oral dose of 10 mg mefruside/kg.


[Metabolism of antiparkinson drugs. An example of competitive hydroxylation].

The investigation of the metabolism of the antiparkinson drugs trihexyphenidyl (1), pridinol (2) and biperiden (3) revealed a graduate tendency for hydroxylation in the different structural elements: If alicyclic, saturated heterocyclic and aromatic ring systems are present in one compound like in 1, the alicyclic ring system is attacked predominately. The amount of metabolites with hydroxy-groups in the saturated heterocyclic ring is much lower, and no hydroxylation takes place in the aromatic ring. In drugs without alicyclic ring systems like 2 the saturated heterocyclus is attacked preferentially, but also some phenolic metabolites are formed. Consequently the following arrangement of falling hydroxylation-tendency can be established: Formula: see text. Probably this arrangement is of common validity and therefore a prediction on the hydroxylation-tendency of other compounds seems to be possible.


[Effect of piracetam on neuronal and synaptosomal phospholipase A2 activity].

In search of the biochemical mechanism of the action of 2-oxopyrrolidine-1-acetamide (piracetam, Normabrain, Nootrop) the influence of the encephalotropic substance on the hydrolysis of different glycerophosphatides by the neuronal and synaptosomal phospholipase A2 was investigated. Pure synaptosomes and neurons were prepared by a new method. The synaptosomal and neuronal phospholipase A2 plays an important role during the process of synaptic transmission. The administration of piracetam enhanced both the neuronal and synaptosomal phospholipase A2-activity by about 50%. The piracetam-induced stimulation of the enzyme activity was in the same order of magnitude for all substrates investigated. Thus piracetam stimulates the synaptic transmission. The stimulation of the phospholipase A2-activity by piracetam appears to be mediated by a neurotransmitter.


Derivatives of benzimidazole: vasodilator activity of 2-(p-chloro-alpha-hydroxybenzyl)-benzimidazole hydrochloride. Preliminary study.

The effects of 2-(p-chloro-alpha-hydroxybenzyl)-benzimidazole hydrochloride (HBBPC) have been studied in the rabbit and rat. Most of these studies were performed comparatively with reference vasodilators and papaverine. HBBPC vasodilator activity is nearly the same as that of papaverine in the isolated rabbit ear. The characteristic of the vasoactive action of HBBPC seems to reside in its duration. The mechanism of action of HBBPC seems of peripheral type, that is to say it acts on the vascular smooth muscle.


Pharmacokinetic approach to proglumide long-term activity.

In order to explain the long-term therapeutic activity of (+/-)-4-benzamide-N,-di-n-propylglutaramic acid (proglumide, Milid) a pharmacokinetic study was carried out in rats by three administration routes. As a result, experimental data could have been fitted to a tri- or tetra-exponential equation, with terminal half-life of about 24 h. Since human pharmacokinetics was found to be rather similar to that in rats, it can be extrapolated that steady state plasma level of drug during therapeutic dosage regimen should range around 60% of peak level of single administration.


Effects of glycyrrhetinic acid and its derivatives on delta 4-5 alpha- and 5 beta-reductase in rat liver.

The effect of glycyrrhetinic acid (GA) and its derivatives on delta 4-5 alpha- and 5 beta-reduction of cortisol, aldosterone and testosterone was investigated on rat liver preparations. In vitro studies demonstrated that GA and its derivatives inhibited 5 beta-reduction to a much greater extent than 5 alpha-reduction. When GA or glycyrrhizin (GL) were administered, 5 beta-reductase activity was significantly suppressed. On the contrary, 5 alpha-reductase was markedly increased though its meachnism remains to be clarified. In human beings 5 beta-reductase is quantitatively the major enzyme and plays an important role in the regulation of cortisol and aldosterone metabolism. Thus from the studies presented here, it can be presumed that the suppression of 5 beta-reductase activity by GA or GL administration may delay the clearance of corticosteroids and prolong the biological half-life of cortisol resulting in the synergism of these steroids and GA or GL.


Ontogenic drug studies in calves. I. Age dependent salicylate levels and metabolism.

Acetylsalicylic acid (ASA) was administered to 52 Friesian calves 1--60 days old by oral route in the field, 63.5 mg/kg body weight constantly between 9 and 10 a.m., i.e., 3--4 h after morning feeding. The animals were divided according to age into groups. Total salicylate levels, salicylic acid and salicyluric acid plasma levels were determined up to 6 h after administration. The older the animals, the lower were the total salicylate and salicylic acid levels and the higher the salicyluric acid levels. The age dependence is highly significant during the first two weeks of life. Glucuronides could not be detected in quantitatively measurable amounts.


The oncogenic effect of immunosuppressive (cytotoxic) agents in (NZB x NZW) mice. II. Emergence of tumors in young animals treated with azathioprine and ifosfamide, including a histologic assessment of the neoplasms.

The age of (NZB x NZW) mice treated with immunosuppressive agents has been associated with an increased incidence of neoplastic disease in certain experimental situations. In this study, azathioprine administered daily over a period of 7 to 8 months significantly increased the occurrence of malignancies in animals aged 6 to 12 weeks at the start of treatment. No such increase was observed for ifosfamide. The resulting lesions observed in azathioprine and ifosfamide treated hybrids were predominantly lymphomas (60 to 80%) and could be classified according to two histologic types: Type I and II. The lymphomas in the ifosfamide groups could not be distinguished histologically from those in the azathioprine groups.


Studies on regional inhibition of carbonic anhydrase by sulpiride in rat brain.

Sulpiride is an antipsychotic which possesses the free sulfonamide radical. From the viewpoint of this phenomenon, the in vitro inhibitory effect of sulpiride on carbonic anhydrase (CAH) was investigated. CAH inhibition was studied in eleven regions of the rat brain. The distribution of sulpiride was estimated on the basis of these findings.