[Studies on the analysis of nifedipine considering in particular transformation products formed by light exposition (author's transl)].

Under the influence of light (VIS and UV) on thin-layer plates and in liquid solutions, 1,4-dihydro-2,6-dimethyl-4-(0-nitro-phenyl)-pyridine-3,5-carboxylic acid dimethylester (nifedipine, Adalat) is converted to the nitroso compound 4-(2-'nitrosophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-pyridine. The article also describes TLC-, GLC-, UV-, IR- and MS-data of nifedipine, the nitroso and the nitro derivative.


Febantel, a new broad-spectrum anthelminthic.

N-(2-[2,3-Bis-(methoxycarbonyl)-guanidino]-5-(phenylthio)-phenyl)-2-methoxyacetamide (febantel, Rintal) is a new compound which is highly active against various species of nematodes and cestodes in mice, rats, dogs, sheep and cattle. In sheep and cattle a single oral dose of 5 mg/kg resulted in an almost complete elimination of larval and adult intestinal nematodes as well as Dictyocaulus. The compound was well tolerated by all animals tested.


[Histamine analogues with nicotine-like action. 11th communication: Structure-activity relationships among histamine analogues (author's transl)].

Structure-activity relationships between histamine and nicrotine are described. If alkyl groups are substituted on the primary amino group of the side chain in histamine the histamine-like action decreases stepwise. While N,N-diethylhistamine (I) clearly shows histamine-like activity, 4-(2-pyrrolidinoethyl)-imidazole (II), an analogue having a pyrrolidine ring in place of the diethylamino group, possesses, on the other hand, distinct nicotine-like properties. The ganglionic stimulation was investigated on the isolated ileum of the guinea-pig, as well as on the blood pressure of the narcotized rat. The nicotine-like effects remained as the imidazole ring was replaced with a pyridine or benzene ring. These results make it plausible to assume that the effect of nicotine-like acting substances is due to an angular conformation, corresponding to nicotine.


[Proliferation of L 929 mouse fibroblasts and their glycosaminoglycan synthesis in monolayer cultures after addition of penicillamine, azathioprine, gold thiopolypeptide, oxyphenbutazone and prednisolone (author's transl)].

L 929 mouse fibroblasts were cultured as monolayers. Proliferation and glycosaminoglycan content in cells and medium were measured, the different glycosaminoglycans fractionated. It was shown that logarithmic cell growth is followed by a stationary phase. Glycosaminoglycan synthesis started later than did cell growth and continued during stationary phase. The glycosaminoglycan pattern changed with the phase of proliferation. All mesenchyma-active substances reduced proliferation and glycosaminoglycan synthesis significantly when added in therapeutical concentrations. The fractionation of the glycosaminoglycans after addition of the exclusively suppressive substances revealed different effectivity on the different components. All substances were directly effective on the connective tissue forming cells as had been expected from clinical experience and former experiments.


Pharmacological findings on cetiedil.

The molecule of cetiedil (Stratène) has strong papaverine-like and weak atropine-like properties. It brings about peripheral vasodilation at doses which do not affect arterial blood pressure, heart beat and cardiac efficacy; this new drug increases the activity of beta-adrenergic stimulants. There may be different hypotheses to explain the therapeutic effect of cetiedil; beside its papaverinic and synergistic beta-stimulant properties, it increases the haemodynamic coefficient, plays a role in the process of membrane Ca++ exchange and inhibits phosphodiesterase and platelet aggregation.


[The effect of prazosin on the hemodynamics of the anesthetized dog].

Effect of prazosin (0.1 and 1.0 mg/kg b.w. i.v.) on the cardiovascular system was investigated in six anaesthetized Beagles (Na-pentobarbital 35 mg/kg i.p.) using the thermodilution and catheter methods. The following parameters were measured: a) mean arterial blood pressure, b) heart rate, c) total peripheral resistance, d) cardiac output, e) cardiac work, f) stroke volume and g) cardiac contractility. Results can be summarized as follows: 1. Prazosin in dose of 0.1 mg/kg i.v. caused a slight drop in arterial blood pressure; prazosin administered in dose of 1.0 mg/kg i.v. decreased blood pressure significantly. 2. Following doses of 0.1 and 1.0 mg/kg i.v. of prazosin, heart rate was significantly increased in each of six dogs. 3. When prazosin was given i.v. (0.1 and 1.0 mg/kg), an initial increase in cardiac output occurred. Later, a reduction in cardiac index below the control values could be observed. 4. The contractility parameters of the left ventricle--dp/dtmax and VCE--were increased after i.v. administration of 0.1 and 1.0 mg/kg b.w. of prazosin.


Nature of the antiadrenergic properties of an indolizine.

Inhibition by 2-ethyl-3-(4-y-di-n-butylaminopropoxybenzoyl)-indolizine hydrochloride (L 9394) and by propranolol of the positive chronotropic effect of isoproterenol on spontaneously beating rabbit right atria has been studied in vitro. Propranolol behaved like a typical competitive beta 1-adrenoceptor antagonist with a pA2 value of 8.33. L 9394 acted as a non-competitive inhibitor with a pD'2 value of about 4.98. Inhibition by L 9394 and phentolamine of the norepinephrine-induced contractions of isolated rat aortic strips has been studied likewise. Phentolamine inhibited the adrenergic alpha-adrenoceptor competitively with a pA2 value of 8.69 while L 9394 behaved like a dual inhibitor, with a competitive component (pA2 value of 6.35) and a non-competitive component (pD'2 value of about 4.72).


[On the circulation compatibility of doxycycline and rolitetracycline in conscious minipigs (author's transl)].

The effect of large doses of doxycycline (Vibravenös) and rolitetracycline on blood pressure, heart rate and ECG was investigated in 36 conscious minipigs. The antibiotics were infused into the v. tibialis at doses of 16, 24 and 32 mg/kg at injection periods of 4, 6 and 8 min. The dosage applied was about 10-20 times higher than the therapeutical single dose of doxycycline and about 4-8 times higher than the single dose of rolitetracycline. 16 mg doxycycline or rolitetracycline/kg resulted in a minor short-lasting increase of blood pressure and extension of the P-Q interval in the ECG. The definitely pathological P-Q value of 160 ms was not observed in any of the cases treated with doxycycline, whereas rotitetracycline led to clearly pathological P-Q values in 2/6 of the cases, and to AV block in 4/6 of the cases. Neither after doxycycline nor after rolitetracycline did the increased dose of 24 and 32 mg/kg result in an enhanced effect on circulation. However, both the blood pressure and the P-Q values following 32 mg rolitetracycline/kg significantly exceeded those following 32 mg doxycycline/kg. These trials suggest that with regard to circulatory tolerance there are no objections to increasing the usual therapeutical dose of intravenous doxycycline if the injection time is adequately extended.


[Studies on granulocytes from inflammatory peritoneal exudates of the rat (author's transl)].

By the help of an animal model, the exudation of neutrophils into the peritoneal cavity of the rat was studied. Exudates were provoked by a repeated challenge with sodium-caseinate. When compared after harvest of the exudates, the cells showed no differences in regard to the quantitative composition but there were definite ones of qualitative kind. By an antiinfectious drug therapy, phagocytosis and inactivation of staphylococcus aureus could be increased significantly, while the controls exhibited a decrease.


Toxicological and teratological studies of azanidazole.

A toxicological study of 4-[(E)-2-(1-methyl-5-nitro-1H-imidazol-2-yl)-ethenyl]-2-pyrimidinamine (azanidazole, Triclose), a new systemic antitrichomonas agent, was run in laboratory animals in order to evaluate its safety. Studies also covered the effects of azanidazole on reproduction in rats treated prior to mating, on fetal development in rabbits and rats, and on fetal survival and growth in rats treated with it during late pregnancy and lactation. The obtained data indicate that azanidazole was well tolerated when administered as a single dose or repeated daily doses for six months. Furthermore, no adverse reproductive effects and no evidence of teratogenic activity were observed in all of the tested animal species. Survival indices were not affected, and body weight of progeny was normal in all studies on reproduction and peri- and post-natal toxicity.


The effect of sympathicomimetics and anticholinergics on antigen-induced airway obstruction.

The prophylactic and therapeutic effects of a sympathicomimetic drug 1-(3,5-dihydroxy-phenyl)-2-([1-(4-hydroxy-benzyl)-ethyl]-amino)-ethanol-hydrobromide (fenoterol HBr, Berotec) and an anticholinergic drug (8r)-8-isorpopyl-3 alpha-[(+/-)-tropoyl-oxy]-1 alpha H,5 alpha H-tropanium-bromide (ipratropium bromide, Atrovent) were tested on a series of 13 boxer dogs, exposed to allergen challenge. The therapeutic and prophylactic influence showed to be similar for both substances. The effect on bronchoconstriction was not followed by a similar influence on arterial blood gas values. The administration of the two drugs during prolonged airway obstruction induced by a continuous exposure to allergen showed no influence on this kind of airway obstruction. Various mechanisms must be assumed in this prolonged airway obstruction when compared to acute obstruction after short exposure to allergen.


A new method for automatic registration of stereotyped behaviour in the rat.

A new and sensitive method for registering stereotyped behaviour in the bucco-oral region of the rat is described. These stereotypies, which can be induced by amphetamines and apomorphine, are regarded as an expression of the activation of dopaminergic receptors within the nigro-neostriatal pathway. The method is based on the fact that it is particularly easy in animals placed in restraining cages to induce stereotyped chewing, licking and gnawing movements which are received by special pick-ups in the head region of the animals and registered automatically and continuously via electro-mechanical transformers or by direct measurement of the change in the electrical resistance of the system. With this well-reproducible procedure it is possible to recognize and quantify the stereotypy-inducing effect of amphetamines and apomorphine and the influence of neuroleptic agents and tricyclic antidepressants on this effect. In comparison to previously described procedures, this method has the advantage of not being dependent on observation of the animals and of being highly suitable for the demostration of dose-effect and time-effect relationships.


Failure to detect dominant-lethal mutations and effects on reproductive capacity in mice exposed to dihydroergotoxine mesylate.

Triethylenemelamine (TEM), a known chemical mutagen, and dihydroergotoxine mesylate (DHETM, Hydergin), an ergot derivative, were tested for mutagenic effects by means of the dominant-lethal test in male mice and the total reproductive capacity test in female mice. In contrast to TEM, which proved to be strongly effective in these test systems, DHETM did not show any effect. It is concluded that this drug, at both subtoxic and pharmacologically active dose-levels, has no potential to affect spermatogenic and oogenic cells.


[Pharmacology of iotroxic acid, a new intravenous cholangiographic agent. II. Experimental animal study of side effects].

The general, neural and cardiovascular tolerance of iotroxic acid (Biliscopin) and its deleterious effect on membranes were investigated in comparison with iodipamic- (Biligrafin), ioglycamic- (Biligram, Bilivistan) und iodoxamic acids in different experimental models. Tolerance (DL50) of iotroxic acid after i.v. injection in the rat proved to be significantly better than that of all the reference substances. The difference was most apparent in animals which had previously been given histamine. Neural tolerance was found to be best after iotroxic acid and iodipamic acid and poorest after iodoxamic acid. In in vitro investigations the erythrocyte membranes were far less damaged by iodoxamic acid and iotroxic acid than by iodipamic acid. Iotroxic acid was also particularly well tolerated after intracisternal injection and after injection into the carotid artery of the rat. The effect of iotroxic acid on the cardiovascular system of the cat was distinctly weaker than that of ioglycamic acid and, when given in high doses, evidently also weaker than that after administration of iodoxamic acid. The excellent general tolerance of iotroxic acid can be explained by the fact that its deleterious effect on membranes is less than that of iodipamic acid and that its neurotoxicity is distinctly lower than that of iodoxamic acid.


[Effects of benzarone on the chloroform edema of the mouse and on the petechiae test in the guinea pig (author's transl)].

1. Chloroform edema. On the backskin of a mouse a wheal was produced by locally applied chloroform containing a fluid rich in protein. It was investigated whether a series of edema-protective drugs, i.e., drugs with anti-inflammatory effect, corticoids, and vascular-active drugs, could inhibit the development of the wheal edema. Only benzarone proved a statistically significant inhibition. The fact that other drugs proved less effective or not at all, could be based on the difference between the mechansim of the chloroform edema and that of other edema models. A reciprocal effect between benzarone and chloroform may be considered as well. 2. Petechiae test. A vitamin C-free nutrition over 3 weeks did not increase the "brittleness of capillaries" in the backskin of guinea pigs; whereas 50 mg benzarone/kg fed daily over a period of 3 weeks caused a significant decrease in the number of petechiae compared to that in the controls. This effect, most likely, was not due to an improved stability of the capillaries but was based on the reduced blood circulation of the skin.


[The influence of benzarone on the polidocanol and thiopental induced edemas in the hind-limb of the cat (author's transl)].

In chloralose-anesthetized cats, a hind-limb was perfused at constant flow and the vascular endothelium was made permeable for protein by intravascular injection of polidocanol and thiopental. Besides parameters of circulation and the transcapillary fluid exchange the contents of plasma protein and water were measured in skin and muscle tissue of the edematous hind-limb as well as in the contralateral untreated hind-limb. Benzarone, 2.5 mg/kg i.v., inhibited the development of the protein edemas when injected before the application of the edema producing substances. In polidocanol and thiopental-induced edemas--except for the thiopental-induced skin edema that was less marked even in the controls--benzarone had a significant effect.


[Pharmacokinetics and metabolism of 3H-synephrine (author's transl)].

The physiological disposition of 1-(4-hydroxyphenyl)-2-methylamino-ethanol-tartrate (synephrine, Sympatol) in man had not been investigated to date. Therefore, we studied pharmacokinetics and metabolism of tritiated synephrine in man. Following short i.v. infusion in six patients about 80% of the administered radioactivity was recovered in urine. Two-thirds of the urinary tritium activity consisted of the deaminated p-hydroxymandelic acid. 10% were excreted as unchanged synephrine only. Following oral ingestion in ten patients the total urinary radioactivity was quite comparable to the i.v. experiments. Therefore, complete enteric absorption has to be stated. The amount of unchanged synephrine amounted, however, only to 2.5% of the dose. The resulting bioavailability has to be calculated to 22% only. The pharmacokinetic parameters are quite comparable to the sympathomimetics similar in structure. The biological half-life was about 2 h. After oral ingestion absorption was fast, the peak concentrations were observed between 1 and 2 h after administration.


[Relative bioavailability of a vincamine retard formulation. Pharmacokinetic study in normal subjects (author's transl)].

The study was carried out in 6 healthy volunteers in cross-over design. The pharmacokinetic parameters were calculated after application of 60 mg vincamine base in comparison to a sustained release formulation (vincamine ratio-pharm 30 mg) on the basis of a GC method. Summarizing it can be stated that the sustained release formulation has a flatter profile and is therefore more adapted to clinical application. The extent of absorption expressed as AUC of the serum concentration-time curve, has three times the extent of the curve with the pure substance.


The pharmacokinetic profile of pyrazinobutazone in man.

The rate of absorption of phenylbutazone from pyrazinobutazone (Ranoroc/Carudol) capsules is distinctly lower than that from phenylbutazone capsules. The capsules are bioequivalent to an equimolar dose of Na-phenylbutazone in solution, as judged by both the area under the plasma level curves (AUC), and the sum of the unchanged phenylbutazone excreted in the urine. A single dose of 300 mg pyrazinobutazone produces maximum plasma levels of 35.2 +/- 1.1 micrograms/ml at 5.5 h after administration (+/- SEM, 70 kg bodyweight, N = 39). Two dosage schedules for long-term therapy were tested (2400 and 1500 mg/week). Both produced accumulation to saturation plasma levels within approximately three days. The concentration of phenylbutazone obtained with the lower dosage was about 110 micrograms/ml plasma. This corresponds with the recommendations for long-term therapy with phenylbutazone. With the higher dosage, the plasma levels were elevated by only 25%, however, the renal elimination of unchanged drug and the number of side-effects were remarkably increased. The recommended dosage scheme is specifically adapted to the pharmacokinetics of pyrazinobutazone.


[Studies on the diffusion rate of cefamandole in various human tissue (author's transl)].

The penetration activity of cefamandole into different human tissues was studied under experimental conditions. The authors obtained samples of corticalis, spongiosa, cutis, subcutis, fascia and muscle during surgery in 42 cases. Cefamandole was given i.v. by means of: 1. single injections of 40 mg/kg body weight. 2. multiple injections with an initial dose of 40 mg/kg body weight and reinjections of 20 mg/kg body weight after reaching half-life, 3. permanent infusions of 50 mg/kg body weight per hour during 70 min. The investigation is based upon 482 serum level and 330 tissue level determinations. In case of tissue levels the extra- and intravascular concentrations had to be separated so that the contamination of the investigated samples by blood could be quantified. This was done first by the usual way of measuring the hemoglobin concentration, and additionally by the dextran method which was used for control of the hemoglobin method for the first time. The cefamandole conentrations following single and multiple injection did not show any differences in all tissues studied. Distinctly higher concentrations were found after permanent infusions, though with a considerably higher total dose.


Oral contraceptives according to the normophasic principle.

A trial of a normophasic-principle oral contraceptive ethinylestradiol (Ovanon) is reported. In 130 women observed for a total of 1354 cycles, there were no pregnancies; good cycle control was attained; side-effects were rare, and there was a very high degree of acceptability.


Effect of cicloxilic acid on the liver damage produced by a choline-free, high-fat low-protein diet.

The effects of cis-2-hydroxy-2-phenylcyclohexanecarboxilic acid (cicloxilic acid) on the liver damage produced by a choline-free, high-fat low-protein diet (Handler's diet) were studied in rats. Treatment with cicloxilic acid significantly counteracted the increase in liver weight, hepatic lipids, serum transaminase and ornithine carbamoyl transferase activities, caused by the unbalanced and deficient diet. Histological examination of the liver showed a near-normal structure of the hepatic cells in the cicloxilic acid-treated animals. Other antihepatotoxic and choleretic drugs, with which cicloxilic acid was compared, showed either much less protective activity or none at all. Furthermore, while cicloxilic acid (which exhibits choleretic activity) did not alter the hepatic glycogen content, another choleretic drug, 1-phenyl-1-hydroxypentane (PC 1), caused marked depletion. It is concluded that the protective activity exerted by cicloxilic acid on the liver is separable from its choleretic activity.


Effects of cicloxilic acid on CCl4-induced liver injury.

The effects of cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) on the liver injury produced by carbon tetrachloride poisoning were studied in rats. It was found that oral treatment counteracts the CCl4-induced increase in liver weight, rise of liver triglycerides, fall of plasma triglycerides and rise of serum transaminase and ornithine carbamoyl transferase activities. Further, cicloxilic acid, when administered alone, altered none of the parameters studied. Cicloxilic acid was found to be more effective at the lowest doses than any of the other antihepatotoxic and choleretic drugs used. When cicloxilic acid was administered at the highest doses, the plasma triglyceride level of the intoxicated animals was not significantly different from that of the controls. To find out whether cicloxilic acid was effective in maintaining a normal lipoprotein secretion after CCl4 poisoning, experiments were carried out with Triton WR-1339. The results indicate that cicloxilic acid maintains the output of triglycerides from the liver to the plasma compartment at near-normal level in CCl4 poisoned rats. Possible mechanisms for the effects of cicloxilic acid on the CCl4-induced liver damage are discussed.


Hepatic microsomal mixed-function oxidase system in rats pretreated with cicloxilic acid.

In a study of the hepatic microsomal drug metabolising system in rats, pretreatment with cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) did not prolong pentobarbital sleeping time or decrease the cytochrome P 450 content of the liver microsomes. The drug interacted with the liver microsomes to yield a type II spectral change. Cicloxilic acid did not affect the metabolism of CCl4 in vivo, as judged by the covalent binding of 14C from 14CCl r to microsomal lipids, or delay the gastrointestinal absorption of CCl4, as judged by the concentration of free CCl4 in the liver. The protection afforded by cicloxilic acid against CCl4 liver damage is therefore due neither to inhibition of the metabolism nor to delayed absorption of the toxin.


Effects of cicloxilic acid on liver subcellular fractions triglyceride content in acute ethanol intoxication.

The action of cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) on the concentration of triglycerides in the subcellular compartments of the liver was investigated in acutely ethanol-intoxicated rats. Cicloxilic acid is able to significantly reduce the accumulation of neutral fats in the homogenate and in the cytosol and to shorten the steatosis regression time. The triglyceride content in total microsomes results slightly higher in the animals treated with cicloxilic acid than in those treated with ethanol only. The data are discussed in relation to the pathogenesis of ethanol fatty liver and to the possible mechanism of action of cicloxilic acid.


Influence of cicloxilic acid on energy production by hepatocyte mitochondria during acute ethanol intoxication.

Liver mitochondria from acute ethanol intoxicated rats show a highly significant uncoupling of oxidative phosphorylation. cis-2-Hydroxy-2-phenyl-cyclohexanecarboxylic acid (cicloxilic acid) early normalizes the P/O ratio and, therefore, the mitochondrial energy producing mechanisms. The significance of these phenomena and the possible role of cicloxilic acid on mitochondrial energy-production are discussed.


Influence of cicloxilic acid on the intracellular transport of 3H-palmitic acid during acute ethanol fatty liver.

cis-2-Hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) modifies the rat's hepatocyte intracellular movements of 3H-palmitic acid in the course of fatty liver by acute ethanol intoxication. It counteracts the impairment of radioactive lipid uptake due to ethanol treatment and promotes the early and complete release of the radioisotope inhibited by ethanol. The relevance of these results to the role of changes in the intracellular transport systems in the pathogenesis of ethanol steatosis is discussed. This and previous studies show that cicloxilic acid acts by stimulating the intracellular lipoprotein transport probably preventing by this mechanism the ethanol induced liver injury.


Effects of cicloxilic acid on secretory function of the liver. I. Effect on bile flow and on biliary secretion of bilirubin and glucuronic acid in anesthetised bileduct-cannulated rat.

Both in normal and experimentally jaundiced rats cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) induces a greater and longer lasting increase in bile flow and a greater increase in bilirubin and glucuronic acid secretion than do the choleretics sodium 2-(2-hydroxy-3n hexoxy-propoxy)-benzoate and dehydrocholic acid. The intense increase in bilirubin secretion is interpreted as the outcome of stimulation of the biliary secretion mechanisms whilst the effect on bile flow and on the biliary secretion of glucuronic acid are attributed to the kinetics of biliary secretion of cicloxilic acid.


Effects of cicloxilic acid on secretory function of the liver. II. Effect on biliary secretion of bile acids, cholesterol and lecithin in anesthetised bileduct-cannulated rat.

cis-2-Hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) increases the output of bile acids and decreases that of cholesterol both in normal and in sodium taurocholate-infused rats; the biliary output of lecithin remains unchanged in normal animals but is increased in taurocholate-treated animals. The increased output of bile acids is interpreted as true stimulation of the bile-forming function of the liver, an activity supposedly mediated by stimulation of the metabolism of cholesterol to bile acids, independent of the drug's hydrocholeretic properties. The changes in the relative molar concentrations of the three micelle-forming bile constituents, namely bile acids, cholesterol, and lecithin, induced by cicloxilic acid lead to an appreciable lowering of the lithogenic index, thus suggesting that the drug may have antilithogenic activity.


Effect of cicloxilic acid on the bile lipid composition in cholelithiasis.

5 patient with cholesterol gallstones were treated with cis-2-hydroxy-2-penyl-cyclohexanecarboxilic acid (cicloxilic acid) 240 mg daily for one year. Before treatment and after 1 month's, 3 months' and 1 year's treatment gallbladder bile was withdrawn by duodenal tube after i.v. cerulein stimulation. The bile was assayed for lipids and the lithogenic index was determined. The pool of bile acids was also determined and liver function tests performed. The results show a gradual lowering of the mean lithogenic index in the course of treatment. The blood chemistry values remained within strictly normal limits.


Stereochemistry of cis-2-hydroxy-2-phenyl-cyclohexanecarboxylic acid (cicloxilic acid).

The configuration of cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) was deduced by comparing its NMR and IR spectra with those of its diastereoisomer and of their respective analogs, the 1-hydroxy(bicyclohexyl)-2-carboxylic acids. The diastereoisomer was prepared by converting cicloxilic acid to the corresponding 2-chloro-2-phenyl-cyclohexanecarboxylic acid and subsequent hydrolysis of the latter with aqueous solvents in the presence of wet silver oxide, or by simple solvolysis. The pair of 1-hydroxy(bicyclohexyl)-2-carboxylic acid was prepared from the respective phenylic terms by catalytic hydrogenation. Comparison of the NMR spectra revealed the spatial arrangement of the -H and -COOH groups on the carbon-alpha atom and the study of the interaction between the substitutents -OH and -COOH by IR spectrography revealed the position of the -OH group with respect to the -COOH group, as a result of which the configuration and conformation of the compounds under study were established. Cicloxilic acid is thus represented by the steric formula 4.


[Beclobrate and eniclobrate hydrochloride, new diphenylmethane derivatives as agents for lowering cholesterol and triglyceride levels. Part I: Synthesis and consideration of structure-activity relationships (author's transl)].

Within the course of a research project for finding new lipid-lowering substances with better therapeutic indices than the standard agent in use, various diphenylmethane derivatives were synthesized and tested with respect to their activity and toxicity. On the basis of these results Sgd 24774 (beclobrate) and Sgd 33374 (eniclobrate-hydrochloride) were selected for further investigation and clinical studies.


Chemical characterization of decomposition products of pyrazolidinedione-3,5 derivatives. Part 2: Chemical transformations of 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (prenazone) and its main decomposition product N,N'-diphenylhydrazide-2-carboxy-5-methyl-4-hexenoic acid in sulphuric acid concentrated.

4-Prenyl-1,2-diphenyl-3,5-pyrazolidinedione (prenazone) in the medium of sulphuric acid concentrated (92-98%) undergoes an intramolecular rearrangement to 6',6'-dimethyl-4',5'-dihydropyrane-[2',3'-d]-1,2-diphenyl-3-pyrazolinone. The main decomposition product of prenazone, formed due to the hydrolytic process in the above conditions, undergoes changes according to two parallel reactions. First, it is hydrolyzed to prenylmalonic acid and hydrazobenzene which is subsequently transformed to benzidine. The second reaction proceeds via cyclization to form prenazone as well as 6',6-dimethyl-4',5'-dihydropyrane [2',3'-d]-1,2-diphenyl-3-pyrazolinone.


Substituted thiatriazoles as possible anticancer compounds.

Eight new 5-arylamino-1,2,3,4-thiatriazoles and seven known (whose activity has not yet been reported in the literature) were readily synthesised through oxidative cyclization of 4-aryl-3-thiosemicarbazides by nitrous acid. Out of the thiatriazoles tested for their anti cancer activity in vitro against "KB" cell by agar-plate culture method using HFS9 cell line, only two compounds showed inhibitory activity. In addition to UV, IR, and TLC studies an investigation of the low resolution mass spectra have been carried out.


Regional blood flow determination in rats by the microsphere method during i.v. infusion of vasodilating agents.

The present experiments were performed to gain information on changes in various organ flow rates during i.v. infusion of vasodilating substances. The microsphere method with the reference sample technique was used in rats to measure simultaneously different organ flow rates. The detection of the spheres (non-radioactive) was performed by macerating the tissues and counting samples under the microscope. As only one microsphere-infection per animal was performed, an untreated experimental group served as a control. The cardiac output was measured in a separate series. The effects of isoproterenol, pentoxifylline, bencyclane, acetylcholine, and dihydroergotoxine (mixture of 3 compounds, Hydergin) consisted of flow increases in several organs while the flow in others remained nearly unchanged. Only during the action of sodium nitroprusside the flow values were found decreased or remained unchanged. This substance led to decreased cardiac output, whereas that in the other groups was unchanged or raised. The experiments point to quantitatively different reactions on cardiac output distribution during application of the vasodilating substances tested.


Vasodilator activity of 2-(p-chloro-alpha-hydroxybenzyl)benzimidazole (HBBPC) on femoral vascular bed of the rabbit.

The effects of 2-(p-chloro-alpha-hydroxybenzyl) benzimidazole HCl (HBBPC) have been studied on the femoral peripheral resistance (i.v. route) and only femoral blood flow (local i.a. injection), in comparison with other vasodilators, i.e., sodium nitroprusside, dihydralazine and piribedil. The vasomotor activity of HBBPC, namely, decreased peripheral resistance and increased femoral blood flow, seems interesting because it begins after pressure has returned to normal. This substance is likely to induce a vasoconstriction in other areas (increased femoral blood flow with decreased peripheral resistance without a fall of blood pressure).


[Bioavailability and elimination of various digoxin preparations in the beagle dog and their possible sex dependence (author's transl)].

The glycoside serum levels were investigated in two healthy male and two healthy female Beagles after oral administration of four different galenic preparations of digoxin. Serum samples were taken at defined intervals and examined by radioimmunology for their glycoside content. Female Beagles eliminated orally administered digoxin considerably more rapidly than did male animals as observed by the disappearance rates of glycoside from the serum. Sex-linked differences in the bioavailability of different galenic preparations of digoxin were not confirmed statistically in this trial. No differences between sexes regarding maximum serum levels were detectable with similar preparations. These results suggest that the serum elimination rate of digoxin is different in male and female Beagles. Possible causes for these findings are discussed.


On the influence of pentoxifylline on the permeability of rat erythrocytes for methyl-O-glucose.

In a series of experiments it was established that in the presence of pentoxifylline (Trental), methyl-O-glucose permeates rat erythrocyte membrane significantly more than in untreated control experiments. Pentoxifylline itself, apparently does not permeate erythrocyte membrane. It is possible that some of the therapeutic effects of pentoxifylline can be related to the facilitation of red blood cell membrane permeability for glucose.


Investigation of rociverine + dipyrone for antispasmodic and analgesic interactions.

The study was designed to elicit any interference on the part of dipyrone with the antispasmodic activity of 2-(diethylamino)-1-methylethyl cis-1-hydroxy(bicyclohexyl)-2-carboxylate (rociverine) and on the part of rociverine with the analgesic activity of dipyrone. No evidence of any reciprocal inhibition of the specific pharmacodynamic activities of the two drugs emerged. Further, dipyrone exerted remarkable antispasmodic effect which in some experimental conditions supplements that of rociverine. The nature of this antispasmodic effect contributed by dipyrone could not be identified from the in vivo work, though in in vitro tests dipyrone revealed appreciable antihistaminic activity and weak muscle-relaxant activity. The value of an association in which neither activity is diminished and one is actually augmented is obvious.


Action of some non-steroid anti-inflammatory drugs on skin anaphylaxis due to ovalbumin in the rat and the guinea pig.

Six non-steroidal anti-inflammatory drugs, metiazinic and niflumic acids, iburofen, indometacin, ketoprofen and phenylbutazone, were tested on two anaphylactic skin reactions to ovalbumin: the passive reaction in the rat and active anaphylaxis in the guinea pig. In the rat, only niflumic and metiazinic acids reduced very slightly the reaction. In the guinea pig, ibuprofen, phenylbutazone, metiazinic acid and ketoprofen had good activity. The results are discussed.


[Effect of a water-soluble derivative of silymarin on morphological and functional alterations of mouse hepatocytes induced by Frog Virus 3 (author's transl)].

Pretreatment of mice with silymarin dihemisuccinate sodium salt (SHS-Na) 300 mg/kg 24 and 16 h before infection completely protected against the lethal effect of Frog Virus 3 (FV3). After the inoculation of 1 LD100 of virus it could be shown that: a) the same amount of radioactively labelled virus was found in the liver of control and SHS-Na treated animals, b) in SHS-Na pretreated animals the shut-off of macromolecular syntheses in the liver was considerably less extensive, c) the histological changes in the hepatocyte nuclei were attenuated in SHS-Na pretreated animals and the serum titer of the transaminases did no increase, d) in SHS-Na pretreated mice there were only limited functional alterations of the sinusoidal cells as studied by carbon phagocytosis and the serum titer of the lysosomal enzymes was only slightly modified, e) inhibition of protein synthesis during the period of pretreatment with SHS-Na did not decrease the level of protection. These results allow us to conclude that SHS-Na exerts its protective effect on the liver and that sinusoidal cells are most likely involved in this protection.


The influence of silybin from Silybum marianum (L.) Gaertn. on in vitro phosphatidyl choline biosynthesis in rat livers.

In rat livers, removed 60 min after i.p. application of 150.6 mg/kg silybin-dihemisuccinate-di-Na-salt, in vitro incorporation of choline-(methyl-14C) into phosphatidyl choline by the postmitochondrial fraction of liver homogenates was enhanced in comparison with controls. These results are associated with increased activities of CTP-choline-phosphate cytidyltransferase. Enzyme activities were also enhanced after addition of 7.5 x 10(-6) mol/l silybin to incubation mixtures obtained from untreated rats.


[Study on the effects of bromopride on intestinal peristalsis (author's transl)].

The effect of 4-amino-5-bromo-N-[2-(diethylamino)-ethyl]-2-methoxy benzamide (bromopride, Viaben) on the intestinal motility was studied in dogs. Highly sensitive transducers were implanted on the intestinal serosa, allowing to measure both electrical and mechanical impulses at the same point from the small intestine. These studies were performed in 5 dogs to which bromopride was administered in i.v. or i.m. doses of 10, 20 and 30 mg. The results of the studies were as follows: 1. Bromopride causes an increase in both the number and amplitude of the spikes; at the same time there is a significant increase in the number and amplitude of the intestinal contractions. 2. The average duration of the cycle of the myoelectric complex does not change. This indicates that bromopride has no effect on the normal cycle of motoric activity in the intestine. 3. Bromopride seems more effective in the fasted state than in the post-prandial phase. 4. The effect of i.v. infection is greater than that of i.m. injection and begins earlier.


[Intravenous administration of insulin and tolbutamide. A mathematical simulation on the different glycolytic activity in the organism (author's transl)].

A system theoretical model is developed for the different effects on the glucose metabolism after i.v. insulin injection and after the release of endogenous insulin release induced by sulfonylurea derivates. The model is based on our clinical results on the change of blood glucose and blood lactate levels after application of insulin or tolbutamide, resp.: Concerning the blood glucose depressing effects equivalent concentrations of insulin and tolbutamide cause an increase of lactate and pyruvate to different extents in healthy subjects. Possible reasons for this behaviour could be additional insulin-independent effects of tolbutamide on the glucose metabolism. The mathematical simulation of glycolysis stimulation as dynamical system with 6 variables and 14 parameters can demonstrate that a different insulin distribution in the blood circulation is sufficient to explain the different glycolytic activities. Simply the different paths of insulin entrance--either evenly distributed in the blood or directly at liver entry--may cause the different increases of lactate levels. The calculations of the time courses between 0 and 60 min after injection are in close agreement with experimental findings.


Cardiomechanical effect of k-strophanthoside administered to healthy volunteers by the rectal route.

Eight healthy volunteers were given k-strophanthoside (Strofopan) 1 mg rectally in order to evaluate changes in the cardiac function. Cardiomechanical measurements were performed by the polygraphic method before administering the drug and 1, 2, 3, 4, 5 and 6 h later. Three of the eight subjects continued to receive k-strophanthoside 1 mg daily for a further 6 days. Similar evaluations were made at the same times on day 3 and on day 7 of treatment. All indices considered varied to a statistically significant extent and showed the maximum effect at about the 4th h. The most evident changes were observed in the ICT and the PEP/LVET ratio. Here, the maximum variations were 46.3% and 29.5%, respectively, as compared with baseline values (P less than 0.01). When treatment was given for 7 days, the baseline values measured on day 3 and day 7 before administration showed a moderate and constant decrease in all parameters as compared with the first baseline value. This proves that k-strophanthoside administered rectally possesses steady-state activity with time. From a comparison of the changes in the same parameters as observed in a previous investigation after administering digoxin 0.50 mg orally there is reason to conclude that the effects obtained after administering k-strophanthoside 1 mg rectally were of the same magnitude.


Suppression of catecholamine excretion by low doses of clonidine in healthy subjects and feasibility study on clonidine application in angina pectoris.

The effect of low doses of clonidine (CL) (150 microgram/day p.o.) on catecholamine (CA) excretion, blood pressure (BP) and heart rate (HR) was investigated in a double-blind way on 9 healthy volunteers. CL administration for two consecutive days led to marked diminution of urinary CA, mainly of epinephrine, with only slight decrease in systolic BP and HR. The results show that this dose of CL is effective in suppressing adrenergic tone as reflected by the magnitude of CA excretion, without marked influence upon systemic BP. Subsequently, the same dose of the drug was administered for two weeks to 30 unselected patients with intractable angina known to be often associated with adrenergic overactivity. Clinical improvement manifested by complete disappearance of coronary pains or marked decrease in the incidence of anginal attacks was achieved in the majority (over 60%) of patients. Although best results were seen in patients with borderline hypertension, the drug was also effective in normotensive patients and no untoward hypotensive symptoms were noted throughout the trial. Blood CA and free fatty acids (FFA) measurements performed in 5 patients showed that favourable clinical effect of CL therapy coincides with lowering of CA and FFA levels. This study indicates that CL administered in a dose which does suppress adrenergic activity might be of value in the treatment of coronary patients. Favourable results of this preliminary trial incline to undertake well controlled clinical study.


[Interaction between naproxen and tolbutamide on metabolism in diabetics].

In a double blind study 16 maturity onset diabetics were treated with d-2-(6-methoxy-2-naphthyl)-propionic acid (naproxen) and tolbutamide with a view to possible interactions between both drugs. There were no significant differences between blood glucose levels after placebo and naproxen, respectively. The concentrations of tolbutamide were not significantly different, either. Thus diabetics on tolbutamide can be treated additionally with naproxen without any clinical side effect on carbohydrate metabolism.


Cicloxilic acid and the bile lipids in oral contraceptive users.

Cholesterol supersaturation of gallbladder bile induced by oral contraceptives is significantly reduced by the administration of cis-2-hydroxy-2-phenyl-cyclohexane-carboxilic acid (cicloxilic acid), a choleretic substance which has been demonstrated to exert an antilithogenic effect in the rat and in man.


[Time course of oxipurinol levels in plasma following single dose and chronic administration of allopurinol in different pharmaceutical preparations (author's transl)].

Oxipurinol plasma levels and plasma elimination half-life were investigated in five healthy volunteers after oral administration of 300 mg allopurinol in customary (A 300) and in slow-release preparation (A ret) in a double blind cross-over study. After a single oral dose of 300 mg allopurinol in customary preparation maximum oxipurinol plasma levels were 5.24 microgram/ml. After allopurinol in slow-release preparation maximum oxipurinol levels were 2.22 microgram/ml. 24-h oxipurinol plasma levels were 3.78 microgram/ml after A 300 and 2.08 microgram/ml after A ret, respectively. Chronic oral administration of a daily dose of 300 mg allopurinol resulted in accumulation of oxipurinol until day 8. 24-h steady-state levels of oxipurinol were found to be 9.98 microgram/ml after A 300 and 7.14 microgram/ml after A ret. All oxipurinol plasma levels on A 300 exceeded those on A ret. The time course of oxipurinol plasma levels after a single oral dose of allopurinol suggests that oxipurinol elimination from plasma follows an exponential function (first-order elimination). Plasma elimination half-life of oxipurinol was 42.65 h after administration of A 300 and 49.91 h after administration of A ret. The difference between the elimination half-lives is statistically not significant.


[Pharmacokinetic analysis of a benzarone preparation. First communication: analytical method (author's transl)].

A new analytical method to determine 3-(4-hydroxybenzoyl)-2-ethyl-benzofurane (benzarone, Fragivix) from human serum and urine is described. The substance is extracted from the biological fluids with chloroform after cleavage of the glucuronide with glucuronidase. Benzarone is detected with the HPLC with a special design method on the base of a gradient elution on a reversed-phase column. The method is suitable to measure the necessary concentrations for a kinetic analysis in the serum as well as in the urine. The limit of assessment could be detected at 0.03 microgram/ml. The serum concentration-time curve after oral as well as after i.v. application could be detected with the method.


[Antimicrobial activity of the broad spectrum antimycotic isoconazole nitrate in humans (author's transl)].

A comparative study (occlusion test according to Marples and Kligman) was conducted in 100 test subjects with several formulations of isoconazole nitrate. The following results were obtained: 1. There are no differences in efficacy between the free base, isoconazole, and the nitrate. 2. Increasing the active substance concentration of isoconazole nitrate above 1% produced a noticeable increase in its effect so that 2% and 4% preparations are appropriate for particular uses. 3. 1% isoconazole nitrate (Travogen cream, Gyno-Travogen cream) is more effective than a commercial cream containing 1% clotrimazole. 4. The addition of a corticosteroid (diflucortolone-21-valerate 0.1%, Travocort cream) does not influence the action of isoconazole nitrate.


[Treatment of diarrhea with difenoxin hydrochloride in children (author's transl)].

In an open clinical study symptomatic treatment was given to 93 children aged 16 days to 24 months who suffered from acute diarrhea. All the patients received antidiarrheal diet suited to their age. If indicated, the children were rehydrated with electrolyte and buffer solutions. In order to reduce the intestinal motility as well as the loss of water and electrolyte in the stool, but not to stop the stools, difenoxin hydrochloride (Lyspafen) in the commercial composition was prescribed. The dose was 1 drop/kg body weight/day administered in 3 single doses. The preparation was administered to the children for 4-6 days on the average. Regardless of the bacteriological findings in the stools, very good results were obtained in 59 patients (63.44%); sufficient results in 19 children (20.43%); and poor results in 15 children (16.13%). In the group with negative stool samples very good results were obtained in 74% of the patients. The therapeutic results were very good to sufficient in the majority of cases belonging to the group with facultative pathogenic germs and pathogenic coli in the stools. In 66.67% (4 cases) of the children infected by Salmonellae and Shigellae the treatment was insufficient. No undesirable adverse reactions were seen in the children treated. Summing-up of the results revealed that cure of or improvement in the diarrhea was obtained in 83.87% of the test population.


Autoradiographic distribution study of 14C-2-phenyl-6-sulfonamido-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone (fenquizone) in mice.

The distribution of 2-phenyl-6-sulfonamido-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone (fenquizone, M.G. 13054) labelled with 14C in mice was studied by means of an autoradiographic technique. High concentration of radioactivity was found in the intestine, liver, kidney, blood, myocardium and skeletal muscles in decreasing order at various times after oral administration. The drug was easily absorbed in the intestine reaching the highest concentration between 2 and 4 hr. The labelled compound did not cross the blood-brain barrier.


Effect of histamine on respiratory movements and isolated ileum of pertussis-vaccinated mice. A negative study.

1. The sensitivity of mice, of the Swiss random bred strain, previously i.p. vaccinated with Bordetella pertussis Phase I cells, to histamine was investigated. 2. No response and no increase of the sensitivity of the respiratory system of the pertussis-vaccinated mice was observed during and after the inhaled histamine. 3. No contractions and no response of the isolated perfused ileum of the pertussis-vaccinated mice were observed after the addition of histamine. 4. No experimental or control mouse died during the whole experiment.


Investigations on the actions of silybin on regenerating rat liver. Effects on Kupffer's cells.

Studies were conducted on the effects of silybin upon the biological activities of Kupffer's cells in regenerating livers of rats subjected to partial hepatectomy. As far as proliferative activity is concerned, which was assessed by the colchicine stathmokinetic method on Kupffer's cells isolated from the liver by enzymatic digestion, it was appreciably increased in rats treated with silybin in respect of controls. Phagocytic and bactericidal activities were not modified. The increased mitotic activity induced on Kupffer's cells by silybin was interpreted as a further expression of the effectiveness of silybin on the cellular components of the liver.


Pharmacokinetics and metabolism of taglutimide (K-2004) in the rat.

Absorption, blood level course, renal, fecal, and biliary elimination and the metabolisation of 2-(bicyclo[2,2,1]-heptane-2-endo-3-endo-dicarboximido)-glutarimide (taglutimide, K-2004), a new hypnotic-sedative substance, were studied in the rat, and the pharmacokinetic constants were calculated. After oral administration of 10 mg per animal, which corresponds to the 7- to 10-fold human dose, a fast and practically total absorption and a quick and complete excretion was observed. Within 1 h 82% of the dose given were absorbed, and 12 h after the dosing 88% had been excreted again. The elimination was effected nearly exclusively (over 95%) via the urine. Besides 10 defined metabolites only 10% of the drug appeared unchanged.


An improvement in digoxin bioavailability. Studies with soft gelatin capsules containing a solution of digoxin.

A study of relative bioavailability of two digoxin formulations was carried out on 28 healthy volunteer human subjects of both sexes. A commercial digoxin in tablet form was compared with a new commercial formulation which contains a solution of digoxin in soft gelatin capsules. The parameters investigated were: plasma levels, area under the plasma level-time curve, daily urinary excretion of digoxin and a series of polycardiographic measurements, all the parameters being evaluated in a steady-state condition (14 days of treatment). All the parameters investigated demonstrated better bioavailability in the capsules than in the tablets, the average improvement being 26.1%. The better bioavailability of digoxin capsules also resulted in more rapid and wider variations in the polycardiographic parameters.


The influence of 1,3,7-trimethyl-xanthine (caffeine) on the pain-caused dilation of pupil.

The pupil dilation in man caused by pain was investigated. The pain stimulus was induced electrically. The size of the pupil was measured according to the "flying spot scanning method". The accuracy of measurement was increased by computer-assisted addition of repeated responses as well as by elimination of the, usually not considered constriction due to light compensation over Maxwellian view. The pure psycho-sensory dilation shows no initial contraction. The central stimulant 1,3,7-trimethyl-xanthine (caffeine) does not influence the course and adaption of the pupil reaction by a pain stimulus over the threshold. The pupil reaction correlates with the subjective feeling of pain. This suggests that caffeine does not influence the feeling of pain.


The effect of certain antiplatelet drugs on in vitro malonylaldehyde (MDA) production.

Several antiaggregating agents were tested with regard to their effect on platelet malonylaldehyde (MDA) production which seems to be a good marker of prostaglandin metabolism. Non-steroidal antiinflammatory compounds, namely acetylsalicylic acid (ASA), ditazole and sulfinpyrazone, showed a sure, statistically significant, inhibitory effect on MDA production while theophylline, adenosine and alpha-blocking agent nycergoline did not. Dipyridamole on the contrary, was demonstrated to have a mild but still statistically significant effect on the inhibition of platelet MDA production.


The synthesis of some bridgehead N,O-heterocycles of biological interest.

The preparation of 5-aryl-6-oxa-1-azabicyclo[3,3,0]octanes, 6-aryl-5-oxa-1-azabicyclo[4,3,0]nonanes and 7-aryl-6-oxa-1-azabicyclo[5,3,0]decanes from the corresponding substituted omega-chlorobutyrophenones and aminoalcohols is described; and the ring opening reactions are studied. A preliminary biologic activity study has also been conducted, and demonstrated that the 5-(2,5-dimethyl)phenyl-6-oxa-1-azabicyclo[3,3,0]octane possesses antiinflammatory activity.


Selective effects of 7 alpha-halogeno substitution on corticosteroid activity: Sch 22219 and Sch 23409.

Two 7 alpha-halogeno substituted corticosteroids, 7 alpha-chloro-16 alpha-methylprednisolone-17,21 dipropionate (Sch 22219) and 7 alpha-bromo-16 alpha-methylprednisolone-17-benzoate-21-acetate (Sch 23409) were compared to other clinically utilized topical corticosteroids for local and parenteral antiinflammatory and glucocorticosteroid activity. Both compounds were at least equivalent to the most potent comparison corticosteroids in topical antiinflammatory activity, and exhibited favorable ratios of local to systemic effects. In mice, Sch 22219 showed a greater dissociation of antiinflammatory activity from side effects than Sch 23409, although the reverse was true in rats. On the basis of the data available, both compounds possess enhanced topical antiinflammatory potency, with the potential for reduced side effects in man.


Synthesis of difuran derivatives and their biological activity.

Visnaginone and khellinone react with chloroacetamide and chloroacetonitrile in dimethyl formamide to give either the cyclised benzo[1,2-b : 5,4-b']difuran or the open form depending on the heating period. The antibacterial activity of the compounds was tested.


[Metabolism of antipsoriatic anthrone derivatives].

The metabolisation of the antipsoriatically active molecules 1,8,9-triacetoxy-anthracene und 1,8-diacetoxy-9-anthrone by serum is described. Under these conditions 1,8-dihydroxy-9-anthrone, 1-hydroxy-8-acetoxy-9-anthrone, 1,8,1',8'-tetrahydroxy-bisanthrone, 1,8-dihyroxy-anthraquinone, 1,8-diacetoxy-anthraquinone and 1-hydroxy-8-acetoxy-anthraquinone arise from both educts. Quantitative determinations of these metabolites indicate that hydrolytic reactions occur prior to oxidation. Contrary to 1,8-dihydroxy-9-anthrone, 1,8,9-triacetoxyanthracene and 1,8-diacetoxy-9-anthrone are effective against psoriatic lesions without accompanying inflammations of the skin. 1,8,9-Trimethoxy-anthracene, however, is ineffective, also indicating that at least 1,8,9-triacetoxy-anthracene is a prodrug.--In agreement with Krebs' hypothesis 10,10-dialkylated 1,8-dihydroxy-9-anthrones described in this paper are ineffective against psoriasis.


[Absence of a teratogenic effect of sodium nitroprusside in wistar rats and rabbits (author's transl)].

In a series of experiments sodium nitroprusside (NNP) was tested in the prenatal phases of development in two animal species with regard to possible teratogenic and embryo-toxic effects. A total of 571 offsprings of rats and 48 offsprings of rabbits was investigated. The application of NNP in the prenatal experiment produced no evidence of an embryo-toxic or teratogenic effect, respectively, in rats and rabbits.


The influence of calcium antagonists on endothelium.

Calcium antagonists possess, similarly to endothelotropic (vasotropic) drugs, a stabilizing effect on endothelium against the disrupting influence of citrate in rats. This was demonstrated with the new method for counting of circulating endothelial cells. The effect is dose related and the effective experimental dosages corresponded closely to the clinical dose range. The common link between both drug groups is probably the mediating effect of ionic calcium.


Effect of propranolol on drug-induced and physiological glycogenolysis in the liver.

The beta-adrenergic blocking agent propranolol had in itself no notable influence on the blood glucose level in rats, but in combination with chlorpropamide it considerably delayed and enhanced the hypoglycaemic and liver glycogenolysis depressing actions of chlorpropamide. This effect was still more pronounced when the rats were treated in addition to propranolol and chlorpropamide with thyroxine or glanduitrine, which in themselves act as stimulators of liver glycogenolysis. The simultaneous administration of propranolol and chlorpropamide depressed considerably the liver glycogenolysis induced by prolonged fasting and inhibited completely the liver glycogenolysis observed after hepatectomy. The reports available in the literature on propranolol-precipitated hypoglycaemia in patients are surveyed and it is supposed that the beta-adrenergic blocking agent produces hypoglycaemia primarily through the depression of liver glycogenolysis. This observation supports the hypothesis that the adrenergic beta-receptors play an important role in the sympathetic control of liver glycogenolysis.


[The effect of D-penicillamine on the trace elements in rat organs (author's transl)].

Rats were fed by means of an esophagal tube with increased doses of D-penicillamine and given a diet with an optimal content of trace elements over a period of up to 6 weeks. There were no identifiable lasting effects of this dosage on cobalt, selenium and particularly zinc content. The reduction of copper in the kidneys was significant. Cu was unchanged in serum and brain. The remarkable increase in the copper content of the liver as a result of a possible counter regulation mechanism with intact ceruloplasmin synthesis is discussed. The potential clinical significance of these findings is pointed out.


Studies on the safety of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The effects of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazinyl-1-yl)propyl-4-benzamido-N,N-dipropyl-glutaramate(+/-)dimaleate(protacine, CR 604) on gastrointestinal physiology and tolerance were investigated. The anti-inflammatory activities and the effects on the gastrointestinal tract showed a very good separation. Protacine showed a smaller influence on gastric prostaglandins and did not stimulate both basal and cAMP enhanced gastric acid output as did other antiinflammatory drugs. This may explain, at least in part, its gastrointestinal safety. Articular cartilage metabolism showed to remain practically unchanged by protacine both in in vitro and ex vivo experiments. All these results show that protacine has very good gastrointestinal safety indexes, that effects on articular cartilage metabolism are very low and that, from these points of view, it is superior to other non-steroidal anti-inflammatory drugs of similar potency.


[Induction of fatty acid oxidation in peroxisomes of rat liver by magnesium-4 chlorophenoxyisobutyrate (Mg-CPIB)].

Magnesium-4-chlorophenoxyisobutyrate (Mg-CPIB) and ethyl-CPIB were administered to adult male rats. After one and two weeks, respectively, the peroxysomal fraction from the livers was isolated and activities of fatty acid beta-oxidation and catalase were measured. With both drugs, catalase activity was only slightly induced (50%), whereas a great increase of fatty acid oxidizing enzymes was observed. After both time intervals the inducing effect of the magnesium salt of CPIB was significantly higher than that of the ethyl ester. The bearing of the induction of peroxysomal fatty acid oxidation on the hypolipidemic effect of CPIB is discussed.


[Effect of coumarin on the livers of DBA/2J and CH3/HeJ mice].

32 weeks chronic feeding of DBA/2J- as well as CH3/HeJ-mice with 0.5 and 1.0% coumarin, respectively, in the diet, caused minimal increases of glutamate-oxalatetransaminase, gamma-glutamyltransferase and sorbitdehydrogenase activities in the serum only, when approximately 2 g coumarin/kg daily were administered. Neither macroscopic nor microscopic examination of liver tissue revealed any pathological alterations caused by coumarin. Correspondingly the animals were unaffected in their behaviour and growth during the coumarin loading.


Acute and subacute (30-day) toxicological investigations of 4-(p-chlorophenylthio) butanol (W-2719) in mice, rats and dogs.

The acute and subacute toxicity of 4-(p-chlorophenylthio) butanol (W-2719), on anti-allergy agent, was investigated in mice, rats and dogs. Acute LD50 values in the mouse (1145.0 mg/kg p.o.) and rat (greater than 1400.0 mg/kg p.o.) and maximum tolerated dose in the dog (420.0 mg/kg p.o.) were very high, indicative of a high degree of safety following a single oral dose. The subacute toxicity studies were conducted by repeated daily oral administration of the compound for 30 days. In the rat, W-2719 did not produce any significant toxicity up to a dose level of 100.0 mg/kg/day, when administered as a drug-diet admixture. A higher dose, i.e., 200.0 mg/kg/day, produced marked reductions in body weight gain, food consumption, RBC and WBC (females especially), and other hematological parameters. In the purebred beagle dog, W-2719 did not produce any significant toxicity up to a dose level of 100.0 mg/kg/day, the highest dose level tested in this species.


Pharmacological properties of taglutimide, a new sedative-hypnotic drug.

2-[Bicyclo(2,2,1)heptane-2-endo-3-endo-dicarboximido]-glutarimide (taglutimide, K-2004) proved to be a new sedative-hypnotic drug which did not produce any toxic effects when administered orally to mice even at a very high dosage. Central-nervous depression was demonstrated by a reduction in spontaneous motor activity, potentiation of the central-depressant effect of pentobarbital, antagonism of the central-stimulant effect of amphetamine after oral administration and by narcotic activity after i.v. administration of the drug. Furthermore, oral administration of taglutimide potentiated the analgesic action of morphine without being effective on its own. Only weak potentiation of chlorpromazine-induced catalepsy, but not of reserpine-induced catalepsy was observed after taglutimide pretreatment. The drug influenced neither motor co-ordination nor the toxicity of ethanol. Taglutimide exhibited no anticonvulsant activity with respect to maximum electroshock or strychnine-induced seizures. No effect on heart rate or blood pressure was demonstrable after taglutimide treatment in conscious dogs.


[The open-field, non-stressed behavior of rats under the acute and chronic effect of imipramine and tranylcypromine, depending on the individual reaction type (emotional and non-emotional)].

The acute and prolonged effects of imipramine and tranylcypromine were studied on 30 emotive and 30 non-emotive mature male Wistar rats to determine whether the drugs affect the behavior of these two reaction types differently. We found that both drugs change the typical behavior of the rats in the open field, each in a different way. Acute doses of imipramine inhibit symptoms of anxiety as well as the exploratory behavior so that the rats appear totally disinterested in their environment. This finding seems to confirm the assumed central nervous suppressing effects of this drug as mentioned in the literature. Single doses of tranylcypromine have effects similar to those mentioned for imipramine; however, long-term use results in a "vitalisation" of behavior: symptoms of anxiety remain inhibited and exploratory behavior becomes dominant. Both drugs produced a certain "flattening" of behavior. Due to the effects of drugs used, the original behavioral differences without stress disappear. Prolonged use of tranylcypromine makes emotive rats totally non-emotive.


Preliminary study of pharmacokinetics and metabolism of sodium 2-n-propylpentanoate in pig and human.

The pharmacokinetics of sodium 2-n-propyl-pentanoate have been studied in pig and human. The drug is excreted in the human urine as a mixture of glucuronide and other unidentified conjugates. It appears that no other conjugates can be found in pig's urine. Treatment with sulfatase does not identify sulfate-conjugates in human urine. Coadministration of acetyl salicylic acid (ASA) increases the fraction of glucuronide and other conjugates in human urine. The rate of renal excretion of the drug appears to be increased during concomitant administration of ASA.


[Chromosome studies before and after phenylbutazone infusion therapy].

Studies on chromosomes of lymphocyte cultures of peripheral blood were performed in 15 patients with rheumatoid arthritis (group I: 48-h culture, n = 8; group II; 72-h culture, n = 7) before and after phenylbutazone infusion therapy (600 mg/d for 10 days). The average rate of cells with exchange aberrations of chromosomal type after this therapy (group I: 0.52%; group II: 0.69%) was higher than the control values found before treatment (group I: 0.13%; group II: 0%); X2 test: group I + II: P less than 0.025. The results obtained are discussed.


[Studies of the blood pool dynamic actions of dipyridamole in pregnancy (author's transl)].

The action of 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido-(5,4-d)pyrimidine (dipyridamole, Persantin) on utero-placental and cardiac blood pool dynamics was examined in 12 pregnant women. 113mIndium was injected i.v. and blood pool changes in the heart, placenta and myometrium were registered by external measurement of the gamma-activity. While there was a significant decrease in blood pool of the heart after dipyridamole, there were no marked changes in the blood pools of placenta or myometrium. The decrease in cardiac blood pool was interpreted as a sign of an increase in the cardiac output.


Effect of an angiotensin II analogue upon blood pressure, plasma renin concentration and plasma aldosterone in hypertensive patients.

Succinamyl-arg-val-tyr-val-his-pro-phenylglycine acetate (succinamyl1-val5-phenylglycine acetate3-A II), an analogue of angiotensin II, has a pressor effect upon patients suffering from primary and secondary hypertension regardless of prevailing plasma renin concentration. It stimulates the release of aldosterone, whereas plasma renin concentration is not influenced. It is concluded, that this new analogue is, as far as its effect upon blood pressure and release of aldosterone in man is concerned, an agonist of angiotensin II.


Local effects produced on intact skin by epicutaneously applied anaesthetic formulations. An experimental study in man.

By means of experiments involving pin-pricking, compositions containing 10% ketocaine base in a mixture of 2-propanol, glycerol and water were found to produce a high frequency of block to cutaneous pain following application to volunteers under an occlusive dressing. The local analgesic efficacy was found to be directly related to the degree of saturation of ketocaine in the vehicle and time of application. The degree of hyperaemia observed in the treated skin areas was found to be related to the degree of local analgesia produced.


[Relative bioavailability of a new spironolactone preparation (author's transl)].

The investigations have been performed to determine the relative bioavailability of canrenon from Acelat 100 capsules in comparison with canrenon from a spironolactone standard preparation available on the German market. This was carried out by comparing the areas under the serum fluctuation curves after oral application of both preparations as well as by urine excretion extrapolated infinitely. The preparations were administered together with a standard breakfast. Subsequently up to 48 h blood was withdrawn from the Vena cubiti. According to a known method serum samples were analysed spectrophotometrically. The data obtained were fitted to an open two-compartment model with the RIP-procedure. The core of the program is a Gauss-Newton iteration (minimising the last squares). These are the results: By intraindividual comparison of the areas under the serum fluctuation curves of canrenon a relative bioavailability of 116.27% (s = 16.84) of canrenon from Acelat 100 could be calculated versus canrenon from the standard. Urine excretion, extrapolated infinitely, showed a 4% higher excretion of canrenon after application of Acelat 100 compared to standard. Both results are not significantly different in the range of biological scattering. The further pharmacokinetic parameters calculated were within the range of the literature available.


[Pharmacological study on treptilamine in man/study on tolerability (author's transl)].

N,N-Diethyl-N-(2-[alpha(tricyclo[2,2,1,0(2,6]hept-3-ylidene)-benzyloxy]-ethyl)amine hydrochloride (treptilamine) which in experiments on animals showed distinct spasmolytic effects, has been investigated first in 6 volunteers with regard to compatibility using different doses p.o. and i.v. In connection with this previous study a double blind study including placebo was performed for verification of the observed effects. In the plot study 30, 40 and 50 mg were applied orally and 10, 15 and 20 mg treptilamine were used i.v. The double blind study was designed for 20 volunteers at dosages of 40 mg p.o. and 15 mg i.v. against placebo. In the pilot study systolic blood pressure decreased significantly 5 to 15 min after i.v. application of the substance for 5 or 30 min. The range of accommodation was restricted depending on the dose used. No alteration of circulation was observed after oral application at any dose. All volunteers felt tired. A significant decrease of systolic blood pressure (15 mmHg for 10 min immediately after application) occurred after 15 mg of substance were applied i.v. in the double blind study. No effect on circulation could be seen after placebo. The range of accommodation was restricted in a significant way both after i.v. application (40%) and after oral application (30%). Two of five volunteers recorded a burning sensation in the venous wall which was followed by drowsiness. One volunteer felt increasingly tired after oral application. No influence of the substance could be seen on the clinicochemical parameters examined.


Surface protein distributions in cells isolated from solid tumours and their metastases.

Methods have been developed which isolate single viable cells from the primary growths of two tumour systems (a lymphosarcoma and a carcinoma) and their secondary deposits. Subsequent comparisons of the surface-membrane structure of pairs of these primary and secondary cells, using lactoperoxidase-catalysed radioiodination coupled with polyacrylamide-gel electrophoresis, suggest that their overall structures are qualitatively very similar. This latter picture is still maintained when the isolated cells are treated with trypsin or incubated in complete medium before radioiodination. Analysis of the incorporated label into defined sections of the electrophoretic patterns revealed small quantitative differences between primary and secondary cells. In particular, slightly reduced incorporation into certain surface components of secondary cell preparations was seen. However, these did not occur for all the animals investigated, and also they did not consistently occur if the isolated cells were incubated in complete medium. The most similar overall change observed for the two tumour systems was a slight reduction in the secondary cells of a 20K mol. wt surface component.


Maturity of fetal lungs tested by production of stable microbubbles in amniotic fluid.

Lung surfactant in amniotic fluid, and hence the maturity of the fetal lungs, can be assessed by observation of stable microbubbles (less than 15 micron diameter). Bubbles are formed by agitation with a Pasteur pipette and examined in hanging drops under the 10 x power of a microscope. Either after a count of bubbles, or after a general survey of hanging drops, the fluid is given a stable microbubble rating. A 'strong' rating indicates that the idiopathic respiratory distress syndrome will not occur after delivery, and that the lecithin/sphingomyelin ratio will indicate maturity. Complete absence of stable microbubbles suggests a high risk of respiratory trouble for the newborn infant, as does a weak or lower rating in the 30 to 37 week gestational age group. The test takes 5 to 10 minutes to perform, is cheap and easy, is not affected by blood, but may be affected by meconium. If a 'strong' rating is found, measurement of the L/S ratio can safely be omitted.


The interaction of adriamycin with small unilamellar vesicle liposomes. A fluorescence study.

The interaction of the antineoplastic agent adriamycin with sonicated liposomes composed of phosphatidylcholine alone and with small amounts (1-6%) of cardiolipin has been studied by fluorescence techniques. Equilibrium binding data show that the presence of cardiolipin increases the amount of drug bound to liposomes when the bilayer is below its phase transition temperature and when the ionic strength is relatively low (0.01 M). At higher ionic strength (0.15 M) and above the Tm (i.e. conditions which are closer to the physiological state) the binding of the drug to the two liposome types is nearly the same. Thus the differences in the interactions of adriamycin with cardiolipin-containing membranes, as opposed to those composed of phosphatidylcholine alone, are not due simply to increased binding but rather to an altered membrane structure when this lipid is present. Quenching of adriamycin fluorescence by iodide shows that bound drug is partially, but not completely, buried in the liposomal membrane. Both in the presence and absence of cardiolipin the bulk of the adriamycin is more accessible to the quencher below the Tm than above it; that is, a solid membrane tends to exclude the drug from deep penetration. Above the Tm, the presence of cardiolipin alters the nature of liposome-adriamycin interaction. Here the fluorescence quenching data suggest that the presence of small amounts of cardiolipin (3%) in a phosphatidylcholine matrix creates two types of binding environments for drug, one relatively exposed and the other more deeply buried in the membrane. The temperature dependence of the adriamycin fluorescence and the liposome light scattering reveal that cardiolipin alters the thermal properties of the bilayer as well as its interaction with adriamycin. At low ionic strength lateral phase separations may occur with both pure phosphatidylcholine and when 3% cardiolipin is present; under these conditions the bound adriamycin exists in two kinds of environment. It is notable that only adriamycin fluorescence reveals this phenomenon; thebulk property of liposome light scattering reports only on the overall membrane phase change. These data suggest that under certain conditions the drug binding sites in the membranes are decoupled from the bulk of the lipid bilayer.


Absorption of 2-acetylaminofluorene in the guinea-pig colon.

Absorption of the known chemical carcinogen, 2-acetylaminofluorene has been measured in the colon of guinea pigs. Unidirectional influx across the luminal cell membrane was determined in vitro, and transmural absorption across colonic mucosa was evaluated in vivo. The kinetics of unidirectional influx into colon in vitro do not indicate that absorption proceeds by simple diffusion. The observed saturable uptake is indicative of binding of 2-acetylaminofluorene to a cellular component. With 2-acetylaminofluorene present in the lumen in vivo at an initial concentration of 3.5 microM, the rate of absorption decreases over a 20 min period, which also indicates some form of specific interaction between 2-acetylaminofluorene and the intestinal mucosa. We have evaluated the hypothesis that surfactants and a bile salt act as cocarcinogens by increasing the rate of intestinal absorption of 2-acetylaminofluorene. The results lend no support to this possibility.


Statistical aspects of comparative bioavailability trials.

The role of comparative bioavailability trials in testing for the bioequivalence of different formulations of a drug is discussed and the statistical aspects of the design and analysis of such trials are reviewed. It is suggested that the design of such trials presents no special problem but that the customary method of analysis, which tests the null hypothesis of no difference between the formulations, is irrelevant to the central purpose of such trials, which is to determine whether the formulations have essentially equivalent therapeutic effects. It is proposed that only those characteristics of the data that possess a meaningful relation to the therapeutic use of the drug should be analysed and also that estimation procedures rather than hypothesis testing techniques should be employed. Several aspects of the statistics of bioavailability trials which require further investigation are listed.


[Polyfunctional role of the alveolar brush cells in the rat lung].

By means of scanning and transmission electron microscopy it was demonstrated that the number of vacuoles located in the apical part of cytoplasm in alveolar brush cells of the regenerating rat lung increases, hyperplasia of Golgi-complex takes place and the activation of the protein-synthetising apparatus is evident. The immature surfactant material (osmiophilic lamellar bodies) and secretory dense core vesicles were found in the cytoplasm of alveolar brush cells. Intramuscular injections of colchicin to rats (0.1 mg/100 g body weight) 6 times during 24 hours before decapitation does not influence the number, topography and structure of microfibrilla bundles contained in a sufficient amount by alveolar brush cells. At the same time a part of microvilli of alveolar brush cells undergoes destruction and resorption under the action of colchicin. The data on ultrastructural organization of alveolar brush cells show that they are able to fulfill several functions: absorptive, contractile and secretory.


Chemotherapy of advanced non-Hodgkin's lymphoma.

From the therapuetic point of view, non-Hodgkin's lymphomas can be classified into two groups: favourable prognosis histology (DWDL, NWDL, NPDL, and NM) and unfavourable prognosis histology (DPDL, DM, DH, NH, DU). The latter group also includes lymphoblastic lymphoma (T cell) and Burkitt's lymphoma (B cell). Further classification by immunological markers (T, B, monocyte, null cell) and functional categories (T-cell subsets) may reveal prognostic groups which require separate consideration. Intensive chemotherapy of unfavourable histoligies can result in long-term disease-free survival as reported in several series. It would appear that the 10 year survival rates will not differ greatly between several multi-drug regimens. At the present time, the histopathological subtype permits selection of patients for a trial of intensive chemotherapy. The progress in the future will be made with improved techniques for the management of bulky abdominal disease and central nervous system invasion. Although the above may result in some statistical improvement in survival of the unfavourable group, the vast majority of patients with favourable histology lymphoma require new approaches. These may take the form of treatment with immunological manoeuvres such as idiotypic-specific antibodies and/or the use of intensive chemotherapy, especially when there is convincing evidence of a change in the biology of the disease.


Purification of Bungarus multicinctus antivenin by affinity chromatography.

Bungarus multicinctus horse antivenin was purified by ammonium sulfate fractionation, gel filtration on Sephadex G-200 column, and affinity chromatography. The specific neutralizing capacity of the antibody preparations showed 2.21-fold, 3.12-fold, and 29.6-fold higher than that of the crude antivenin, respectively.


Bioavailability of two tablet preparations of carbimazole in man.

1. The bioavailability of two 5 mg tablet formulations of carbimazole (Neomercazole [A] and Carbazole [B]) have been compared in six euthyroid subjects. There was considerable inter-patient variation in absolute bioavailability although, for each subject, peak plasma concentrations of methimazole were similar with both formulations. 2. Mean peak plasma concentrations were seen on average 62 min after administration of tablet A as compared to 40 min after tablet B. This is consistent with the finding that the disintegration and dissolution times were shorter for formulation B than for formulation A. The mean area under the plasma concentration curve and the 6 h plasma concentration of methimazole tended to be greater after tablet A. These differences could be of significance in the treatment of thyrotoxicosis.


201Tl in the scintigraphic evaluation of the "cold" thyroid areas.

201Tl-chloride, which has a metabolic behaviour similar to that of potassium and cesium, has been used in 68 patients for the evaluation of thyroid nodules previously recognized as "cold" on 131I or 99mTc scans. All patients were re-examined with gamma-camera and/or sequential scintigraphic recordings during 60 min after i.v. administration of thallium. In some cases, simultaneous imaging and integral digital plot with 131I or 99mTc and 201Tl were performed. In all 12 malignant nodules, 201 Tl has showed a high uptake, while it did not concentrate in 47 benign nodules (cystic or macrofollicular adenomas); thallium uptake was nevertheless found in 10 solid neoformations in which histological pictures were negative for malignancy or atypical lesions. The computerized study of the 201Tl intranodular concentration, with the analysis of its dynamic function curves, seems to offer further possibility in differentiating and in a more objective evaluation of the "cold" areas on the thyroid scan.


Plasma renin activity and plasma aldosterone concentration in infants with various sodium intakes.

Plasma renin activity (PRA) and plasma aldosterone concentration (PA) were measured in 20 healthy infants 2-12 months of age, after taking a commercial modified cow's milk formula with 8.2 mmol/l sodium for at least five days, and after at least five days on a home-made, undiluted acidified cow's milk formula with 12.6 mmol/l sodium. The mean sodium intakes were 1.20 and 1.87 mmol/kg of body weight per day respectively. The arithmetic means for the corresponding PRA were 6.16 and 1.08 ng/ml . h (difference not significant) and the corresponding arithmetic means for PA were 603 and 355 pg/ml, the difference being highly significant (P less than 0.01). It is concluded that one has to consider the sodium intake in the milk formula when studying plasma aldosterone in infancy.


Comparative bioavailability of two commercial preparations of carbamazepine tablets.

A comparative bioavailability study was performed using two commercially available types of carbamazepine tablets, by statistical analysis of serum levels and other bioavailability parameters. After single oral dose the extent of absorption from the two preparations was similar, although a statistically significant difference in absorption rates was observed. In a multiple-dose study no significant difference in serum carbamazepine levels was found, so the tablets could be considered as bioequivalent drug products.


Lymecycline and concurrent ingestion of milk.

It has been suggested in the past that milk causes an impaired absorption of tetracycline and this paper describes a study set up to examine any inhibition of absorption of a tetracycline derivative, lymecycline (Tetralysal) with the concurrent intake of milk. The results of the study show no clinical reason for restricting a moderate intake of milk in conjunction with lymecycline therapy.


The gastrocolic response: evidence for a neural mechanism.

The aim of this study is to determine the effect of anticholinergic therapy on the gastrocolonic response to a standard meal or its major constituent fat. A rapid increase in rectosigmoidal spike activity occurs after ingesting the standard meal or the fat meal (P less than 0.01). Distal colonic motility returns to fasting levels 50 min after both meals. There is no further increase in spike activity after the 1000-calorie meal, but spike activity increases again 70 min after ingesting the fat (P less than 0.02). The anticholinergic drug, clidinium bromide, inhibits the early increase in spike activity after both meals. However, the anticholinergic has no effect on the delayed peak of activity following the ingestion of fat. This study suggests that (a) the early gastrocolic response to a standard meal and a fat meal is cholinergically mediated and (b) the late increase in rectosigmoidal motility occurs only after fat ingestion and may be controlled by other neural mediators or possibly the gastrointestinal hormones.


Comparative bioavailability of sustained-release and conventional tablets of hydroxyethyltheophylline in man.

The comparative bioavailability of sustained-release and conventional tablets of hydroxyethyltheophylline was studied in normal subjects. In a single dose study on 7 subjects, 3 conventional tablets or 2 sustained-release tablets were administered orally after a light breakfast and blood samples taken for 6 and 12 hours respectively. With conventional tablets the mean peak concentration (8.10 +/- 0.751 microgram/ml) was reached at 3 hours and concentrations less than 5 microgram/ml were observed in 4 out of 7 subjects at 6 hours. In contrast, with sustained-release tablets of theophylline and hydroxytheophylline complex the mean peak concentration (8.90 +/- 0.88 microgram/ml) was reached at 6 hours and levels above 5 microgram/ml were observed in 4 out of 7 cases at 12 hours. Administration of 2 sustained-release tablets twice a day produced trough plasma concentrations varying between 6.9-13.8 microgram/ml, i.e. within the therapeutic range in all the 5 subjects. It is concluded that this new oral sustained-release preparation provides therapeutic plasma theophylline concentration on a 12 hourly dosage schedule.


Lymphosarcoma and cryptococcosis in a cat.

Cryptococcosis and lymphosarcoma were diagnosed in a 3-year-old Domestic Shorthair cat. The cat was studied immunologically, and abnormal findings included absolute lymphopenia, with a low percentage of the lymphocytes having cell surface markers of normal T and B cells, decreased responsiveness to mitogens, and low immunoglobulin concentrations in serum. Necropsy revealed cryptococcal lesions in the facial area. The cortex of the left kidney was replaced by a diffuse pattern of undifferentiated large cells compatible with those of histiocytic cell type lymphosarcoma.


A study of nuclear diameters in lymph node imprints using the Zeiss Microvideomat.

The diameters of the cell nuclei were measured in imprint preparations of eight tonsils and 28 lymph nodes, each specimen being from a separate patient. The lymph nodes were from cases of Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), and reactive benign states. The nuclear diameters were measured by means of an image-analysing device, the Zeiss Microvideomat. For accurate measurements, the cells had to be well separated, and tissue sections could not be used because the close juxtaposition of nuclei gave erroneous readings. However, cell imprints proved suitable. The results show that the mean nuclear diameters for the HD, NHL, and reactive groups differ and show a considerable scatter. However, the distributions for the NHL and reactive nodes are sufficiently different to suggest that the method may have diagnostic value for the former.


Metabolic clearance and production rates of prolactin in man.

Metabolic clearance rates (MCR) and production rates (PR) of prolactin (PRL) have been determined by the constant infusion to equilibrium technique in 11 normal subjects, 6 patients with hyperthyroidism, 4 patients with hypothyroidism, and 9 patients with hyperprolactinemia. PRL MCR was also determined tin four patients during dopamine infusion. Mean PRL MCR was 46 +/- 1 ml/min per m2 in women and 44 +/- 3 ml/min per m2 in men, and was significantly correlated with body mass (r = 0.84, P less than 0.001). In contrast with controls, PRL MCR was higher in hyperthyroidism (MCR = 52 +/- 8 ml/min per m2, P less than 0.05), was slightly lower in hypothyroidism (MCR = 38 +/- 10 ml/min per m2, P = NS), and was significantly correlated with serum thyroxine (r = 0.46, P less than 0.02). PRL MCR was lower than controls in hyperprolactinemia (MCR = 40 +/- 5 ml/min per m2, P less than 0.01) and was inversely correlated with serum PRL (r = -0.72, P less than 0.001). PRL MCR was not significantly changed by dopamine infusion. Mean PRL PR for women and men was 211 +/- 74 and 187 +/- 44 micrograms/d per m2, respectively (P = NS). In hyperthyroidism the PRL PR was elevated (PR = 335 +/- 68 micrograms/d per m2, P less than 0.02), but in hypothyroidism the increase (PR = 233 +/- 159 micrograms/d per m2) was not significant. In hyperprolactinemia the PRL PR was extremely high (PR = 31,000 +/- 29,000 micrograms/d per m2). Dopamine infusion decreased RPL PR from 270 to 66 micrograms/d per m2 indicating that its effect was on pituitary PRL secretion and not PRL metabolism. To evaluate possible circulating PRL heterogeneity that might arise during infusion, gel filtration of infusate and serum obtained during the MCR procedure was performed. Labeled monomeric PRL (peak III, Kav (partition coefficient) = 0.4) was partially converted to two larger forms (peaks I and II) in vivo. Peak I (Kav = 0) was 30--40% immunoprecipitable, although peak II (Kav = 0.2) was not immunoprecipitable. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of peak I resulted in greater than or equal to 90% conversion to peak III and restoration of full immunoactivity. Thus, peak I is a noncovalently linked aggregate that is partially immunoactive, and therefore able to alter MCR determinations. These studies demonstrate the impact of hormone heterogeneity on MCR estimations and suggest that gel filtration of immunoprecipitable material be an integral part of future MCR measurements.


Introduction to the modelling of venereal disease.

The continually rising trend in the incidence of venereal diseases, especially gonorrhoea, in a large number of countries, both developed and developing is causing considerable public health concern. There is a disquieting volume of human suffering involved, as well as large economic losses in treatment and hospitalization. The present paper reviews the existing state of development in the mathematical modelling of the relevant disease dynamics. The 'criss-cross' nature of the infections, which in heterosexual contacts switch between the male and female populations, together with the nonlinear form of the rate of spread normally occurring in infectious diseases, leads to special types of simultaneous nonlinear differential equations.


HLA in primary atrophic hypothyroidism and Hashimoto goitre.

The prevalence of HLA-B8 was found to be significantly increased in patients with primary atrophic (no goitre) hypothyroidism, but not in goitrous patients with Hashimoto thyroiditis, whether euthroid or hypothroid. There was no correlation between the occurrence of HLA-B8 and the presence of titres of thyroid antibodies at diagnosis or their persistence for at least three years after diagnosis.


Dysthyroid ophthalmopathy: an update.

Since the original description of dysthyroid ophthalmopathy, much has been learned about its etiology, pathology, course, and management. The subject is reviewed in depth and the author suggests explanations relating to some of the poorly understood aspects of the disorder.


[Comparative examination of endocrine ophthalmopathy by means of ultrasonography, computerized tomography and fish bioassay].

In 35 patients with Graves' ophthalmopathy (GO) thyroid function was tested by T3-RIA, T4-RIA, TBI, TRH-test, thyroid scanning, and determination of thyroid autoantibodies. Additional ultrasonography (A-scan), computed tomography (CT) of the orbit, and the determination of an exophthalmogenic serum activity in fish bioassay was performed. Typical alterations for GO were observed in 26 cases with ultrasonography. CT showed an enlargement of medial and/or lateral rectus muscles in 24 of 33 patients, and in 17 cases a region of high density in the apex of the muscle cone. The density of retrobulbar fat after i.v. injection of contrast medium did not differ significantly from that observed in normal men. Characteristic signs of GO were not detected in only 2 cases using both methods together. Exophthalmogenic serum activity was found in the IgG fraction of serum protein. The incidence rate was high (69%), but for diagnostic purpose the fish bioassay cannot be recommended.


Development of an 82.2 degrees C (180 degrees F) temperature indicatior system for monitoring equipment washing and sanitizing programs.

A survey performed at 12 institutions showed that while the temperatures in the water tanks of mechanical cage washers were monitored, these temperatures deviated from the temperatures obtained on the items actually being washed. Most surveyed facilities were not meeting the 82.2 degrees C (180 degrees F) standard in the washing chamber. A temperature indicator was developed which revealed whether 82.2 degrees C had been reached at the surface of the items being sanitized. The indicator was a sealed glass ampule which produced a visible color change when exposed to temperatures of 82.2 degress C or higher. The indicator was located on the items being washed. Due to the variability of water heating in washing machines, it was recommended that one indicator be used in each load of equipment being sanitized.


Glycine encephalopathy.

4 cases of nonketotic hyperglycinemia (glycine encephalopathy), one with autopsy, are presented and the literature on 61 cases is reviewed. Major clinical signs include early hypotonia, lethargy and erratic and massive myoclonias with respiratory distrubances, starting during the first days of life after a symptom-free interval. Early death is common. Survivors are severely retarded and exhibit various types of seizures including infantile spasms. The EEG pattern consists initially of periodical paroxysmal bursts on an almost flat tracing, evolving later into a hypsarrhythmic pattern. Spongiosis of the myelinated pathways is the main pathological finding. Elevated CSF glycine seems to be the essential determinant of the neurological disturbances and it is, therefore, suggested that the term glycine encephalopathy be used instead of non-ketotic hyperglycinemia. A classification of disorders associated with hyperglycinemia is proposed.


Respiration during the first six months of life in normal infants: II. The emergence of a circadian pattern.

The objective of the present study was to investigate the emergence of circadian patterns in respiratory rates. Twenty-five neurologically normal infants were monitored for 12-hours during the first week of life and at one, two, three, four and six months of age. Each minute of the recordings of EEG, eye movements, somatic activity, respiration, ECG and temperature was coded into Active sleep (AS), Quiet sleep (QS), Indeterminate (IN) and Awake (AW). The night was divided into four equal intervals and a computer program calculated the mean respiratory rate for each interval as a function of state and age. During the first week of life group means of respiratory rates increased linearly with each interval in all states. A circadian pattern with lowered respiratory rates between 10:00 p.m. and 1:00 a.m. emerged at different ages in different sleep states. This pattern was first seen at one month of age in AS and IN, and at three months in QS. It was also observed in AW at three months of age, suggesting that the circadian rhythm is not solely an expression of the sleep wakefulness cycle. Feeding patterns contributed to but did not explain these observations.


Variation of phenotype in Charcot-Marie-Tooth disease.

A two year old from a family with typical Charcot-Marie-Tooth disease has extensive ocular and central abnormalities, severe generalized neuropathy, and amyotrophy. Many abnormalities previously described in association with Charcot-Marie-Tooth disease are combined in this patient, including chorioretinal degeneration, optic atrophy, facial weakness, oligophrenia, and generalized amyotrophy. Documentation of the diagnosis in the child's ancestors and the precedent for each of his abnormalities suggest that these features represent a virulent expression of the inherited defect.