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The uptake of imipramine- 14 C, desipramine- 14 C, amitriptyline- 14 C and chlorimipramine- 14 C was studied in rat isolated atria incubated in a medium containing concentrations of the drugs ranging from 10 −8 to 10 −5 M: the tissue levels were linearly related to the concentration in the incubation medium, the four lines sharing almost the same equation: accumulation appeared to be a passive unsaturable process for each drug. Desmethyldoxepin, desmethyl-chlorimipramine, nortriptyline were 4–5 times less potent than desipramine in inhibiting l- 3 H-noradrenaline uptake, while the tertiary amines (imipramine, amitriptyline, chlorimipramine and doxepin) were far less potent. Apart from desipramine, which showed some sympathomimetic activity, the main effect of the drugs was a slowing of the spontaneous atrial rate which was more evident for the dimethyl than for the monomethyl compounds. All drugs potentiated l-noradrenaline chronotropic response to varying degrees, but the potentiation of noradrenaline response was not always correlated with the inhibition of its uptake. Thus, inhibition of uptake is not a valid parameter for prediction of noradrenaline potentiation and vice versa. Drug tissue concentrations correlated with l- 3 H-noradrenaline uptake inhibition but not with potentiation of l-noradrenaline chronotropic response.

1. A gas chromatographic-mass fragmentographic method has been developed to determine piribedil and its metabolite S-584, using diazepam as internal standard. The metabolite was derivatized as a trimethylsilyl ether for gas chromatographic analysis. The minimum detectable amount of piribedil and the metabolite was 10 ng/g tissue. 2. Levels of piribedil and its metabolite in the striatum were determined by mass fragmentography.

Gas chromatographic-mass spectrometric techniques have been used for the measurement of tetrahydropapaveroline (THP) from brain. The formation of THP from 1-DOPA or dopamine in vitro has been confirmed by obtaining a complete mass spectrum of the product as its trifluoroacetylated derivative. Following chronic administration of 1-DOPA or 1-DOPA in combination with ethanol to rats, THP formed in vivo in in brain could be detected in small quantities although it could not be detected when ethanol alone was administered.

I.p. administration of d-amphetamine sulphate and fenfluramine · HCl at various doses induced significant modifications of brain noradrenaline (NA) and MOPEG-SO4 (3-methoxy-4-hydrorxyphenylethyleneglycol) in the rat. Both drugs induced a decrease in brain noradrenaline but the two compounds seem to interact with the central noradrenergic system through a different mechanism. The decreased levels of noradrenaline after 1-fenfluramine administration were paralleled by increased MOPEG-SO4 levels. The d-isomer of fenfluramine was less active than the l-isomer. Amphetamine was considerably more effective than 1-fenfluramine in reducing NA concentration. However, in spite of the long lasting effect on noradrenaline levels the i.p. administration of amphetamine did not lead to an increased MOPEG-SO4 concentrations suggesting a more complex interaction with the noradrenergic system.

Nomifensine, at a dose of 10 mg/kg i.p., completely antagonized the decrease of brain dopamine induced by an intraventricular injection of 6-hydroxydopamine. The decrease of brain noradrenaline was also significantly antagonized by nomifensine. Desipramine antagonized the effect of 6-hydroxydopamine on noradrenaline but not on dopamine. The decrease of brain serotonin induced by fenfluramine was antagonized by chlorimipramine but not by nomifensine. The findings indicate that nomifensine specifically blocks the uptake mechanism for catecholamines in the brain without significant effects on serotonin.

Piribedil and its metabolite (pyrimidyl-2′)-1-(dihydroxy-3′,4′-benzyl)-4-piperazine dichlorhydrate (PdHBP), like apomorphine, decrease the level of HVa in the rat striatum. The effect appears rapidly and it lasts for about 2 hr. Piribedil antagonizes the rise of striatal HVA elicited by chlorpromazine, haloperidol and fenfluramine. Piribedil, PdHBP and apomorphine did not counteract the increase of striatal HVA induced by d-amphetamine.

A method is described for the determination C3-hydroxylated benzodiazepine glucuronides in biological samples. Oxazepam and lorazepam glucuronides are measured as methyl esters and trimethylsilyl derivates by a gas chromatographic procedure. The applicability of the method has been tested on the urine of rats, guinea pigs, rabbits and man, receiving oxazepam orally. Oxazepam glucuronide was not found in rat urine but it was present in the urine of rabbits (5.7% of the administered dose), guinea pigs (9.5%) and man (13.4-26.9%).

Previous findings show that experimental tumors of the mouse, such as Ehrlich carcinoma and Sarcoma 180, transplanted in different sites, elicit a different sensitivity to the same drug according to the site of tumor implantation. Cyclophosphamide is highly active on intraperitoneal or subcutaneous tumors, but is ineffective on intracerebral tumors. However, the opposite is true for drugs such as nitroso-derivatives, which are active only on intracerebral tumors. The studies presented in this report were performed in order to elucidate whether different concentrations of drugs at the three tumor sites are related to the different antitumoral effects. It was found that measurements of blood and tissue concentrations explain fairly well the different activities of the drugs being tested.

Penfluridol is a long-lasting neuroleptic drug which accumulates in the adipose tissue of rats and mice. The concentration in this tissue, depending on the time, may be 50–100 times higher than in blood or in brain. Penfluridol does not selectively distribute in various brain areas of rats including hemispheres, striatum, diencephalon, mesencephalon and cerebellum. The concentration of penfluridol in rat brain necessary to exert significant anti-amphetamine activity is around 7 ng/g.

1. (+)-Flenfluramine reduces the central stores of 5-hydroxytryptamine (5-HT) by a poorly understood mechanism. 2. Rat blood platelets have been used in this study as a simple model for serotoninergic nerve endings. 3. (+)-Fenfluramine shows a dual effect: it inhibits the uptake of (14C)-5-HT by platelets and it releases newly absorbed (14C)-5-HT from platelets. 4. The inhibition of (14C)-5-HT uptake induced by (+)-fenfluramine appears very rapidly, is concentration-dependent and seems not to be competitive. (+)-Fenfluramine is ten times less effective than chloroimipramine but tem times more effective than (+)-amphetamine; (+)-fenfluramine is more active than its (-)isomer or its metabolite norfenfluramine ((+)- or (-)-form). 5. The release of (14C)-5-HT from platelets induced by (+)-fenfluramine is concentration-dependent but increases wtih increased incubation time. Both chloroimipramine and (+)-amphetamine are in comparison very poor release inducers; (+)-fenfluramine is more active than its (-)-isomer or its metabolites. 6. The effect on (14C)-5-HT uptake exerted by (+)-fenfluramine and chloroimipramine in vitro could not be observed in vivo. 7. The observed effect on fenfluramine on the uptake and release of 5-HT may explain the lowering action of fenfluramine on the brain 5-HT level, an effect considered of importance for the anoretic effect on this drug.

The effect of different dosage combinations of lynoestrenol and mestranol were studied in rats that have been subjected to selective lesioning of brain serotonin or catecholamine-containing neurons. Lesions of the midbrain raphe, which cause a marked decrease of serotonin in the forebrain, were without any effect on the estrus cycle, fertility and activity of the steroids under study. An intraventricular injection of 6-hydroxydopamine, which causes a selective decrease of noradrenaline and dopamine in the forebrain, produced a transient effect only on the estrus cycle but did not significantly change the fertility or the activity of the substances investigated. The data indicate that the integrity of monoaminergic neurons in the brain is not an essential condition for the aspects investigated in the present study.The effect of selective lesioning of brain serotonin or catecholamine-containing neurons on the activity of oral steroid contraceptives was examined in rats. Dosage combinations of lynestrenol and mestranol were administered orally to the animals. The midbrain raphe (MR) lesion or the intraventricular injection of 6-hydroxydopamine (6-OHDA) produced, respectively, a marked decrease of serotonin and catecholamines in the forebrain. In the sham-operated or MR-lesioned animals, the estrous, cycle, fertility, and activity of the steroids studied were not affected. In pargyline plus 6-OHDA-treated rats the estrous cycle was irregular in 4 out of 17 animals (p less than .05). No marked differences in the number of pregnant rats were found between MR-lesioned or 6-OHDA treated rats. These negative results obtained with the MR lesion or with the 6-OHDA treatment indicate that neither serotonin nor catecholamines play an important role in fertility or contraceptive action of the steroids studied.

Stimulation of the nucleus medianus of the midbrain raphe in rats caused an increase of 5-HT turnover in the forebrain without changes in the 5-HT turnover of the posterior part of the brain and of the spinal cord.

A procedure for determining carbamazepine in biological specimens both from animals and humans is described. Carbamazepine was found to enter the brain relatively rapidly and its distribution is uniform through the body. In animals absorption and tissue distribution was found to be influenced to a certain extent by the vehicle employed. A clear correlation between the brain levels and the protection towards maximal electroshock was observed. Preliminary data on humans suggest a relatively slow absorption. An oral dose of 6 mg/kg gives plasma levels comparable to the ones obtained after an administration of 400 mg/kg in rats.

Electrical stimulation of MR in rats induces a marked increase of 5HIAA and a decrease of 5HT in the forebrain. At the same time the onset of electroencephalographic pattern of sleep and behavioral signs of calmness were observed. The most intense biochemical effects were obtained with 10 c/sec stimulation whereas 2 c/sec stimulation produced the clearest behavioral depression. 5HT Midbrain raphe 5HIAA Electroencephalographic changes Behavior Sleep pattern Electrical stimulation

Chlorpromazine induces in rats a marked and long-lasting hyperglycaemia which (a) is more marked at low than high room temperatures, (b) is inhibited by phentolamine but not by dibenamine, and (c) is prevented by adrenalectomy, by removal of the adrenal medullae and by treatment of the rats with reserpine. Other experimental results suggest that there is a correlation between the hyperglycaemia and the hypothermia induced by chlorpromazine and by its congeners. The hyperglycaemia seems to be the result of at least two factors: an activation of the adrenergic mechanisms and an impaired peripheral utilization of glucose.

The hyperthermia and the hypothermia elicited by 5 mg/kg, i.p. or 30 mg/kg i.p. of morphine in rats are abolished by a previous lesion of the midbrain raphe resulting in a lowering of forebrain 5-HT and 5-hydroxyindolacetic acid. Lesions lateral to the midbrain raphe which do not modify brain 5-HT are without effect on body temperature changes induced by morphine. Animals lesioned in the midbrain raphe are still able to respond with a hyperthermia or with a hypothermia when they are treated respectively with 2,4-dinitrophenol or phentolamine.

A method to measure butyrophenones as such in GLC was developed and applied for the determination of these drugs in biological materials. Haloperidol and trifluperidol show many properties in common when they are injected. They penetrate very rapidly into brain where they reach levels several times higher than in plasma. The brain concentration able to inhibit completely the effects of amphetamine is for both drugs between 30 and 40 ng/g. Haloperidol and trifluperidol are different in their capacity to accumulate in the adipose tissue in vivo and in vitro. The GLC method to measure butyrophenones has been employed for determining haloperidol in the plasma of psychiatric patients treated with this drug for therapeutical reasons.

Brain concentrations of acetylcholine and choline were measured within 5–30 min after an i.p. injection of central stimulant or depressant drugs. The acetylcholine concentration in whole mouse brain of controls was 2.35 ± 0.06 μ g/g wet wt. (16.1 nmol/g wet wt.) while the choline concentration was 6.52 ± 0.21 μ g/g wet wt. (62.7 nmol/g). Physostigmine, 0.5 mg/kg, oxotremorine, 2 mg/kg free base, and haloperidol, 4 and 8 mg/kg, increased both acetylcholine and choline 20 min after administration. Pentobarbital, 55 mg/kg, and diazepam, 5–40 mg/kg, increased only acetylcholine without affecting choline. Atropine, 50 mg/kg, lowered acetylcholine without affecting choline. Haloperidol, 1 mg/kg, chlorpromazine, 10 mg/kg, reserpine, 2.5 mg/kg, 20 hr, desmethylimipramine, 20 mg/kg, and amphetamine, 7 and 15 mg/kg, had no effect on either acetylcholine or choline. No drug studied caused a simultaneous decrease in these two quaternary amines. The possible significance of these findings on the mechanism of action of these drugs is discussed.

N-demethyldiazepam, diazepam and oxazepam incorporated in the diet were fed to albino Swiss male and female mice (10–50 mg per day per kg of body weight) for 6 months. Increased mortality was observed in grouped male mice but not in female or isolated male mice. Multiple skin lesions and necroses found in grouped male mice were probably due to increased aggression.

Resume Differents produits, antipurines, antifoliques, antipyrimidines agents alcoylants, alcaloides de la pervenche, mitomycine C, actinomycine D, puromycine, chloramphenicol, methylhydrazine, imidazoline terephtalanilide, methyl-glyoxal-bis (guanylhydrazone), acide epsilon-amino-caproique, sont etudies pour leur action immunodepressive chez la Souris, a l'aide d'un test comportant trois stimuli antigeniques differents (albumine humaine, poliovirus, greffon de peau allogenique) et l'administration du produit a une dose infraletale, rapportee a la dose letale sur 6 jours, par cures de 20 jours se terminant ou commencant le jour du stimulus antigenique. Les resultats obtenus montrent qu'a toxiciteegale, les corps essayes ont des activites immunodepressives tres differentes. Les corps qui interferent avec la synthese de l'ADN (antipurines, antifoliques, mitomycine C) sont surtout actifs avant le stimulus antigenique, alors que la cyclophosphamide et la methyl-hydrazine sont surtout actives apres le stimulus antigenique. Les enseignements apportes par les resultats obtenus sur le mecanisme des reactions immunitaires et les mecanismes d'action des produits utilises sont discutes. Les indications qui peuvent etre tirees de ces resultats pour les traitements immunodepresseurs chez l'Homme, destines a obtenir et maintenir la tolerance a des greffons et transplants incompatibles sont envisagees.

The typical symptomatology induced by amphetamine in laboratory animals is dependent not only on the species but also on the strain of the animals employed in the experiments. In different strains of mice the hyperthermic response and the lethality to amphetamine showed extreme variations, from more sensitive strains (Albino Swiss) to more resistant strains (C 57 B1/6 and C 3 H). d-Amphetamine toxicity Brain and liver amphetamine Different mice strains

Desipramine increases the sensitivity of the isolated tail artery of the rat to extraluminal noradrenaline much more than to intraluminal noradrenaline. Accumulation of radioactivity after infusions with dl -7- 3 H-noradrenaline is inhibited when noradrenaline is given by the extraluminal route and is unaffected when noradrenaline is given into the lumen.

Cyclophosphamide (CP) injected at different treatment schedules into CD male rats, prolongs narcosis after either parenteral or oral administration of pentobarbital. However, it takes 7 days before any change appears after CP pretreatment. The level of pentobarbital in blood and brain at different times after injection was higher in CP pretreated than in untreated animals. Since previous studies reported a decreased rate of inactivation of drugs after treatment with cytotoxic agents, experiments were performed to ascertain whether, beside the impairment of the metabolism, the animals respond differently to the same brain concentration of pentobarbital.

Nicotine given subcutaneously to rats raised the levels of plasma free fatty acids (FFA) and blood glucose, the content of FFA and glycerol in adipose tissue also being increased. The basal lipolysis

A “tissue culture” method for testing the cytotoxic activity of compounds active through the formation of metabolites is described and cyclophosphamide (CPA), which is known to exert its effect only after hepatic biotransformation, has been chosen as “model” substance. A monolayer of cultured KB cells is treated for one hour with CPA at 37°C, in the presence of different amounts of microsomal enzymes (105,000 × g fraction) and their co-factors and at the end of the incubation the medium is removed and changed. A dose-effect relation is observed by measuring the inhibition of growth or the destruction of the KB cells after 24 hr. The significance of this procedure for screening purposes or for studying the possible cytotoxicity of unstable metabolites is outlined.

Levels of diphenylhydantoin (DPH) and phenobarbital (PB) in plasma and brain of rats after single or combined, acute or chronic treatment have been determined. The results obtained indicate (a) drug plasma levels are not always a reliable index of brain levels because DPH disappearance from plasma is frequently more rapid than from brain; (b) DPH administration enhances the plasma and brain levels of PB; (c) levels of DPH or PB in brain correlate with the protection against a maximal electroshock.

Tryptophan injected intracerebrally in rats increases the level of brain serotonin. This increase occurs also in animals pretreated with reserpine or with a monoamineoxidase inhibitor. Other studies show that tryptophan, tryptamine or 6-hydroxytryptamine are not interfering in the determination of brain serotonin.

1. Acetylcholine and choline were measured in the spleens and irides of normal and 6-hydroxydopamine-treated cats. In addition, choline acetyltransferase activity was measured in the spleens. 2. No acetylcholine or choline acetyltransferase activity were found in spleens of normal or treated cats. The choline content of normal spleens was 12·4 ± 1·5 μg/g wet wt. (mean ± S.E. of mean), which was not significantly altered by chemical sympathectomy. 3. The acetylcholine and choline contents of the cat iris were 3·0 ± 0·3 μg/g wet wt. and 7·7 ± 0·9 μg/g wet wt., respectively. There was no difference in acetylcholine and choline concentrations between left and right or normal and sympathectomized irides. 4. These results are discussed in relation to the question of a cholinergic link in post-ganglionic sympathetic transmission.

1. The uptake of unlabelled and [(14)C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 mug/ml. The uptake was found to be dose- and time-dependent. Equilibrium was not reached after 2-3 h of incubation unless concentrations of desipramine higher than 1 mug/ml were used.2. The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration.3. The binding appeared to be at non-specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6-hydroxydopamine accumulated the drug at the same rate as control atria.4. The inhibition of (-)-noradrenaline uptake and the potentiation of the chronotropic response to (-)-noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 0.01 to 1 mug/g. Higher tissue levels show less potentiation of the effect of (-)-noradrenaline or even inhibition of the maximal response to (-)-noradrenaline. These concentrations of desipramine (> 7 mug/g) markedly depressed the atrial rate.5. The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.

3, 5-Dimethylpyrazole and its metabolite 3-carboxy-5-methylpyrazole lower plasma FFA and decrease the level of plasma triglycerides. The metabolite given intravenously is more rapidly effective than 3, 5-dimethylpyrazole. Plasma cholesterol and phospholipids as well as blood glucose were not affected by these acute treatments.

The reticulo-endothelial system (RES) activity in normal and in intracerebral Sarcoma 180-bearing mice was investigated after acute or subchronic treatment with the non-ionic surface-active agent: Triton WR 1339 (TWR). While the single treatment is ineffective, the subchronic treatment markedly raises the phagocytic index not only in normal mice but also in tumor-bearing animals where the RES is depressed by the presence of disseminating cancer cells. A possible relation between the RES stimulatory capacity and the antimetastatic effect exerted by TWR is envisaged.

TRITON WR 1339 (TWR), a formaldehyde polymer of polyoxyethylene ether of octylphenol, decreases the formation of lung metastases in C 57 B1/10 J/Sel mice transplanted in the leg with Lewis lung carcinoma, it reduces the number of lymph node metastases in Swiss albino mice transplanted intratibially with Ehrlich carcinoma and it reduces the number of cancer cells in the lung of Swiss albino mice transplanted intracerebrally with Sarcoma 180. These effects are achieved without any effect on the primary tumor. Furthermore TWR does not affect the growth of other tumors of the mice transplanted in different sites. Two main effects of TWR may be involved in its antimetastatic action: an effect on the host because TWR enhances the reticular endothelial system activity in tumor-bearing animals for foreign particles; an effect on the cancer cells because TWR, at concentrations present in vivo, affects the adhesiveness of cancer cells with an altered membrane, increases the volume, and decreases the movements of cancer cells. These effects may make in turn the cancer cells more susceptible to the defenses of the host. TWR is presented as the first example of antimetastatic agents differing from known antitumoral drugs also because it does not affect the primary tumor and the normal cells such as leukocytes.

Amitriptyline, nortriptyline and dibenzepine prolong the increase in temperature produced by amphetamine in rats and also increase the level of brain amphetamine above that effected by amphetamine alone. After chlorpromazine and propericiazine, brain amphetamine levels are also higher but the rise of body temperature elicited by amphetamine is inhibited. Phenelzine prolongs and α-methyl-p-tyrosine inhibits the rise in body temperature without modifying the accumulation of brain amphetamine. In reserpinized rats amphetamine causes a temperature increase several degrees greater than in control animals although its level in the brain is lower.

SummaryThis paper summarizes some studies recently carried out in this Institute in the field of cancer chemotherapy.Three main groups of data are reported:a) different sensitivity to chemotherapy of the same tumor transplanted in different sites of the body;b) a method to study cancer dissemination as a basis for cancer chemotherapy;c) a system to perfuse tissue culture with the blood of living animals as an approach to study duration of action of antitumoral drugs.

The metabolic pathways by which diazepam and its metabolites are transformed in vitro by rat and mouse liver microsomes were studied in detail. Using a gas chromatographic technique to measure benzodiazepines, it was demonstrated that the predominant reactions were N-demethylation in rat liver microsomes and C 3 hydroxylation in mouse liver microsomes. When N-demethyldiazepam or N-methyloxazepam was used as a substrate there was a clear formation of oxazepam. No exazepam was found in vitro when diazepam was incubated with liver microsomes. Some preliminary data indicate that the presence of diazepam inhibits the further hydroxylation of N-demethyldiazepam and the N-demethylation of N-methyloxazepam.

1. (+)-Amphetamine sulphate elicits a dose-dependent hyperthermia in NMRI mice but it does not significantly increase the body temperature of C3H mice. 2. When low doses of (+)-amphetamine are given, the body temperature of C3H mice decreases. 3. (+)-Amphetamine decreases the noradrenaline concentration in the brain-stem and increases the homovanillic acid concentration (HVA) in the striatum of NMRI mice, but only slightly reduces the noradrenaline concentration and does not change the HVA concentration in the brains of C3H mice. 4. The two strains appear to show a difference in the metabolism of dopamine in the striatum. The rates at which dopamine disappears from the tissue after blocking catecholamine synthesis with α-methyltyrosine and the rates at which HVA accumulates after blocking the active transport of this metabolite out of the brain with probenecid suggest that the turnover of dopamine is lower in C3H mice than in NMRI mice.

The 7-nitro group of nitrazepam (1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one) was reduced to the 7-amino derivative and then acetylated to the 7-acetylamino derivative during perfusion of the isolated rat liver. These compounds were present mainly in perfusion fluid, only small amounts were found in bile or liver tissue, homogenized at the end of the experiment. Other metabolites were not detected with the techniques used. Similar results were found with livers of guinea-pigs and rabbits. In contrast, the 7-amino derivative was the final product of nitrazepam metabolism in perfused mouse livers.

Resume On a etudie la sensibilite a la chimiotherapie de differentes tumeurs du rat ou de la souris implantees a des endroits differents, soit par voie sous-cutanee, soit par voie intracerebrale, ou encore intraperitoneale. Les resultats obtenus montrent, par exemple, que la 1-methyl-1-nitriso-uree (MNU) a un effet preferentiel sur les tumeurs implantees dans le cerveau, tandis que le cyclophosphamide et la dl -Sarcolisine sont plus efficaces sur les tumeurs implantees par voie sous-cutanee ou intraperitoneale.

The anticonvulsant activity of diazepam lasts longer in mice than in rats. The brain levels of diazepam are similar in both species but N-demethyl diazepam and oxazepam accumulate in mouse brain while they are practically undetectable in rat brain. This difference occurs also in blood and adipose tissue. N-methyloxazepam was not detected in rats or mice after an intravenous administration of diazepam. It is suggested that the N-methyl diazepam and oxazepam formed in mice may be responsible for the prolonged anticonvulsant action of diazepam in this species.

SUMMARY A comparative study of the immunosuppressive activities of 6-mercaptopurine and its derivative azathioprine has been performed. It has been shown that in mice and rats, 6-mercaptopurine is markedly superior to azathioprine in reducing the number of spleen hemolytic plaque-forming cells when injected by parenteral routes, whereas azathioprine is more effective by the oral route. Determinations of the levels of 6-mercaptopurine in serum and spleen after injection of both agents did not reveal substantial differences in the concentration of this compound. The possible role of the imidazole moiety released from the in vivo splitting of azathioprine in the reduced activity of the latter drug given parenterally is advanced.

Diazepam showed an antimetrazol activity which was longer-lasting in mice than in rats. The levels of diazepam in blood and brain were similar in both species but N-desmethyl metabolites ofdiazepam accumulated in mouse brain while they were practically undetectable in rat brain. The three main metabolites of diazepam, namely N-methyloxazepam, N-desmethyldiazepam and oxazepam showed strong anticonvulsant activity in mice.