Human circulating dopamine-Β-hydroxylase and epilepsy

The activity of circulatory dopamine--hydroxylase (DBH) in humans is shown to be lower in some epileptic subjects than in normal subjects. The activity of the enzymes was found to be dramatically low in subjects who experienced an epileptic seizure 24 hrs before DBH activity was determined. The activity varied through the course of epileptic seizures induced by a convulsant drug and these variations might be due to the en masse changes of the sympathetic nervous system.Abbreviations DBH Dopamine--hydroxylase - Bemegride 4-methyl-4-ethyl-2,6-dioxopiperidine This work is a part of the Doctorat d'Université Thésis of M.T. M.-P., recipient of the Juan March Fundation.D.A. is Attaché de Recherche at the INSERM.Service d'Exploration fonctionelle du Système Nerveux.     

The essential oil of Apium graveolens var. secalinum and its cercaricidal activity

The composition of the essential oil of the fresh aerial parts ofApium graveolens var.secalinum at its flowering stage, obtained from three different locations in Egypt, was investigated. The identification of the components of this oil was carried out by means of analytical GC and GC-MS. The main components in the oil are: - and -pinene, myrcene, limonene,cis--ocimene, -terpinene,cis-allo-ocimene,trans-farnesene, humulene, apiol, -selinene, senkyunolide and neocnidilide. Data concerning the relative concentrations of the main components of the different celery oil samples are given. The cercaricidal effect of the essential oil has been examined on cercariae, being one of the stages in the life cycles ofSchistosoma mansoni, which causes schistosomiasis. The essential oil showed in addition to a cercaricidal effect also a chemotactic effect.     

Urgent problems in the search for and creation of β-adrenergic blocking agents

The results are presented of a search for hybrid -adrenergic blocking agents (combining -adrenergic blocking activity with -adrenergic blocking, vasodilating properties, and also the ability to inhibit the angiotensin-converting enzyme) and -adrenergic blocking agents with a prolonged effect among the derivatives of 5-phenoxymethyl-1,2,4-oxadiazole and 4-(2-hydroxy-3-alkylaminopropoxy)indole. One of the studied substances (proxodolol) was introduced into medical practice as a highly efficacious antihypertensive. antianginal, and antiglaucoma drug.     

The effect of pretreatment with iproniazid on the behavioral activities of Β-phenylethylamine in rats

Rats were trained on DRL 15-sec schedule to choose between two response levers in the operant chamber in order to obtain food pellet. Choice of lever depended upon intraperitoneal injection of either 0.8 mg/kg d-amphetamine sulfate or saline as cue for response. -Phenylethylamine HC1 (1 mg/kg) or iproniazid phosphate (100 mg/kg) alone did not produce the discriminative cue in the animals similar to d-amphetamine. However, with treatment of animals with iproniazid prior to the administration -phenylethylamine to prevent the metabolism of the latter, the discriminative cue similar to d-amphetamine can then be generated by 1 mg/kg of -phenylethylamine. Iproniazid (100 mg/kg) caused decreased spontaneous locomotor activity in rats while -phenylethylamine (1 mg/kg) did not affect this behavior. When animals were pretreated with iproniazid for 3 h, -phenylethylamine could not increase spontaneous locomotor activity as d-amphetamine produced. It is probable that the amphetamine-like increase in motor activity produced by -phenylethylamine was masked by iproniazid which was shown to decrease spontaneous locomotor activity.     

Dopaminergic mediation of the interoceptive cue produced by d-amphetamine in rats

After rats were trained to differentiate between the effects of d-amphetamine and saline in a state-dependent task, pretreatment with the tyrosine hydroxylase inhibitor, -methyl-p-tyrosine, significantly decreased amphetamine discrimination. Pretreatment with the dopamine--hydroxylase inhibitor, disulfiram, or with the tryptophan hydroxylase inhibitor, p-chloro-phenylalanine, was observed to have no effect on the rats' ability to discriminate d-amphetamine. Administration of haloperidol, a selective dopamine receptor blocker, completely abolished the amphetamine discrimination, whereas - and -adrenergic receptor blockade had no effect. Apomorphine, a dopamine receptor stimulant, produced amphetamine-like responses and this was, likewise, abolished by pretreatment with haloperidol. These data suggest that dopaminergic systems mediate the interoceptive cue produced by d-amphetamine in rats, and these results are discussed in relation to possible dopamine mediation of amphetamine psychosis and paranoid schizophrenia.Supported as an Americal Medical Association Education and Research Foundation Senior Research Fellow.     

19-Norsteroids. Preparation of acetates of 5α-halo-6β,19-oxidoandrostan-3β-ol-17-one

Conclusions Conditions were found for oxidation of the 3-acetate of 5-bromoandrostan-3,6-diol-17-one with lead tetraacetate from which the pure acetate of 5-bromo-6,19-oxidoandrostan-3-ol-17-one could be obtained in 87–89 % yield. It was shown that the technical product obtained under these conditions can be used without purification for further transformations.Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 4, No. 2, pp. 5–9, February, 1970.     

Action of metyrapone on the redox state of free nicotinamide-adenine dinucleotide and on oxygen consumption of perfused rat livers and isolated mitochondria

Summary Metyrapone [2-methyl-1,2-bis-(3-pyridyl)-1-propanone] in a concentration of 5 mM increased the lactate/pyruvate ratio and the-hydroxybutyrate/ acetoacetate ratio in the perfusion fluid of the isolated rat liver by a factor of 6 indicating a considerable shift in the ratio of free [NAD]/[NADH] in both the cytoplasmic and the mitochondrial compartment. Oxygen uptake of the isolated liver was decreased to about one half. The onset of the inhibitory effect on the respiration of the isolated organ was immediate. The inhibition lasted for at least 1 h.In experiments with isolated mitochondria utilizing-hydroxybutyrate as a substrate, a decrease of the respiration rate and of the rate of ferricyanide reduction to about one half was observed after the addition of 5 mM metyrapone. Thein vitro findings indicate that the effect of metyrapone on the metabolic state of the isolated organ is due to an attack by the substance on the respiratory chain. The entrance of hydrogen into the chain mediated by-hydroxybutyrate dehydrogenase as well as the terminal oxidation in the chain were not affected by metyrapone.We thank Professor Dr. W. Staib, Düsseldorf, for the demonstration of his liver perfusion technique.The able and careful technical assistance of Miss Ingeborg Raab is gratefully acknowledged.     

Comparison of tyrosine hydroxylase and dopamine-Β-hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity

The significance of central noradrenergic and dopaminergic neural systems for the locomotor stimulant effects of d-amphetamine were investigated in rats with depletions of norepinephrine, dopamine, or both catecholamines produced by treatment with either reserpine, L--methyl-tyrosine (-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine--hydroxylase inhibitor 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by -MPT but not by U-14,624 when amphetamine was given l h after these catecholamine synthesis inhibitors. In rats with chronic depletions of brain norepinephrine, dopamine, or both catecholamines produced by different 6-OHDA treatments, both amphetamine-stimulated motor activity and stereotyped behavior were antagonized by treatments reducing dopamine or both catecholamines but not in animals in which brain norepinephrine was reduced. Results are consistent with the view that the locomotor stimulation and stereotyped behaviors produced by d-amphetamine are dependent upon functional dopaminergic neural systems in brain.     

Relationship between in vitro relaxation of the costo-uterine smooth muscle and mesovarial leiomyoma formation in vivo by Β-receptor agonists

The three -agonists, salbutamol, ritodrine, and terbutaline have been shown to possess differing potentials to induce leiomyomas in rat costo-uterine muscle following chronic exposure (salbutamol > terbutaline > ritodrine). It has been suggested that the potential to induce leiomyomas is related to the relaxant properties of these agonists in the costo-uterine muscle. In order to test this hypothesis, the potencies of salbutamol, terbutaline, and ritodrine were compared to isoproterenol and norepinephrine in vitro in the rat costo-uterine smooth muscle, a ₂-adrenergic receptor rich tissue. All compounds produced relaxation of potassium chloride (KCl) contracted costo-uterine smooth muscle. Significant differences in potency were observed, with isoproterenol being the most potent, followed in rank order by salbutamol, terbutaline and ritodrine. The relative potency of the non-selective -blocker propranolol in inhibiting the agonist mediated relaxant activity was similar for all agonists examined, indicative of interactions at the same receptor site (Tallarida and Jacob 1979). When tested for -agonist activity in the guinea pig atria, salbutamol and ritodrine were less potent in these tissues compared to the costo-uterine muscle.In summary, the in vitro pharmacological potency of salbutamol, terbutaline and ritodrine correlated with the potential to induce leiomyoma formation in rat costouterine muscle following chronic exposure to the respective -agonists. These results indicate that the isolated rat costo-uterine muscle is a sensitive model for comparing the potency of -agonists, and may assist in establishing the risk of costo-uterine leiomyoma formation in chronic rat studies relative to agents such as salbutamol.     

Avoidance conditioning in different strains of rats: Neurochemical correlates

Two-way avoidance conditioning was compared in three strains of rats: Roman high avoiders (RHA), Roman low avoiders (RLA) and control Sprague-Dawleys (SD). RHAs performed more and RLAs fewer avoidance responses than SDs. RLAs injected with d-amphetamine improved their performance to levels comparable to SDs; however, d-amphetamine caused a time-dependent increase in intertrial crossings for the RLAs. Of the three strains, the RLAs had the lowest activities of tyrosine hydroxylase, dopamine--hydroxylase and phenylethanolamine-N-methyltransferase in their adrenal glands. Although there were no significant differences among the strains in respect to tyrosine hydroxylase activity in whole brain or regions, RLAs had higher dopamine--hydroxylase activity in the whole brain and cerebral cortex as compared to the SDs. RLAs and RHAs together had a significantly different turnover of intracisternally administered ³H-norepinephrine than SDs. After the intracisternal injection of ³H-L-tyrosine, twice as much ³H-dopamine accumulated in the brains of RLAs as compared to RHAs and SDs.     

CNS stimulant properties and physiologic disposition of Β,Β-difluorophenylethylamine in mice

,-Difluorophenylethylamine, because of the strong electrophilic nature of the fluorines, is a much weaker base than is phenylethylamine. The pK for the difluoro compound is 6.75 compared to 9.55 for phenylethylamine. At physiologic pH, difluorophenylethylamine exists primarily as a neutral molecule, whereas phenylethylamine is almost entirely cationic. Difluorophenylethylamine caused increased locomotor activity in mice, and its effects were enhanced by a monoamine oxidase inhibitor (tranylcypromine) as were the effects of phenylethylamine. Comparable levels of difluorophenylethylamine and phenylethylamine in brain appeared to lead to equivalent increases in locomotor activity. At doses above those giving the maximum increase in locomotor activity, behavioral differences between phenylethylamine and difluorophenylethylamine were observed. Difluorophenylethylamine localized in adipose tissue to a greater degree than in other organs; it disappeared from adipose tissue and from brain with a physiologic half-life of 8 min in mice.     

Serum dopamine-Β-hydroxylase (DΒH) activity and affective states

Using a sensitive assay system recently developed, dopamine--hydroxylase (DH) was examined in the serum of 56 psychiatric patients and 33 normal control subjects. Blood values of this enzyme failed to differentiate between the various diagnostic populations explored and were compatible with values obtained for normal control subjects within the same age range. The findings are critically evaluated and their possible relevance discussed with regard to the role of catecholamines in affective disorders.This work was supported by USPHS Grants Nos. 17436 and MH 02717.     

Synthesis and pharmacological study of 5-phenoxymethyl-1,2,4-oxadiazole derivatives

Novel 3-amino-2-hydroxypropoxy derivatives of 5-phenoxymethyl-1,2,4-oxadiazole were synthesized. Compounds were discovered among them that had pronounced -adrenergic blocking activity combined with moderate -adrenergic blocking properties.     

Comparative induction of cytochrome P450IVA1 and peroxisome proliferation by ciprofibrate in the rat and marmoset

Chronic ciprofibrate administration resulted in distinct differences in hepatic responses between the two species examined. In the rat, hepatomegaly was observed with the coordinate induction of carnitine acetyltransferase, peroxisomal -oxidation and cytochrome P450IVA1 activities. The latter induction of cytochrome P450IVA1-dependent fatty acid hydroxylase activity was specific to this cytochrome P450 sub family, as ciprofibrate pretreatment resulted in an inhibition of the enzyme activities associated with the cytochrome P450 IIB and IA sub-families. Induction of mitochondrial enzymes were also noted in the rat, but at a substantially lower level than the microsomal and peroxisomal enzyme changes noted above. The majority of these enzyme changes were reversible in the rat after a 4-week, inducer-free period. In contrast, the marmoset displayed a different pattern of enzyme changes in response to ciprofibrate and at the high dose level, inhibition of microsomal fatty acid hydroxylase activity was observed in addition to no change in carnitine acetyltransferase activitiy. Although peroxisomal -oxidation activity was induced in the marmoset, the specific activity was 10-fold lower than in the rat, concomitant with only minimum changes in the liver: body weight ratio. Taken collectively, our data have demonstrated that the marmoset is relatively refractory to ciprofibrate-induced liver enzyme changes with the implication that the extrapolation of the associated hepatotoxicity clearly documented in rodents must be viewed with extreme caution in non-human primates.     

Effect of α- and Β-adrenergic blocking agents and para-chlorophenylalanine on morphine- and caffeine-stimulated locomotor activity of mice

5 and 15 g/g morphine caused marked excitation in mice. This effect could be completely abolished by simultaneous treatment of the animals with 50 g/g of the -sympatholytic drug phenoxybenzamine. The adrenergic -receptor blocking agents propranolol (5 and 20 g/g) and INPEA (5 and 25 g/g) and the serotonin depletor p-chlorophenylalanine (3 times 600 g/g) were ineffective in this respect.On the other hand, the excitatory effect of 40 g/g caffeine could be reduced only by p-chlorophenylalanine (3 times 600 g/g) but not by phenoxybenzamine and propranolol. These results suggest, that the central stimulating effect of morphine is probably mediated by catecholamines, whereas serotonergic mechanisms may be involved in the effect of caffeine.     

Application of semilinear canonical correlation to the measurement of opioid drug effect

To examine the relationship between the electroencephalograph (EEG) and plasma opioid concentration, one would like to collapse the high-dimensional EEG signal into a univariate quantity. Such a simplification of the EEG is desirable because a univariate quantity can be modeled using standard nonlinear regression techniques, and because most of the information in the EEG is redundant or unrelated to drug concentration. In previous studies of the EEG response to opioids, the manner in which a univariate component was extracted from the EEG was ad hoc.In this paper, this extraction was performed optimally using a new statistical technique, semilinear canonical correlation. Data from 15 patients who received an intravenous infusion of the semisynthetic opioid alfentanil were analyzed. The components of the EEG that were nearly maximally correlated with plasma drug concentration were found, based on a standard pharmacokinetic-pharmacodynamic model. Two new EEG components were produced from the powers in the frequency spectrum of the EEG: a weighted sum of the logarithms of the powers, and a weighted sum of the powers expressed as percentages of the total power. These components both had a median R² of 0.84, compared to median R²sranging from 0.37 to 0.83 for five commonly used ad hocEEG components. The new components also had less variability in R² between subjects.Effect-site model t Time - C _E(t Effect-site concentration at timet - k _e0 Rate constant for drug transfer from the plasma to the effect site Hill equation E EEG effect - E ₀ Baseline effect, when no drug is present in the effect site - E _max Maximum possible effect caused by the drug - IC ₅₀ Effect-site concentration resulting in an effect equal to (E ₀+E _max/2 - Shape parameter - Additive error Semilinear canonical correlation model q Number of dependent variables - Y ₁,Y ₂,...,Y _q Dependent variables - ₁, ₂, ..., ₁ Coefficients of the dependent variables - p Number of independent variables - X ₁,X ₂,...,X _p Independent variables - f Nonlinear regression function - r Number of parameters off - ₁, ₂,..., _r Parameters off - Additive random error - n Number of observations - y _tk tth observation ofY _k ,t=1, 2,...,n,k= 1,2,..., q - y _t () tth observation of the univariate response obtained as a linear combination of the multivariate response, ₁ y _t1 + ₂ y _t2 +...+ _q y _tq - x _tj tth observation ofX _j,t=1, 2,...,n,j=1,2,...,p - x _t The vector (x _t1,x _t2, ...,x _tp) - R ² Proportion of variability in they _t () explained by thef(x _t ;) - MaximumR ² estimate of - MaximumR ² estimate of - ^(j) MaximumR ² estimate of, for thejth subject - Average of the (possibly renormalized) ^(j) Linear regression model (special case of SCC model) Y Dependent variable (i.e.,q=1) - p Number of independent variables, and the number of coefficients of the independent variables (i.e.,r=p) - X ₁,X ₂,...,X _p Independent variables - =( ₁, ₂,..., _p ) Coefficients of the independent variables - Additive random error - n Number of observations - y _t tth observation ofY,t= 1, 2,...,n - x _tj tth observation ofX _j,t= 1, 2,...,n,j=1, 2,...,p - b=(b ₁,b ₂,...,b _p ) Estimates (not necessarily optimal) of the coefficients - _t(b) Responses predicted using the estimatesb, b ₁ x _t1+b ₂ x _t2+...+b _p x _tp - SSE(b) Sum of squared errors from estimating byb, ⁿ _t=1[y _t – _t (b]² - y Average of the observed responses, ⁿ _t=1y _t /n - SST Total sum of squares, ⁿ _t=1 (y _t–y)² - Estimate of that is least squares (minimumSSE) and maximumR ² - R ² Coefficient of multiple determination, 1–SSE()/SST Miscellaneous P Edge frequency percentage Supported in part by the Veterans Administration Merit Review Program, a Starter Grant from the American Society of Anesthesiologists, and Biomedical Research Support Grant RR05353 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health, and the Anesthesia/Pharmacology Research Foundation.     

Behavioral and electrophysiological effects of phenylethanolamine and 2-phenylethylamine

The electrophysiological and behavioral effects of phenylethanolamine (OHPEA) and of its precursor 2-phenylethylamine (PEA) were studied in mice and rabbits. In animals pretreated with MAOI, PEA was found to exert strong amphetamine-like effects, EEG alerting, reduction of visual evoked responses, increased locomotor activity, and blockade of tonic seizures induced by electroshock. OHPEA exerted weaker amphetamine-like effects. Inhibition of dopamine--hydroxylase increased most of the effects of PEA. In non-pretreated animals, OHPEA was found to shorten electroshock latency and to prolong the duration of visual evoked responses. PEA (but not OHPEA) potentiated the excitement induced by ⁹-tetrahydrocannabinol in MAOI-pretreated mice. Reserpine pretreatment reduced but did not abolish the CNS effects of OHPEA and PEA. One may speculate that endogenous PEA is more likely to serve as a modulator for ergotropic functions than is endogenous OHPEA.     

Synthesis and pesticidal activity of 1,2,3,4-tetrahydroquinoline derivatives

Some new 4-methyl-1,2,3,4-tetrahydroquinolines containing propyl, phenyl and pyridyl radicals at the C-2 position were synthesized from readily available N-aryl-N-alkenylamines. The latter and the tetrahydroquinolines obtained were tested for bactericidal, fungicidal, and herbicidal activities. Among the tetrahydroquinolines tested, those containing an -, -, or -pyridyl substituent have found to be most potent as fungicides.     

Pharmacokinetics and pharmacodynamics of diprophylline

Diprophylline is used in many countries as a bronchodilator. It is an N-substituted theophylline derivative which does not release theophyllinein vitro orin vivo. It therefore has its own pharmacokinetic and pharmacodynamic properties. In a cross-over study in ten healthy volunteers serum concentrations and urinary excretion were studied after administration of diprophylline.Its serum decay after intravenous administration shows two-compartment kinetics with a rapid distribution. The-phase lasted on average 0.75 h and was 0.427±0.118 h^–1, corresponding with a-phase half-life of 1.7±0.4 h. The mean volume of distribution was 0.70±0.20 l/kg, total body clearance 0.29±0.09 l.kg^–1.h^–1. About 84% of the drug is excreted unchanged in the urine. A comparison of the area under the curve suggests that the drug was almost completely absorbed from the gastro-intestinal tract. Its bioavailability is about 90%. Mean renal clearance values are higher than paired creatinine clearance values, which is an indication for active renal transport.Peak levels of diprophylline were 7.4±2.2 mg/l at about 30 min after oral administration. The normal dose advocated is 200–400 mg three times a day. Inin vitro studies and in pharmacological animal studies diprophylline appears to be much less active than theophylline. Consequently estimated effective dosages are irrationally high.In honour of ProfessorHuizinga on the occasion of his retirement.     

Evidence for a noradrenergic and dopaminergic mechanism in the hyperactivity produced by 4, α-dimethyl-m-tyramine (H 77/77) in rats

The effect of H 77/77 on motility was investigated after s. c. injection to rats in a familiar cage. The doses 2.5 and 5 mg/kg produced hypermotility consisting of locomotion, sniffing, rearing, head twitch and various grooming movements.H 77/77 5 mg/kg was administered to rats treated s. c. with various drugs affecting brain monoamines. The H 77/77-hyperactivity was antagonized by: the tyrosine hydroxylase inhibitor H 44/68 (250 mg/kg), the dopamine--hydroxylase inhibitor FLA 63 (40), the NA receptorblockers aceperone (1.1) and phenoxybenzamine (0.8), the thymoleptics imipramine (0.7), desipramine (6.3), chlorimipramine (1.5), amitriptyline (0.1), nortriptyline (1.0), protriptyline (0.7) and doxepine (0.3) as well as the neuroleptics chlorpromazine (0.015), thioridazine (0.7), perphenazine (0.008), chlorprotixene (0.03), haloperidol (0.02), spiramide (0.03), pimozide (0.04) and clozapine (0.014).The serotonin synthesis inhibitor H 69/17 (200), the -blocker propranolol (10) and the antiparkinsonian agent benztropine (10) showed no H 77/77 antagonism.These results indicate that release of catecholamines, especially NA, is involved in the mediation of H 77/77-induced hypermotility and that NA-membrane blocking thymoleptics inhibit uptake of H 77/77 into brain NA-neurons. Activation of both NA- and DA-receptors are necessary for the production of the H 77/77 behavioral syndrome as selective blockade of either system can prevent it.