NG-nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from l-arginine

Summary We studied the effects of the l-arginine analogue N^G-nitro-l-arginine (l-NNA), in comparison with its d-isomer (d-NNA), on endothelium-dependent dilations of rabbit femoral arteries (RFA) and on the release of endothelium-derived relaxant factor (EDRF) from native and cultured endothelial cells. In addition, we examined the effects of l- and d-NNA on the l-arginine- and NADPH-dependent synthesis of nitric oxide (NO) in the cytosol of porcine aortic endothelial cells. l-NNA enhanced the noradrenaline-induced contraction of endothelium-intact, but not of endothelium-denuded segments of RFA, indicating an inhibition of basal EDRF release. l-NNA also inhibited significantly the endothelium-dependent dilations to acetylcholine (ACh). Both effects of l-NNA were attenuated by l-arginine. l-NNA rapidly inhibited the release of EDRF from cultured and native endothelial cells stimulated with thimerosal or ACh. l-NNA concentration-dependently and reversibly antagonized the l-arginine- and NADPH-dependent activation of a purified soluble guanylate cyclase (GC) by cytosol from.Sreshly harvested porcine aortic endothelial cells, suggesting a direct competition between l-NNA a l-arginine at the level of endothelial NO-synthesis. d-NNA was ineffective in all instances. These results prove l-NNA to be a stereospecific inhibitor of the cytosolic NO formation from l-arginine in endothelial cells. Therefore, l-NNA will be a useful tool to elucidate the molecular mechanism of mammalian NO synthesis. Send offprint requests to A. Mdlsch at the above address     

A comparison of drug-seeking behavior maintained by d-amphetamine, l-deprenyl (selegiline), and d-deprenyl under a second-order schedule in squirrel monkeys

l-Deprenyl (selegiline) is used in the treatment of Parkinson’s disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. l-Deprenyl is metabolized in the body to l-methamphetamine and l-amphetamine, suggesting that it may have abuse potential. The current study assessed whether l-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether l-deprenyl would alter drug-seeking behavior maintained by d-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of d-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of d-amphetamine (0.3–1.0 mg/kg), l-deprenyl (0.1–10.0 mg/kg), and d-deprenyl (0.1–3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg l-deprenyl intramuscularly 30 min prior to d-amphetamine baseline sessions. d-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. d-Deprenyl maintained high rates of drug-seeking behavior similar to d-amphetamine. l-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with l-deprenyl failed to alter drug-seeking behavior maintained by d-amphetamine. These results indicate that d-deprenyl, but not l-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by d-amphetamine, l-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.     

Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist

thip (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a potent and specificgaba receptor agonist which does not influence thegaba uptake system orgaba metabolizing enzymes. The specificity for thegaba receptor is also demonstrated by lack of action on monoaminergic, cholinergic, histaminergic or opiate receptors.Since in recent yearsgaba receptor stimulants — among othersthip — have become available many have speculated as to what clinical indicationgaba-ergic stimulation might be an important element. The first suggestion was thatgaba-ergic drugs by an inhibitory effect on the dopamine neurons would improve the antischizophrenic effect of neuroleptics and improve tardive dyskinesia. Furthermore, studies on brains of deceased Parkinson and Huntington's chorea patients have demonstrated a low level ofgaba and its synthesizing enzyme glutamic acid decarboxylase (gad) in the basal ganglia. Also in epilepsy and diseases with dementia a deficit in thegaba system has been proposed. Therefore a therapeutic strategy for these diseases may be supplementary treatment with drugs which increasegaba receptor activity.Furthermore, recent results in humans have shown thatgaba agonists perhaps also could be of benefit in mania and depressions. When considering the neurophysiological elements of nociception and muscle tone it is also reasonable to suggest thatgaba-ergic stimulation may reduce pain perception and muscle tone.     

Beta-blockade and angina pectoris: a controlled multi-centre clinical trial

Summary A double-blind multicentre investigation has been set up in patients with angina pectoris to compare the activity of a beta-blocker (Ciba 39'089-Ba, Trasicor) with a placebo. Further, a follow-up study of the clinical effects after long-term treatment was carried out. — As criteria of evaluation the following were considered: number and severity of anginal attacks, consumption of nitroglycerin pills, physical condition, and performance. At the end of the trial the patients were asked to state which drug they preferred. The patients were checked for body weight, blood pressure, heart rate, ECG and side-effects. The data obtained on 62 patients were evaluated statistically. The analysis proved that Trasicor is more effective than the placebo in reducing the number of anginal attacks and the consumption of nitroglycerin pills, and is more effective in improving physical performance. No change was noticed in body weight but the heart rate and systolic blood pressure decreased with the drug. — Only mild side-effects were reported in a small number of patients. — A clear-cut reduction or total remission of anginal attacks and diminished nitroglycerin consumption were observed during the long-term study.The following investigators took part in the study: G. Antonioli (Ferrara) ; E. Azzi (Treviso) ; G. Bianchi, (Sassari); G. Bovo (Rovereto); F. Brunori (Pisa); F. Camerini (Trieste); S. Campus (Torino); C. Dal Co' (Venezia); C. Forattini (Monselice); R. Gallinelli (Modena); R. Lazzaretto (Padova) ; E. Martinoli (Trieste) ; R. Mezzena (Cles) ; M. Motolese (Roma) ; G. Muiesan (Perugia); C. Rossi (Roma); G. Salvato (Merano); R. Starcich (Parma); G. Vettori (Vicenza).The statistical analysis was carried out by A. Colombi (Milano). Coordinators: C. Bianchi (Parma) and P. E. Lucchelli (Milftnol)     

De morfinebepaling in opium volgens de nederlandse farmacopee editie VIII

Samenvatting Bij de bepaling van morfine in opium volgens de methode vanMannich is het volgens verscheidene onderzoekers (Teijgeler; schultz enSchnekenburger;Böhme enHühnermann) noodzakelijk de begeleidende alkaloïden vooraf door uitschudden uit alkalisch milieu te verwijderen.Porsius merkt na onderzoek hierbij op, dat de morfineverliezen hierbij groter zijn dan de voordelen welke door zuivering worden verkregen. Zijn proeven werden door ons herhaald, waarbij werd vastgesteld dat de verliezen minder zijn danPorsius veronderstelt. De gevonden verliezen bedroegen ca. 1.7%.Verder werden enige details van de bepaling gecontroleerd en wijzigingen voorgesteld. De wijzigingen zijn reeds in de methode van de Nederlandse Farmacopee, Ed.viii verwerkt.

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In the determination of morphine in opium according to the method ofMannich several investigators (Tfijgeler:Schultz andSchnekenburger;Böhme andhuhnermann) think it is necessary first to remove the other alkaloids from alkaline medium by extraction. After investigation porsius notices that the losses of morphine are higher than the advantages obtained by purification. His experiments were repeated by us at which was established that the losses are less thanPorsius supposes. The losses found amounted to circa 1.7%.Further some details of the determination were checked and some changes were proposed. These changes have already been introduced to the method described in the Dutch Pharmacopoeia Edition viii.

     

Possible involvement of l-arginine-nitric oxide pathway in modulating regional blood flow to brown adipose tissue of rats

To evaluate whether the l-arginine-nitric oxide (NO) pathway is involved in the regulation of regional blood flow to brown adipose tissue (BAT), the effects of two specific NO synthase inhibitors, N^G-nitro-l-arginine methyl ester (l-NAME) and N^G-monomethyl-l-arginine (l-NMMA), on the blood flow to interscapular brown adipose tissue (IBAT) were studied in urethane-anesthetized rats. Regional blood flow in MAT was measured with laser-Doppler flowmetry.An intravenous injection of l-NAME and l-NMMA, but not of either d-enantiomer, caused a transient and dose-dependent increase in IBAT blood flow. Dose-response curves for these NO synthase inhibitors showed that l-NAME was more potent than l-NMMA in increasing IBAT blood flow. We also observed a concomitant pressor effect accompanied by a slight decrease in heart rate following intravenous injection of l-NAME and l-NMMA. An elevation of IBAT blood flow and blood pressure induced by both l-NAME and l-NMMA was reversed by l-arginine in an enantiomerically specific manner. The increase in IBAT blood flow induced by NO synthase inhibitors was of shorter duration and less sensitive to l-arginine than the increase in blood pressure.Our results show that the WAY blood flow is increased by inhibition of NO synthase and that the response of IBAT vasculature to NO synthase inhibitors is different from that of the resistance vessels which regulate blood pressure. The involvement of l-arginine-NO pathways in modulating microcirculation in IBAT is suggested. Correspondence to: Y. Uchida at the above address     

Potentiation of opioid — Induced cataracts by catecholamines injected into the mouse brain

Summary The cataractogenic effect of parenteral levorphanol was increased by the injection of catecholamines into the mouse brain. Although l-epinephrine potentiated this effect most strongly, the potency of dl-isoproterenol unexpectedly equaled that of l-norepinephrine. Phenoxybenzamine, however, blocked the effect of l-norepinephrine, whereas pronethalol failed to inhibit dl-isoproterenol. That dl-isoproterenol may act indirectly is supported by the finding that treatment of the mouse with reserpine blocked the potentiation induced by dl-isoproterenol but did not inhibit the action of the pressor catecholamines.     

Molecular pharmacology of somatostatin receptors

The neuropeptide somatostatin (SRIF) is widely expressed in the brain and in the periphery in two main forms, SRIF-14 and SRIF-28. Similarly, the presence of SRIF receptors throughout the whole body has been reported. SRIF produces a variety of effects including modulation of hormone release (e.g. GH, glucagon, insulin), of neurotransmitter release (e.g. acetylcholine, dopamine, 5-HT), and its own release is modulated by many neurotransmitters. SRIF affects cognitive and behavioural processes, the endocrine system, the gastrointestinal tract and the cardiovascular system and also has tumor growth inhibiting effects. Initially, two classes of SRIF receptors have been proposed on the basis of biochemical and functional studies. However, the recent cloning of five putative SRIF receptor subtypes which belong to the G-protein coupled receptor superfamily suggests that SRIF mediates its various effects via a whole family of receptors. Here we review, in this new context, the molecular pharmacology of the SRIF receptor subtypes present in the brain and in the periphery, and address the question of nomenclature of SRIF receptors.Abbreviations BIM-23003 c[Cys-Lys-Asn p-Cl-Phe-Phe-d-Trp-Lys-Thr-Phe Thr-Ser-Cys] - BIM-23014 d-Nal-c[Cys Tyr-d-Trp-Lys Val-Cys]-Thr-NH₂ - BIM-23023 d-Phe-c[Cys Tyr-DTrp-Lys-Abu-Cys]-Thr-NH₂ - BIM-23027 c[N-Me-AlaTyr-d-Trp-Lys-Abu-Phe] - BIM-23030 c[MPA-Tyr-d-Trp-Lys-Val-Cys]-Phe-NH₂ - BIM-23049 d-Nal-Ala-Tyr-d-Trp-Lys-Val-Ala Thr-NH₂ - BIM-23052 d-Phe-Phe-Phe-d-Trp-Lys-Thr-Phe-Thr-NH₂ - BIM-23055 d-Phe-Phe-Tyr-d-Trp-Lys-Val-Phe-d-Phe-NH₂ - BIM-23056 d-Phe-Phe-Tyr-d-Trp-Lys-Val-Phe-d-Nal-NH₂ - BIM-23058 d-Phe-Phe-Tyr-d-Trp-Lys-Val-Phe-Thr-NH₂ - BIM-23059 d-Nal-c[Cys-Tyrd-Trp-Lys-Thr-Cys]-Thr-NH₂ - CGP 23996 c[Asu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser] - L-362,823 c[Aha-[Cys-Phe-DTrp-Lys-Thr-Cys]] - L-362,855 c[Aha-Phe-Trp-d-Trp-Lys-Thr-Phe] - L-362,862 c[Aha-Phe-p-Cl-Phe-DTrp-Lys-Thr-Phe] - L-363,301 c[Pro-Phe-d-Trp-Lys-Thr-Phe] - L-363,572 c[d-Ala-d-Phe-d-Trp-Lys-d-Thr-N-Me-d-Phe] - MK-678 c[N-Me-Ala-Tyr-d-Trp-Lys-Val-Phe] - SA c[Aha-Phe-d-Trp-Lys-Thr(Bzl)] - SMS 201-995 d-Phe-c[Cys-Phe-d-Trp-Lys-Thr-Cys]-Thr-ol Correspondence to: D. Hoyer at the above address     

Joint international quality control programme on the determination of antiepileptic drugs

In a joint effort, 4 existing Quality Control programmes organized in September 1978 a test on the determination of antiepileptic drugs and made an inventory of the various methods of analysis used. To approx. 700 laboratories 3 lyophilized calf s serum specimens, each of them spiked with 8Ae drugs, were distributed together with an extensive questionnaire. The number of laboratories reporting results, were: phenobarbital 601, phenytoin 624, carbamazepine 398, 10, 11- epoxide-Cbz 15, primidone 434, ethosuximide 302, valproic acid 167 and clonazepam 26; approx. 95% of them also completed the questionnaire. As to themethods per Q.C. programme,Emit was mainly used in USA,Glc in Europe,Hplc in USA (Rp systems) and in The Netherlands (sp systems),Ria in USA and Scandinavia. As to theresults per method,Emit, Glc andHplc produced similar results in therapeutic and sub-toxic concentrations ofPb, Dph andPri; in the sub-therapeutic range of these drugs,Glc andHplc gave better results thanEmit (which produced values 10–20% higher than the theoretical ones). InEsm andVal, Glc-methods are preferred while inCbz, Hplc is the method of choice, followed byEmit. InClona, severalGlc andHplc methods are still under investigation. Spectrophotometric determinations (mainly used inPb, Dph andCbz) proved to be not reliable. In tables, results per technique are subdivided into approx. 5 methods. This enables to distinguish betweene.g. Glc-derivatization with and without previous clean up or betweenEmit-automatic < 10Μl and 50Μl samples. Per drug, the various methods of assay are discussed; also, methods and results are given when drugs were determined simultaneously. Bovine serum (calfs serum) proved to be a suitable matrix in all methods used.     

Some effects of chlordiazepoxide and meprobamate with psychiatric outpatients

Summary 85 psychiatric outpatients were treated under double-blind, flexible dosage conditions for 8 weeks with either chlordiazepoxide, meprobamate, or placebo. Patients were tested—on measures of tension, anxiety, and related criteria—prior to treatment and at weekly or biweekly intervals after receiving medication. Each drug group was compared with a different matching placebo group. Despite the small number of cases and relatively low anxiety levels of many patients, there was evidence that chlordiazepoxide was probably somewhat more effective than placebo with the kinds of outpatients normally treated principally or solely with tranquilizers. Most of the evidence suggested that the maximum benefits of chlordiazepoxide appeared between 4 and 6 weeks for this sample. There was no evidence to suggest that meprobamate was more effective than placebo. Meprobamate clearly did not produce the expected effects; with some patients it appeared to act contrary to expectations. The meprobamate findings were presented in some detail because other investigators might want to check their data for similar patterns.A Veterans Administration Cooperative Study of Chemotherapy in Psychiatry.We gratefully acknowledge the contributions of the thirteen Mental Hygiene Clinic staffs and, especially, the investigators who directed the study at each clinic: Albany (Ronald Tiffany, Ph.D.), Atlanta (Louis A. Cibelli, M.D.), Chicago (Irvin Roth, Ph.D.), Coral Gables (Jack Sandler, Ph.D.), Denver (Harl H. Young, jr., Ph.D.), Des Moines (Leo Subotnick, Ph.D.), Jackson (Veronica Pen-Nington, M.D.), New York (Melvin Weiderlight, M.D.), Philadelphia (Werner K. R. Welz, M.D.), San Diego (Loren E. Conner, M.D.), San Francisco (Donald A. Shaskan, M.D.), and Spokane (Alfred J. Hewitt, M.D.). We are also grateful to George J. Weinstein, M.D., Chief of Veterans Administration Outpatient Psychiatry, who was extremely helpful in making the study possible.     

Participation of nitric oxide in the relaxation of the rat gastric corpus

Nitric oxide is an important mediator of the relaxation in the rat gastric fundus. The present study investigates the role of NO in the rat gastric corpus in vitro, since the corpus differs from the fundus with regard to its physiological function and its spontaneous motor behaviour.In the presence of guanethidine electrically induced relaxations of circular, mucosa-free corpus strips precontracted with bethanechol were concentration-dependently reduced by the NO-synthase inhibitors l-N^G-nitro-arginine (l-NNA) or l-N^G-nitro-argininemethyl-ester (l-NAME). The d-enantiomers were markedly less active. The inhibitory effect of l-NAME could be prevented by l-arginine. l-NNA and l-NAME, however, did not influence spontaneous motility or the bethanechol-induced contraction. Vasoactive intestinal polypeptide or sodium nitroprusside also relaxed the muscle strips, but these relaxations were not affected by l-NAME. When the corpus strips were stimulated electrically from baseline, they reacted with a contraction followed by relaxation. l-NNA or l-NAME blocked the relaxatory and enhanced the contractile component. In strips that also reacted with a rebound contraction, it was blunted by l-NAME. These effects of the NO-synthase inhibitors were abolished in the presence of atropine. Apamin increased the electrically induced contraction of the muscle strips. Inhibition of the relaxation together with a further shift to contraction could only be seen when apamin was combined with l-NNA. The inhibitory action of apamin and apamin + l-NNA was not influenced by atropine.The results demonstrate a role of NO in the relaxation of the circular muscle of the rat gastric corpus both at a postsynaptic site and via inhibition of acetylcholine release. The relaxation induced by vasoactive intestinal polypeptide does not involve NO.     

Prostaglandines en de nier

Teneinde de leesbaarheid te bewaren is het aangeven van literatuurverwijzingen tot een minimum beperkt. Veel gegevens zijn ontleend aan de overzichtsartikelen vanFlamenbaum enKleinman (1977),de Leeuw enBirkenhäger (1978),Weber e.a. (1979a en b) enZins (1975).     

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core

Rationale Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (d-amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% l-amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for d-amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between d-amphetamine and l-amphetamine have not been well characterized.Objectives To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes.Results The presence of l-amphetamine in the d,l-amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The d,l-amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When l-amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of d,l-amphetamine.Conclusions These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that l-amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.     

(<Emphasis Type="Italic">Z</Emphasis>)-3-Hexenyl diglycosides from <Emphasis Type="Italic">Spermacoce laevis</Emphasis> Roxb.

A new (Z)-3-hexenyl O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside was isolated from the aerial part of Spermacoce laevis, along with 17 known compounds: (6S,9R)-roseoside, (Z)-3-hexenyl O-β-d-glucopyranoside, (Z)-3-hexenyl O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside, (Z)-3-hexenyl O-α-l-arabinopyranosyl-(1→6)-β-d-glucopyranoside, phenyethyl O-β-d-glucopyranoside, phenyethyl O-α-l-arabinopyranosyl-(1→6)-β-d-glucopyranoside, phenyethyl O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside, benzyl O-α-l-arabinopyranosyl-(1→6)-β-d-glucopyranoside, benzyl O-β-d-xylopyranosyl-(1→6)-β-d-glucopyranoside, asperuloside, 6α-hydroxyadoxoside, asperulosidic acid, kaempferol 3-O-β-d-glucopyranoside, kaempferol 3-O-rutinoside, quercetin 3-O-β-d-galactopyranoside, quercetin 3-O-α-l-rhamnopyranosyl-(1→6)-β-d-galactopyranoside, and rutin. The structure determinations were based on physical data and spectroscopic evidence.     

Intranigral infusion of enkephalins elicits dyskinetic biting in rats

Leu- and Metenkephalin (Lenk and Menk) and their more stable analogues d-Ala-Leu- and d-Ala-Meten-kephalin (DALenk and DAMenk) as well as d-ala-d-Leu-and d-Ala-d-Metenkephalin (DADLenk and DADMenk) were infused bilaterally into substantia nigra in awake rats and oral movements were recorded for 90 min. DADLenk and DADMenk elicited dose-dependent biting dyskinesias with a chewing rate of about 90 jaw movements/min. DALenk produced a similar but weaker effect, whereas DAMenk, Lenk and Menk were ineffective in the doses given. These findings suggest a possible enkephalinergic mechanism underlying neuroleptic-induced tardive dyskinesias.     

Untersuchungen über die Stereospezifität der decarboxylasehemmenden Wirkung von α-Methyldopa

Zusammenfassung 1. l--Methyldopa (lMD) hemmt die Dopadecarboxylase in vitro 10–30mal stärker als d--Methyldopa (dMD).2. Während lMD die Decarboxylierung von Dopa auch ohne Zusatz von Pyp vermindert, setzt sie dMD nur herab, wenn Pyp zugesetzt ist und die Reaktion dadurch aktiviert wird.Die durch Pyp nicht zu steigernde Decarboxylierung von 5-Hydroxytryptophan kann mit lMD, nicht aber mit dMD gehemmt werden.3. Durch Isonicotinsäurehydrazid (INH) wird die mit lMD gehemmte Decarboxylierung in gleichem Umfang wie die normale erhöht, d. h. unter INH bleibt die Hemmwirkung von lMD nahezu quantitativ erhalten. Die Wirkung von dMD wird dagegen von INH vollständig ausgelöscht.4. Aus den Ergebnissen wird geschlossen, daß die decarboxylasehemmende Wirkung von dMD durch die optisch unspezifische Bindung des freien Pyp zustande kommt. Die optische spezifische Wirkung von lMD erstreckt sich dagegen auf das Ferment als solches und ist möglicherweise durch eine Komplexbildung aus lMD-Coenzym und Apoenzym bedingt.

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Summary 1. l--Methyldopa (lMD) is 10–30 times more potent than d--Methyldopa (dMD) as dopadecarboxylase inhibitor in vitro.2. The decarboxylation of Dopa can be inhibited by lMD without the addition of Pyridoxalphosphate (Pyp), while dMD is only active in the presence of additional amounts of Pyp by which the decarboxylation is normally increased.The decarboxylation of 5-Hydroxytryptophane, which cannot be stimulated by Pyp, is inhibited by lMD but not by dMD.3. The inhibition of the decarboxylation provoked by lMD is not markedly diminished by Isoniazid (INH) while the action of dMD can be abolished.4. It is concluded that dMD is effective only by the optically non specific binding of the free Pyp. The optically specific action of lMD depends on its reaction with the enzyme itself, perhaps by forming an lMD-coenzyme-apoenzyme complex.

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Mit 3 Textabbildungen     

Die Wirkung von Pharmaka auf die Elimination von Noradrenalin aus der Perfusionsflüssigkeit und die Noradrenalinaufnahme in das isolierte Herz

Ohne ZusammenfassungMit 7 TextabbildungenÜber einen Teil der Ergebnisse wurde auf der Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft 1962 in Mainz (Lindmar u. Muscholl 1962) und auf ihrer 27. Tagung im September 1962 in Wien (Lindmar u. Muscholl 1963) berichtet.     

Wirkung von Thiolen auf Harnvolumen und -osmolarität beim Kaninchen

Summary In conscious, moderately hydrated female rabbits the effect of NaCl,l-alanine,l-serine,l-cysteine, 2,3-dimercapto-1-propanol, S-(2-aminoethyl)-isothiouronium, Na₂S₂O₃, S-methyl-l-cysteine andd-penicillamine upon renal secretion of water and osmotically active substance was investigated.All compounds, except NaCl,l-alanine andl-serine, caused a decrease of urine volume and an increase of osmolarity.The effect is similar to that of the antidiuretic hormone and is dependent upon the presence of the SH-group.

Auszugsweise vorgetragen auf der 9. Frühjahrstagung der Dtsch. Pharmakol. Ges., 10.–13. 3. 1968 in Mainz.     

Potential anthelmintic: d-psicose inhibits motility, growth and reproductive maturity of L1 larvae of Caenorhabditis elegans

No anthelmintic sugars have yet been identified. Eight ketohexose stereoisomers (d- and l-forms of psicose, fructose, tagatose and sorbose), along with d-galactose and d-glucose, were examined for potency against L1 stage Caenorhabditis elegans fed Escherichia coli. Of the sugars, d-psicose specifically inhibited the motility, growth and reproductive maturity of the L1 stage. d-Psicose probably interferes with the nematode nutrition. The present results suggest that d-psicose, one of the rare sugars, is a potential anthelmintic.     

Discriminative stimulus and reinforcing effects of <Emphasis Type="Italic">p</Emphasis>-fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-deprenyl in monkeys

Rationale para-Fluoro-l-deprenyl (Fludepryl), a halogenated derivative of l-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives p-Fluoro-l-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Results Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-l-deprenyl. l-Deprenyl and the metabolites of p-fluoro-l-deprenyl, p-fluoro-l-amphetamine, and p-fluoro-l-methylamphetamine were more potent, producing full generalization at doses of 1.0–3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-l-deprenyl up to 1.0 mg/kg. However, p-fluoro-l-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-l-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or d-amphetamine. Conclusions p-Fluoro-l-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, l-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.