Solid-State 13C Nuclear Magnetic Resonance Spectroscopic Study on Amorphous Solid Complexes of Tolbutamide with 2-Hydroxypropyl-α-and -β-Cyclodextrins

Purpose. The objective of the study was to obtain structural information of inclusion complexes of tolbutamide with HP-- and --cyclo-dextrins in amorphous state. Methods. The solid complexes of tolbutamide with HP-- and --CyDs in molar ratios of 1:1 and 1:2 (guest:host) were prepared by the spray-drying method, and their interactions were investigated by solid-state ^I3C nuclear magnetic resonance (NMR) spectroscopy. Results. The solid 1:1 and l:2tolbutamide/HP-CyD complexes showed halo pattern on the powder X-ray diffractogram and no thermal change in DSC curves, indicating they are in an amorphous state.¹³C NMR signals of the butyl moiety were broader than those of the phenyl moiety in the HP--CyD solid complex, whereas the phenyl moiety showed significantly broader signals than the butyl moiety in the HP--CyD solid complex. As temperature increased, signals of the phenyl carbons became markedly sharper, whereas the butyl carbons only sharpen slightly in the HP-d-CyD complex. In contrast, signals of the butyl carbons became significantly sharper whereas those of phenyl carbons only slightly changed in the HP--CyD complex. Conclusions. Solid state ¹³C NMR spectroscopic studies indicated that the butyl moiety of tolbutamide is predominantly included in the HP--CyD cavity, whereas the phenyl moiety in the HP--CyD cavity in amorphous complexes.     

Activation of β2-adrenoceptors by isoprenaline and adrenaline enhances noradrenaline release in cortical kidney slices of young spontaneously hypertensive rats

Summary The aim of the present study was to investigate -adrenoceptor modulation of noradrenaline release from sympathetic nerves in superfused cortical kidney slices of 4-week-old spontaneously hypertensive rats (SHR) and age-matched controls (WKY). After preincubation with ³H-noradrenaline the kidney slices were electrically stimulated in superfusion chambers. The stimulation induced (S-I) outflow of radioactivity was mainly composed of unmetabolized 3H-noradrenaline in both strains and thus taken as an index of noradrenaline release. There was a frequency-dependent (1.25–20 Hz) increase in the S-1 outflow of radioactivity. At all stimulation frequencies tested S-I outflow of radioactivity was similar or even slightly lower in SHR than in WKY kidney slices in either the absence or presence of cocaine (10 mol/l). The non-selective -adrenoceptor agonists isoprenaline (0.l gmol/1) and adrenaline (0.01 and 0.1 mol/l) enhanced S-I outflow of radioactivity. The facilitatory effects of isoprenaline (0.1 mol/l) and adrenaline (0.1 mol/l) were blocked by the selective ₂-adrenoceptor antagonist ICI 118551 (0.1 mol/l) but not by the selective ₁-adrenoceptor antagonist atenolol (0.3 mol/l). The cell-permeable CAMP analogue 8-bromo-cAMP (300 mol/l) enhanced S-1 outflow of radioactivity to a similar extent in both SHR and WKY kidney slices. A combination of 8-bromo-cAMP (300 mol/l) and adrenaline (0.1 mol/l) did not enhance S-1 outflow of radioactivity to a greater extent than 8-bromo cAMP (300 mol/l) alone in both strains. However, the facilitatory effects of isoprenaline (0.1 mol/l) and adrenaline (0.1 mol/l) but not that of adrenaline (0.01 mol/l) were significantly greater in SHR than in WKY. The results suggest that stimulation of prejunctional ₂-adrenoceptors by adrenaline even in the absence of a-adrenoceptor blockade enhances noradrenaline release in kidney cortex of young SHR and WKY. This ₂-adrenoceptor mediated effect may possibly be dependent on cAMP formation. The greater facilitatory effects of isoprenaline (0.1 mol/l) and adrenaline (0.1 mol/l) in SHR as compared to WKY are in accord with receptor binding studies which show a higher density of ₂-adrenoceptors in SHR than in WKY kidney cortex.Abbreviations SHR Spontaneously hypertensive rats - WKY WistarKyoto rats - cAMP 3-5-cyclic adenosine monophosphate - S-I stimulation induced Send offprint requests to: L. C. Rump     

Dose-response relationship of the β-adrenoceptor antagonist bisoprolol in patients with coronary heart disease and chronic obstructive bronchitis

Summary The effects of single, consecutively increased, oral doses of the -adrenoceptor antagonist bisoprolol (5, 10, 15, 20, 30 and 40 mg) on blood pressure, heart rate and bronchomotor tone were investigated in an open acute trial with 16 patients suffering from angina pectoris due to coronary heart disease and reversible chronic obstructive bronchitis. Even the lowest dose of bisoprolol (5 mg) caused a marked, long-lasting reduction in blood pressure and heart rate. After doses exceeding 20 mg, the incidence of an exaggerated pharmacodynamic effect on heart rate ( ₁-blockade) increased with dose. At doses above 30 mg, bisoprolol showed incipient impairment of bronchomotor function ( ₂-blockade) in individual patients. It is concluded that bisoprolol exhibits high ₁-selectivity, i.e. a wide ₁/ ₂ split, since blockade of bronchial ₂-receptors only occurred at doses well above the therapeutically relevant dose range. The results may not be applicable to chronic treatment.     

Über die Wirkung von α-Methyl-Dopa auf den Brenzcatechinamingehalt von Meerschweinchenorganen

Zusammenfassung 1. Versuche über die Wirkung von -Methyl-Dopa auf den Brenzcatechinamingehalt von Meerschweinchenorganen haben ergeben, daß Noradrenalin im Herzen, sowie Dopamin und Noradrenalin im Gehirn durch äquimolare Mengen von -Methyl-Noradrenalin bzw. -Methyl-Dopamin ersetzt werden.2. Die Adrenalinverarmung der Nebennieren nach Vorbehandlung mit -Methyl-Dopa wird demgegenüber nur zu einem geringen Teil durch die methylierten Brenzcatechinamine -Methyl-Noradrenalin und -Methyl-Dopamin ausgeglichen. Ein weiteres Brenzcatechinamin konnte nicht nachgewiesen werden, so daß -Methyl-Adrenalin wahrscheinlich nicht gebildet wird.3. Im Meerschweinchenherzen gespeichertes -Methyl-Noradrenalin wird durch Reserpin in vivo schlechter freigesetzt als Noradrenalin.4. Das in isolierten Herzgranula (Sediment 100 000·g) gespeicherte -Methyl-Noradrenalin wird durch Segontin bei der Inkubation in vitro ebenfall schlechter freigesetzt als Noradrenalin aus normalen Herzgranula.5. Der Mechanismus der -Methyl-Dopa-Wirkung wird diskutiert.6. Es wird eine fluorimetrische Methode zur Bestimmung von -Methyl-Noradrenalin angegeben.

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Summary 1. The catecholamine content of guinea pig organs after administration of -methyldopa has been determined. The results show that the loss of noradrenaline from heart and that of noradrenaline and dopamine from brain is compensated by a stoichiometric uptake of -methylnoradrenaline and -methyldopamine respectively.2. On the contrary the loss of adrenaline from the suprarenal medulla induced by pretreatment with -methyldopa is not completely restored by the -methylated amines, -methyldopamine and -methylnoradrenaline. -methyladrenaline could not be detected even by paperchromatography.3. The release of the stored -methylnoradrenaline from guinea pig heart by reserpine is very small in comparison with that of noradrenaline.4. Furthermore only small amounts of the stored -methyl-noradrenaline are released from isolated granules of the guinea pig heart after incubation in vitro with segontin. Whereas the same amount of segontin depleted completely the noradrenaline content of the granules isolated from normal hearts.5. The mechanism of action of -methyldopa is discussed.6. A method for the fluorimetric determination of -methylnoradrenaline is described. It is at first separated from -methyldopamine, dopamine and histamine by column chromatography, condensed with o-phthaldialdehyd and the obtained fluorescense is measured by using an Aminco-Bowman spectrophotofluorimeter.

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Mit 6 Textabbildungen

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Herrn Dr. H. Blaschko zum 65. Geburtstag gewidmet.

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Über einen Teil der Ergebnisse wurde auf der Frühjahrstagung der Deutschen Pharmakologischen Ges. in Mainz, April 1964, berichtet. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 247, 297 (1964).

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Ausgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

The subjective,behavioral and cognitive effects of subanesthetic concentrations of isoflurane and nitrous oxide in healthy volunteers

A prospective, crossover, double-blind trial was conducted in nine healthy volunteers in which the subjective, psychomotor and memory effects of isoflurane (0.0, 0.3 and 0.6%) and nitrous oxide (N₂O) (0, 20 and 40%) were examined. Dependent measures included visual analog scales and a standardized drug effects inventory (subjective effects), reaction time and eye-hand coordination (e.g., psychomotor performance), and immediate and delayed free recall (memory). There were some similarities in subjective effects between the two inhaled drugs (e.g., increased ratings of drunk and spaced out), but isoflurane had effects which N₂O did not have. Isoflurane but not N₂O increased visual analog scale ratings of confused, sedated, and carefree, and decreased ratings of in control of thoughts and in control of body. An odor was detected with isoflurane and it was disliked. Psychomotor performance was more grossly impaired during isoflurane inhalation than during N₂O inhalation. Psychomotor recovery from both agents was rapid and complete so that 5 min after the inhalation period had ceased, performance had returned to baseline levels. Both isoflurane and nitrous oxide impaired immediate and delayed free recall. The feasibility of using isoflurane in conscious sedation procedures is discussed.     

Evans blue blocks P2X-purinoceptors in rat vas deferens

Summary In rat vas deferens, Evans blue 100 M increased contractions elicited by high K⁺ and by noradrenaline but markedly reduced contractions elicited by the P_2X-purinoceptor-selective agonist ,-methylene ATP (3 M). The concentration-response curve of ,-methylene ATP was shifted to the right by Evans blue 30 M and the maximal contraction was increased. In tissues incubated with nifedipine 10 M, Evans blue 100 M tended to increase the residual contraction elicited by noradrenaline and abolished the residual response to ,-methylene ATP (3 M). The concentration-response curve of ,-methylene ATP was progressively shifted to the right by increasing concentrations of Evans blue in the presence of nifedipine; maximal contractions were increased by Evans blue 10 and 30 but not 100 M. From the shifts to the right caused by Evans blue 30 M, apparent pK_B values of 5.9 (no nifedipine) and 6.0 (nifedipine present) were calculated. It is concluded that Evans blue blocks P_2X-purinoceptors in rat vas deferens and in addition causes a non-receptor-specific enhancement of contractions.Correspondence to: R. Bültmann at the above address     

Synthesis and investigation of compounds with potential biological activity. IV. Synthesis of pteroyl-d,L-γ-fluorglutamic acid

Conclusion Pteroyl-D, L--fluorglutamic acid was synthesized by a triple condensation of 2,4,5-triamino-6-oxypyrimidine with ,-dibromopropionic aldehyde and n-aminobenzoyl-D, L--fluorglutamic acid in an aqueous alcoholic medium at pH 3.0–4.0.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 10, pp. 30–31, October, 1968.     

Über den Mechanismus der Wirkung des Reserpins auf den Glykogengehalt der Organe

Zusammenfassung Untersuchungen an Mäusen über die durch Reserpin verursachte Zunahme des Glykogengehaltes der Organe und den zugrunde liegenden Mechanismus haben zu folgenden Ergebnissen geführt:1. Nach der subcutanen Injektion von 5 mg/kg Reserpin kommt es zu einem Anstieg des Organglykogens, der in Skeletmuskulatur, Herz und Leber nach 12 Std mit 100 bzw. 174 bzw. 300% sein Maximum erreicht und im Gehirn nach 18 Std 100% beträgt. Von dieser Zunahme des Glykogengehaltes ist nur die Fraktion des freien, mit Trichloressigsäure extrahierbaren Glykogens betroffen.2. Versuche mit ¹⁴C-Alanin ergaben, daß der in Gehirn und Leber nach Reserpin erfolgende Anstieg des Glykogengehaltes mit einer vermehrten Gluconeogenese verbunden ist, d. h. mit einer erhöhten Inkorporierung von ¹⁴C in das Organglykogen. Hiervon war auch die Fraktion des gebundenen Glykogens betroffen, obwohl ihr absoluter Glykogengehalt nach Reserpin unverändert blieb.3. Die Fraktion des gebundenen Glykogens stellt wahrscheinlich den Anteil des Gewebsglykogens dar, in dem zuerst der enzymatische Auf- und Abbau stattfindet. In ihr ist nach Injektion von ¹⁴C-Alanin die spezifische Aktivität primär (1–3 Std p.i.) höher als in der Fraktion des freien Glykogens, nimmt aber unter Reserpin auch schneller ab: bereits nach 6 Std, bei den Kontrolltieren erst nach 9 Std (vgl. Abb. 7). Der mit einer vermehrten Gluconeogenese verbundene Glykogen anstieg nach Reserpin in Gehirn und Leber geht daher offensichtlich auch mit einem erhöhten Glykogen umsatz einher.4. Die nach Reserpin gesteigerte Gluconeogenese ist in der Leber mit einem erhöhten Einstrom von Aminosäuren verbunden, im Gehirn jedoch mit einem verminderten exogenen Aminosäureangebot, wie Versuche mit ¹⁴C--Aminoisobuttersäure (AIB) als Modellsubstanz für körpereigene, einem aktiven Transport unterliegende Aminosäuren ergaben. Iproniazid wirkte umgekehrt wie Reserpin, indem es die ¹⁴C-AIB-Konzentration im Gehirn erhöhte.5. Die Frage einer Mitbeteiligung von Nebennierenrindenhormonen am Zustandekommen der beschriebenen Reserpinwirkungen wird diskutiert.

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Summary Experiments in mice were carried out to elucidate the mechanism by which reserpine increases the glycogen content in several organs.1. 12 hours after the injection of reserpine (5 mg/kg) the glycogen content of the sceletal muscle, heart muscle and liver reached maximum values (100, 174 and 300% resp. above the controls). The glycogen content of the brain was increased by 100% (18 hours after reserpine injection). This accumulation was found only in the fraction of free glycogen (TCA extractable fraction).2. Following a single injection of ¹⁴C-alanine reserpine increased the incorporation of radioactivity into the glycogen of brain and liver, indicating that the accumulation of glycogen in these organs is due to an enhanced gluconeogenesis. Increased specific activity was found in the fraction of free glycogen as well as in the fraction of bound glycogen, although the amount of bound glycogen was not increased by reserpine.3. Changes in specific activity following the injection of ¹⁴C-alanine first occured in the fraction of bound glycogen, indicating, that this fraction of glycogen is metabolized predominantly: at first (1–3 hours) the specific activity is higher in the bound than in the free fraction, while lateron (6 hours) the distribution is reversed (higher specific activity in the free than in the bound fraction). After pretreatment with reserpine this reversal in the distribution of specific activity takes place earlier (after 3 hours) which is due to an accelerated decrease of specific activity in the fraction of bound glycogen.Thus, the reserpine induced increase of glycogen in brain and liver is due to gluconeogenesis and probably associated with an increased metabolic turnover of glycogen.4. Experiments with ¹⁴C--aminoisobutyric acid — a model substance for endogenous amino acids subject to an active transport through cell membranes—have shown, that the reserpine induced gluconeogenesis is accompanied by a rapid influx of amino acids into the liver, while the influx into the brain is significantly lowered. Iproniazid, in contrast to reserpine, enhanced the AIB transfer into the brain.5. The significance of the data presented is discussed regarding a possible involvement of adrenocortical hormones in these actions of reserpine.

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Mit 7 Textabbildungen

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Herrn Professor Dr. P. Holtz zum 60. Geburtstag gewidmet.

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Ausgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

The selective P2X purinoceptor agonist, β,γ-methylene-L-adenosine 5′-triphosphate,discriminates between smooth muscle and neuronal P2X purinoceptors

The effects of the putative selective P_2X purinoceptor agonist, ,-methylene-l-adenosine 5-triphosphate (me-l-ATP), were determined at rat neuronal and smooth muscle P_2X purinoceptors.Me-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 M. In contrast, the archetypal P_2X purinoceptor agonist, , methylene ATP (meATP;1–100 M), produced concentration-related depolarisation responses with a mean EC₅₀ value of 10.8 M. The depolarising effects of meATP were not attenuated by me-l-ATP (100 M). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 M), but not me-l.-ATP (1–300 M), evoked rapid ( < 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, me-d-ATP and meATP competed with high affinity for [³H]Lx meATP binding sites, with mean pIC₅₀ values of 7.7 and 8.3, respectively. However, me-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 M (mean pIC₅₀ value 4.1).In prostatic segments of the rat vas deferens, me-l-ATP (1–100 M) and meATP (0.3–100 M) each produced concentration-related contractile responses with mean EC₅₀ values of 17.1 and 3.6 M, respectively. Me-l-ATP (1–10 M) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [³H]meATP exhibited high affinity for me-l-ATP, meATP and me-d-ATP with mean PIC₅₀ values of 7.7, 8.4 and 7.3, respectively.These results indicate that me-l-ATP exhibits neither agonist nor antagonist properties at P_2X purinoceptors on rat vagal neurones and possesses only very low affinity for [³H]meATP binding sites in rat brain. In contrast, me-l-ATP is a potent, high affinity agonist at smooth muscle P_2X purinoceptors of the rat vas deferens. This selective agonist action of me-l-ATP suggests that P_2X purinoceptors in smooth muscle and neurones are different and represent distinct P_2X purinoceptor subtypes.     

Vasopressin stimulates release of β-lipotropin and β-endorphin in conscious rats as measured by radioimmunoassay of unextracted plasma

Summary Using a newly developed radioimmunoassay to determine the -endorphin-like immunoreactivity (-EI) in unextracted plasma, the effect of vasopressin injections on plasma -EI was investigated in conscious rats. Arginine vasopressin caused a dose-dependent increase of plasma -EI from 34.5±7.8 fmol ml^–1 (n=6) in vehicle-treated animals to 205.0±36.1 fmol ml^–1 (n=7) after injection of the highest vasopressin dose employed (486 ng/100 g b.w.). In view of the appreciable cross-reactivity of -lipotropin (-LPH) in the radioimmunoassay used, plasma was extracted and subjected to gel chromatography on a Sephadex G-50 column. On average, about 70% of the -EI co-eluted with human -LPH and about 30% with human -endorphin in plasma extracts obtained from both control and vasopressin-treated rats. No peripheral conversion of human -LPH occurred under the experimental conditions, since after i.v. bolus injection of human -LPH 97% of the -EI comigrated with human -LPH during gel filtration. A similar blood pressure increase to that induced by the vasopressin injections, when elicited by noradrenaline or angiotensin II i.v., was not followed by an elevation of plasma -EI.These data indicate that vasopressin stimulates -lipotropin and -endorphin release into the systemic circulation in vivo.     

Modification of Δ9-THC-actions by cannabinol and cannabidiol in the rat

Cannabinol (CBN) and Cannabidiol (CBD) were tested in several test procedures known to be altered by ⁹-tetrahydrocannabinol (THC) or crude cannabis preparations. They were inactive in doses up to 80 mg/kg in tests on animal motility, food and water intake, body temperature and catalepsy. In contrast, CBD enhanced the hexobarbitone sleeping time more pronounced than ⁹-THC whereas CBN increased the sleeping time only slightly. When administered in combination CBD prolonged all actions of THC, whereas CBN selectively blocked the effect of THC on hexobarbitone sleeping time. The enhancement by CBD is best explained by an inhibition of THC-metabolism.This paper was in part presented at the C.I.N.P., Copenhagen, 1972.Supported in part by a research grant of the Bundesminister für Jugend, Familie und Gesundheit.     

Comparative pharmacology of human β-adrenergic receptor subtypes—characterization of stably transfected receptors in CHO cells

Although many ₁-receptor antagonists and ₂-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of -adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of human -adrenergic receptors in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three -adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist ¹²⁵I-cyanopindolol as a radioligand. Furthermore, we analyzed the -receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three -receptor subtypes. In particular, a number of ₂- or ₃-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, ₁-receptor antagonists with agonistic activity at ₂- and ₃-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds.     

The effect of midazolam and β-carboline carboxylic acid ethyl ester on behaviour,steroid hormones and central monoamine metabolites in social groups of talapoin monkeys

Established social groups of talapoin monkeys show rank-related differences in aggressive, social and sexual behaviours and visual monitoring, as well as in endocrine and monoamine profiles. Here we describe the effects on these variables of an anxiogenic drug, -carboline carboxylic acid ethyl ester (-CCE), and an anxiolytic drug (midazolam) given to either dominant or subordinate male talapoins. In dominant animals -CCE increased aggression and visual monitoring but reduced sexual behaviour. Treatment of subordinate animals with -CCE served only to increase visual monitoring. Conversely, treatment with a non-sedative acute dose of midazolam in dominants reduced aggressive behaviour and increased sexual behaviour, whereas in subordinates no behavioural changes were noted. Significant effects on endocrine and neurochemical variables were not seen with the acute drug treatments employed. Nevertheless, the results show that drugs which modulate anxiety produce status-dependent behavioural effects.     

Change of Phase-Solubility Behavior by Gamma-Cyclodextrin Derivatization

The effect of -cyclodextrin and its four derivatives on the solubility of progesterone in phosphate buffer pH 7.4 was investigated. -Cyclodextrin forms a complex precipitating from solution at low cyclodextrin concentrations. No precipitation of complexes was observed with the -cyclodextrin derivatives. This change in phase-solubility behavior is probably due to low crystallization tendencies of the derivatives.     

Relaxation of hormonally stimulated smooth muscular tissues by the 8-bromo derivative of cyclic GMP

Summary Substances that cause contraction or relaxation of smooth muscle have been shown to increase intracellular levels of cyclic GMP. Because of the unclear role of cyclic GMP in the control of smooth muscle tone, cyclic GMP derivatives were exogenously applied to various smooth muscle preparations and their effects on tissue tone were studied.Whereas the basal tone of the rat ductus deferens was not affected by exogenous cyclic GMP or its dibutyryl or 8-bromo derivatives, the contractile responses of this tissue to noradrenaline and acetylcholine were depressed by preincubation with 10 M 8-bromo cyclic GMP (Br-cGMP). The 8-bromo derivatives of 2:3-cyclic GMP, 5-GMP and guanosine were without effects. Cyclic AMP levels were not changed by Br-cGMP. The frequency of oxytocin-stimulated rat uteri was also depressed by Br-cGMP (10 M). In helical strips of rat and rabbit aortae, Br-cGMP (1–100 M) caused a concentration-dependent, rapid decrease in noradrenaline-stimulated tissue tension. Br-2:3-cyclic GMP was ineffective. Noradrenaline-stimulated strips from hog spleen arteries were less sensitive to Br-cGMP than aortic tissue. In ductus deferentes and aortic strips stimulated by K⁺ at a depolarizing concentration, Br-cGMP caused less relaxation than under hormonal stimulation.These findings support the concept that cyclic GMP is involved in the control of smooth muscle tone and that hormone- and drug-induced elevations of the cyclic GMP level can reduce contractile responses to neurotransmitters and hormones.Abbreviations cGMP Guanosine 3:5-monophosphate, cyclic GMP - dibutyryl cGMP N², 2-O-dibutyryl guanosine 3:5-monophosphate - Br-cGMP 8-bromo guanosine 3:5-monophosphate - Br-2:3-cGMP 8-bromo guanosine 2:3-monophosphate - Br-GMP 8-bromo guanosine 5-monophosphate - Br-Guo 8-bromo guanosine, Br-guanosine - cAMP adenosine 3:5-monophosphate, cyclic AMP - dibutyryl cAMP N⁶, 2-O-dibutyryl adenosine 3:5-monophosphate - Br-cAMP 8-bromo adenosine 3:5-monophosphate This work was supported by grants from the Deutsche Forschungsgemeinschaft. Preliminary reports were presented (Schultz, 1977b; Schultz et al., 1978).     

β-funaltrexamine antagonizes the discriminative stimulus effects of morphine but not naltrexone in pigeons

Antagonistic actions of the irreversible, -selective antagonist -funaltrexamine (-FNA) were evaluated in pigeons trained to discriminate among intramuscular injections of morphine (5.6 mg/kg), saline, and naltrexone (10.0 mg/kg). -FNA administered alone (1.0 or 10.0 mg/kg) failed to mimic the discriminative stimulus effects of morphine or naltrexone. -FNA attenuated the discriminative stimulus effects of morphine. A three-fold larger dose of morphine was required for complete generalization when pigeons were pretreated with a dose of 1.0 mg/kg -FNA. A dose of 10.0 mg/kg -FNA completely antagonized the morphine discriminative stimulus, so that pigeons responded predominantly on the saline key up to doses of morphine that suppressed responding. Doses of -FNA that attenuated the effects of morphine had no effect on the discriminative stimulus effects of naltrexone. These results demonstrate that, like naltrexone, -FNA attenuates the discriminative stimulus effects of morphine in pigeons and, at sufficiently large doses, antagonizes morphine in an unsurmountable manner. -FNA does not, however, share discriminative stimulus properties with naltrexone in these pigeons, and fails to attenuate the discriminative stimulus effects of naltrexone, lending support to the suggestion that naltrexone exerts discriminative stimulus effects under these experimental conditions predominantly by a non-mu opioid mechanism.     

Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with -lapachone (-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between -lap and four cyclodextrins (-, -, -, and HP-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and ¹H-NMR spectroscopy. Biologic activity and bioavailability of -lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that -lap solubility increased in a linear fashion as a function of -, -, or HP-CD concentrations but not -CD. Maximum solubility of -lap was achieved at 16.0 mg/ml or 66.0 mM with HP-CD. Fluorescence and ¹H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between -CD and HP-CD with -lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of -lap in -CD or HP-CD inclusion complexes (TD₅₀ = 2.1 M). Animal studies in mice showed that the LD₅₀ value of -lap in an HP-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of -lap with HP-CD offers a major improvement in drug solubility and bioavailability.     

Cannabis and alcohol: Effects on estimation of time and distance

The effect of cannabis and alcohol on estimation of time and distance during simulated car driving was studied. Cannabis resin containing 4% 1-tetrahydrocannabinol (THC) was administered orally in 3 doses equivalent to 8, 12, and 16 mg THC. Alcohol was given orally in one dose of 70 g. The subjects were 8 men, 21 to 29 years old. Cannabis showed much stronger effect than alcohol on the estimation of time and distance. The effect of cannabis was more marked on the subjective than on the objective estimation. A dose-response type of effect was seen on cannabis.     

Investigation into the positive inotropic effect of clondine in isolated hearts

Summary Clonidine in doses 2.5–40 g injected into the aortic cannula of isolated, perfused hearts of guinea pigs produced an increase in contraction amplitude. This positive inotropic effect was not antagonised by infusions of doberol (10 g/min), phentolamine (10 g/min) or pheniramine (50 g/min), it was antagonised by burimamide (30 g/min), a histamine H₂ receptor blocking agent. Clonidine showed some similarities to histamine such as parallel dose-response curves and during infusions of burimamide the curve of clonidine was shifted in a way which indicated competitive inhibition. It is suggested therefore that the action of clonidine is due to stimulation of histamine H₂ receptors.     

Viscoelasticity of Anionic Polymers and Their Mucociliary Transport on the Frog Palate

The influence of formulation variables on the rheology of polyanionic formulations and the relationships between viscoelastic properties and mucociliary transport rate were investigated. Polymeric samples were oscillated from 0.001 to 5 Hz using either a "cone and plate or a "coaxial cylinder measuring system. The mucociliary transport rates of polymeric samples were determined and compared movement of charcoal powder on the frog palate. For the linear polymeric solutions, sodium carboxymethylcellulose and sodium alginate, the elastic modulus (G) increased with increasing amplitudes during frequency scan. However, the G or viscous modulus (G) of partially cross-linked polyacrylic acid (cPAA) samples did not change significantly under oscillation. Both G and G of cPAA samples were significantly influenced by the amount of salt present in the formulation. The rheology of 2% (w/w) cPAA in 90:10 (w/w) propylene glycol:alcohol changed from a viscous fluid to a coarse suspension after neutralization. The pH increased gradually when the nonaqueous formulation reacted with water and the maximum dynamic moduli were obtained after incorporating 20% (w/w) water in the formulation. A negative correlation was found between the G of linear polyanionic samples and the relative transport rate. However, the lowest mucociliary transport rate was observed when the loss tangent (G/G) was around 0.4–0.5.