Metabolism of methaqualone in geriatric patients

Summary The urinary excretion of fiveC-monohydroxy metabolites and theN-oxide of methaqualone has been measured in a group of eleven geriatric patients aged 71–90 years. The total excretion of the six metabolites in 24 h after the oral administration of a single dose was approximately one-half of that in a group of young healthy adults. The relative importance of the six metabolites was 4-hydroxy N-oxide> 2-hydroxymethyl = 3-hydroxy > 6-hydroxy = 2-hydroxymethyl which was the same order as that in young adults. The ratio ofC-toN-oxidation was also the same in the two groups. There was no impairment of conjugation of theC-hydroxy metabolites with glucuronic acid in the geriatric group but there was greater interindividual variation in metabolite excretion. There was also evidence for delayed metabolism in the geriatric patients.     

Difference in metabolic profile of potassium canrenoate and spironolactone in the rat: Mutagenic metabolites unique to potassium canrenoate

The metabolic fates of potassium canrenoate (PC) and spironolactone (SP) were compared for the rat in vivo and in vitro. Approximately 18% of an in vivo dose of SP was metabolized to canrenone (CAN) and related compounds in the rat. In vitro, 20–30% of SP was dethioacetylated to CAN and its metabolites by rat liver 9000 g supernatant (S9). Thus, the major route of SP metabolism is via pathways that retain the sulfur moiety in the molecule. PC was metabolized by rat hepatic S9 to 6, 7- and 6, 7-epoxy-CAN. The -epoxide was further metabolized to its 3- and 3-hydroxy derivatives as well as its glutathione (GSH) conjugate. Both 3- and 3-hydroxy-6, 7-epoxy-CAN were shown to be direct acting mutagens in the mouse lymphoma assay, whereas 6, 7- and 6, 7-epoxy-CAN were not. These mutagenic metabolites, their precursor epoxides and their GSH conjugates were not formed from SP under identical conditions. The above findings appear to be due to inhibition of metabolism of CAN formed from SP by SP and/or its S-containing metabolites, since the in vitro metabolism of PC by rat hepatic microsomes was appreciably reduced in the presence of SP. The hypothesized mechanism(s) for this inhibition is that SP and its S-containing metabolites specifically inhibit an isozyme of hepatic cytochrome P-450 or SP is a preferred substrate over PC/CAN for the metabolizing enzymes. Absence of the CAN epoxide pathway in the metabolism of SP provides a possible explanation for the observed differences in the toxicological profiles of the two compounds.     

The effect of phenytoin and metamphetamine on spinal motor activity

Summary The investigation was initiated by the idea that reserpine might exert its action on spinal motor activity through facilitatory impulses in descending pathways to the spinal motoneurones. Therefore, the effect of conditioning by repetitive stimulation of descending and segmental pathways on and reflex discharges was studied in the rat. Conditioning by stimulation of the dorsolateral funiculus increased a and decreased reflex discharge. Conditioning by stimulation of the dorsal funiculus increased reflex discharge without changing reflex activity. In partially or totally spinalized preparations, conditioning by repetitive stimulation of the same dorsal root to which the test stimulus was applied, produced an increase in a reflex activity which was associated with a decrease in motor activity. In the preparations with an intact neuraxis, repetitive stimulation of the dorsal root facilitating reflex discharge did not change motor activity. motor activity also remained unchanged when reflex discharge was inhibited by repetitive stimulation of the dorsal root in the intact or totally spinalized preparation.Phenytoin 50 mg/kg increased the unconditioned response in all types of preparations, apart from that in which the dorsal funiculus was isolated. Facilitation of reflex discharge elicited by repetitive stimulation of segmental and descending pathways was depressed by phenytoin, whereas inhibition remained unchanged.Metamphetamine 2 mg/kg increased the unconditioned reflex discharge in all types of preparations, and decreased the response in the preparations with an intact neuraxis and also in those in which the dorsal funiculus was isolated. Metamphetamine did not depress the facilitatory or inhibitory effects produced by repetitive stimulation of descending or segmental pathways.From the results obtained it is concluded that reserpine rigidity in the rat may be mediated by an increased facilitatory impulse input reaching the a motoneurones by way of descending pathways in the dorsolateral column of the spinal cord, and that phenytoin may antagonize, at least in part, the effect of reserpine by a depressant action on facilitatory processes at the spinal level, whereas abolition of reserpine rigidity produced by metamphetamine must be due to a supraspinal site of action of this drug.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

Dose-dependent excretion of DDE(1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene) in rats

Dose-dependent excretion of p,pDDE in rats was investigated. p,pDDE itself was the major excreta in rats. But some o,p'isomer of DDE was detected in feces by GC-MS analysis. The excretion of p,p'DDE after a single administration was modified by its dose level.The time pattern of p,pDDE excretion agrees well with the modified Hill equation. The value of the equilibrium constant (K) increases in proportion to time t after p,pDDE administration.Using the modified Hill equation and the linear K equation, the excretion rate of p,pDDE during the experimental time t can be estimated. The estimated p,pDDE excretion rate in feces agrees well with the measurements.     

Relationship of metabolism of 2′-, 3′- and 5′-adenine nucleotides to presynaptic inhibition of transmitter release in rat vas deferens

Summary In the isolated rat vas deferens stimulated at 0.2 Hz, a series of 2, 3-, and 5-substituted adenine nucleotides all inhibited the twitch responses, their actions being potentiated by the nucleoside transport inhibitors, HNBTGR, NBMPR and dipyridamole.The metabolism of these nucleotides was examined utilising HPLC analysis of the bathing medium after exposure to 30 M nucleoside or nucleotide for 5 min. 5-AMP, 5-ADP, 5-ATP, and NAD⁺ were all partially hydrolysed to adenosine, the relative extent of this being 5-AMP>5-ADP=5-ATPNAD⁺. However, the other nucleotides examined were not detectably converted to adenosine or to adenosine deamination products.These results indicate that the 2-, 3- and 5-substituted nucleotides studied act at a P₁-purinoceptor in rat vas deferens to inhibit neurotransmission and, with the exception of 5-AMP, 5-ADP, 5-ATP and NAD⁺, all appear to act directly at this receptor. However, the 5-adenine nucleotides (AMP, ADP and ATP) and NAD⁺ all appear to act at least partially indirectly subsequent to their hydrolysis to adenosine.Abbreviations. The following abbreviations are used ADA adenosine deaminase (EC 3.5.4.4) - 5-ADP adenosine 5-diphosphate - 2,5-ADP adenosine 2,5-diphosphate - 3 5-ADP, adenosine 3,5-diphosphate - 2-, 3 or 5-AMP adenosine 2-, 3-, or 5-monophosphate - 5-ATP adenosine 5-triphosphate - cNADP⁺ -nicotinamide dinucleotide 2,3-cyclic monophosphate - CoA coenzyme A - HNBTGR 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine - NAD⁺ -nicotinamide adenine dinucleotide - NADP⁺ -nicotinamide adenine dinucleotide phosphate - NBMPR 6-(4-nitrobenzylthio)-purine riboside     

Cyclodextrins as Nasal Absorption Promoters of Insulin: Mechanistic Evaluations

The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl--cyclodextrin (DMCD) > -cyclodextrin (-CD) > -cyclodextrin (-CD), hydroxypropyl--cyclodextrin (HPCD) > -cyclodextrin (-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5-nucleotidase (5-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HPCD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5-ND and total absence of LDH activity. On the other hand, 5% DMCD caused extensive removal of the membrane-bound 5-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption.     

Studies on the constituents of Scutellaria species (XXI): constituents of the leaves of Scutellaria strigillosa Hemsley

From the leaves of Scutellaria strigillosa, 14 compounds, chrysin, apigenin, 5,7,2-trihydroxyflavone, norwogonin, ursolic acid, 6-hydroxy-4-stigmasten-3-one, 6-hydroxy-4,22-stigmastadien-3-one, 2 R,4 R,8 R--tocopherol, (S)-5,5 -bi--tocopheryl, (R)-5,5 -bi--tocopheryl, solanachromene, tocopherylquinone, jodrellin T, and 14,15-dihydrojodrellin T were isolated. The structures were determined on the basis of chemical and spectral data.     

Synthesis and Anti-inflammatory Effect of Chalcones and Related Compounds

Purpose. Mast cell and neutrophil degradations are the important players in inflammatory disorders. Combined with potent inhibition of chemical mediators released from mast cells and neutrophil degranulations, it could be a promising anti-inflammatory agent. 2,5-Dihydroxychalcone has been reported as a potent chemical mediator and cyclooxygenase inhibitor. In an effort to continually develop potent anti-inflammatory agents, a novel series of chalcone, 2- and 3-hydroxychalcones, 2,5-dihydroxychalcones and flavanones were continually synthesized to evaluate their inhibitory effects on the activation of mast cells and neutrophils and the inhibitory effect on phlogist-induced hind-paw edema in mice. Methods. A series of chalcones and related compounds were prepared by Claisen-Schmidt condensation of appropriate acetophenones with appropriate aromatic aldehyde and the anti-inflammatory activities of these synthetic compounds were studied on inhibitory effects on the activation of mast cells and neutrophils. Results. Some chalcones showed strong inhibitory effects on the release of -glucuronidase and histamine from rat peritoneal mast cells stimulated with compound 48/80. Almost all chalcones and 4-hydroxyflavanone exhibited potent inhibitory effects on the release of -glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP). Some chalcones showed potent inhibitory effects on superoxide formation of rat neutrophils stimulated with fMLP/cytochalasin B (CB) or phorbol myristate acetate (PMA). 2,3-Dihydroxy-, 2,5-dihydroxy-4-chloro-, and 2,5-dihydroxychalcone showed remarkable inhibitory effects on hind-paw edema induced by polymyxin B in normal as well as in adrenalectomized mice. Conclusions. These results indicated that the anti-inflammatory effects of these compounds were mediated, at least partly, through the suppression of chemical mediators released from mast cells and neutrophils.     

Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT)

The enterohepatic circulation of cefixime in rat was evaluated by a nonlinear least square analysis program, MULTI(FILT), into which the fast inverse Laplace transform (FILT) was incorporated. The plasma time course in the bile duct-cannulated rat exhibited a biexponential curve after the rapid iv administration of cefixime. Several pharmacokinetic models for the enterohepatic circulation were constructed based on the recirculatory concept and the Laplace-transformed equations corresponding to these models were derived by means of the method of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula. The optimum model was selected based on the Akaike's information criterion (AIC). The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the amount excreted into the bile. The recovery ratio (F_c and the mean circulatory time (¯t_c through a single pass of enterohepatic circulation were estimated 27.9% and 1.07 hr, respectively. The recovery ratio (F_a and the mean absorption time (¯t_a for the absorption process from the intestinal tract into the systemic circulation were 68.3% and 0.0234 hr, respectively. The recovery ratio (F_b and the mean transit time (¯t_b)for the disposition process through the systemic circulation into the bile were 40.8% and 1.05hr, respectively.Notation A _i coefficient - a _i exponent - (s) Laplace transform of the time course of plasma following intravenous dose - (s) Laplace transform of the time course of plasma following oral administration dose - (s) Laplace transform of the time course of plasma concentration without EHC - CL_b clearance into the bile - CL¹ total clearance through the single EHC (=CL_b/F_b) - D_iv intravenous dose - D_po oral administration dose - F_a recovery (availability) from intestinal tract to systemic circulation - F_b recovery from systemic circulation to intestinal tract - F_a recovery from oral dose (absolute availability) - F_c recovery through a single pass of EHC - F_g recovery through the stomach - (s) transfer function corresponding to the process outside the body through the intestinal tract - (s) transfer function for oral dose - (s) transfer function through the systemic circulation into the bile - (s) transfer function for a single pass of EHC - (s) transfer function through the stomach - f_i(t) weight function for the processi - (s) Laplace transform off _t (t) - (s) transfer function corresponding to the recirculatory process - k_a absorption rate constant - s Laplace variable - mean transit time for the absorption process from the intestinal tract - _a mean transit time for oral dose (=MAT) - mean transit time for the disposition process in the body - mean transit time for a single pass of EHC - t ₀ gap time     

Trennung und Bestimmung der Nucleotide des Gehirns

Ohne ZusammenfassungFolgende Abkürzungen werden in der Arbeit verwendet AMP Adenosin-5-monophosphat - ADP Adenosin-5-diphosphat - ATP Adenosin-5-triphosphat - GMP Guanosin-5-monophosphat - GDP Guanosin-5-diphosphat - GTP Guanosin-5-triphosphat - IMP Inosin-5-monophosphat - UMP Uridin-5-monophosphat - UDP Uridin-5-diphosphat - UTP Uridin-5-triphosphat - UDPAG Uridin-5-diphosphat-N-acetylglucosamin - UDPG Uridin-5-diphosphat-glucose - DPN Diphosphopyridinnucleotid - TPN Triphosphopyridinnucleotid Mit 10 TextabbildungenMit Unterstütznng der Deutschen Forschungsgemeinschaft.     

Localization of Purine Metabolizing Enzymes in Bovine Brain Microvessel Endothelial Cells: An Enzymatic Blood-Brain Barrier for Dideoxynucleosides?

Purpose. The specific activities of the purine and pyrimidine metabolizing enzymes, purine nucleoside phosphorylase (PNP), adenosine deaminase (ADA) and cytidine deaminase (CDA) were determined in bovine brain microvessel endothelial cells (BBMECs), whole cerebral tissue and erythrocytes. In addition, the substrate specificities (K_m and V_max) of purified calf spleen PNP for inosine and 2,3-dideoxyinosine (ddl) and of purified calf intestinal ADA for 2,3-dideoxyadenosine (ddA), 6-chloro-2,3-dideoxypurine (6-Cl-ddP), and 2--fluoro-2,3-dideoxyadenosine (F-ddA) have been explored. Methods. BBMECs were isolated from bovine cerebral cortex by a two step enzymatic dispersion treatment followed by centrifugation over 50% Percoll density gradients. Activities of alkaline phosphatase, -glutamyl transpeptidase, ADA, PNP and CDA were determined in various tissue homogenates (cerebral cortex, BBMECs and erythrocytes). Enzyme kinetic studies were also conducted using commercially available enzymes and several nucleoside analogs of interest. Results. The activities of ADA and PNP were 42-fold and 247-fold higher in the cerebral microvessels than in the cerebral cortex, respectively, while there was no detectable CDA activity in the microvessel fraction and very little overall activity in the cortex. Conclusions. ADA and PNP may serve as an enzymatic blood-brain barrier for some of the anti-HIV dideoxynucleosides. Simulations of brain availability for ddl, ddA, 6-Cl-ddP, and F-ddA demonstrated that the quantitative significance of enzyme localization may vary dramatically, however, depending on the membrane permeability of the drug and its bioconversion rate constant within the endothelial cell.     

Metabolism of3H-digoxin and some acetyl-digoxins: Time-dependent formation of hydrophilic metabolites after oral application in man

Summary After oral administration of³H-digoxin,³H-(= 16)-acetyldigoxin,³H-(=15)-acetyldigoxin and³H-(15,16)-diacetyldigoxin water-soluble metabolites have been found in the urine of three persons. A maximum is reached after 4–5 h. These metabolites are very polar and are not identical with neither digoxigenin nor with its mono- and bis-digitoxosides.     

Wirkung von cyclischem Adenosin-3′,5′-Monophosphat (3′,5′-AMP) und seinem Dibutyrylderivat (DBA) auf Lipolyse,Glykogenolyse und Corticosteronsynthese

Zusammenfassung 1. Am isolierten Fettgewebe von Ratten hatte das Dibutyrylderivat des cyclischen Adenosin-3,5-Monophosphat (DBA) eine etwa 100 mal stärkere lipolytische Wirkung als das nicht substituierte cyclische Adenosin-3,5-Monophosphat (3,5-AMP). Hormone (ACTH, Noradrenalin) waren an diesem Testobjekt 10000 mal wirksamer als DBA. Durch Hemmung der Phosphodiesterase mit Theophyllin ließ sich auch die Wirkung des DBA verstärken.2. An isolierten Nebennieren von Ratten stimulierte DBA die Corticosteronsynthese etwa 100 mal stärker als 3,5-AMP; ACTH war aber 500 mal wirksamer als DBA. Durch Theophyllin ließ sich die Wirkung von ACTH, DBA bzw. 3,5-AMP nicht verstärken. Hohe Konzentrationen des Xanthinderivates hemmten die Corticosteronsynthese.3. An Ratten war die hyperglykämische Wirkung des DBA wesentlich stärker als diejenige des 3,5-AMP: Für eine Erhöhung des Blutzuckerspiegels um 40 mg/100 ml benötigten wir von DBA weniger als 1 mol/kg, von 3,5-AMP aber 30 mol/kg. Diese Wirkung der Nucleotide ließ sich durch Theophyllin nicht verstärken. Der Fettsäuren- und Glyceringehalt des Plasmas wurde durch Injektion von DBA bzw. 3,5-AMP nicht erhöht, sondern erniedrigt. — Die Ergebnisse wurden im Zusammenhang mit dem Second Messenger Concept von Sutherland u. Mitarb. diskutiert.Über einen Teil der Ergebnisse wurde auf der 8. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft (Stock u. Westermann, 1967; Bieck u. Westermann, 1967) sowie in einer kurzen Mitteilung (Bleck et al., 1968) berichtet.     

Toxic effects of some “mono-n-butyl-tin compounds” on white mice

The toxic effects of mono-n-butyl-tin-trichloride, mono-n-butyl-tin-tris-(2-ethyl-hexyl-mercaptoacetate), mono-n-butyl-tin acid and mono-n-butyl-thiotin acid on white mice were investigated. These compounds were administered to white mice by means of a stomach tube in a single dose of 4000 mg/ kg b.w. at the start of the experiment. All mice were sacrificed 24 hours after the administration.The clinical course as well as the macroscopic findings in all experimental groups indicated general signs of an acute intoxication. The histological findings in the mono-n-butyl-tin-trichloride group showed pronounced changes in the digestive tract, where haemorrhages in the mucous membrane and in the inner layer of the gastric and intestinal walls had been found. In the mice of the other experimental groups, steatosis of the hepatocytes and an irregular steatosis of the renal tubular epithelium were observed.     

Development and Use of Enzyme-Linked Immunosorbent Assays (ELISA) for the Detection of Protein Aggregates in Interferon-Alpha (IFN-α) Formulations

Purpose. Protein aggregates are thought to be involved in the immunogenicity of recombinant proteins in humans. To probe human IFN- formulations for the presence of soluble protein aggregates, enzyme-linked immunosorbent assays (ELISA) were developed. Methods. For the detection of IFN--IFN- and HSA-IFN- aggregates, sandwich ELISAs were developed using a monoclonal anti-IFN- antibody as a capture antibody and the same anti-IFN- antibody and an anti-human serum albumin (HSA) antibody (HRP-labeled), respectively. Results. Marketed freeze-dried, HSA-containing IFN- formulations tested in the ELISAs all contained IFN--IFN- and/or HSA-IFN- protein aggregates, although in varying amounts. These aggregates were predominantly IFN- dimers and 1:1 conjugates of HSA with IFN-. Test formulations revealed that aggregation of IFN- was strongly affected by the presence of pharmaceutical excipients, pH of the formulation, lyophilisation procedure, and storage temperature and time. Conclusions. The ELISAs are rapid, highly specific for aggregates in the presence of both IFN- and HSA monomers and allow the direct detection of both types of aggregates in formulations in the nanogram range. The new assays will assist the monitoring of the aggregate-inducing processes during IFN- formulation and storage in an early phase and the development of aggregate-free IFN- formulations.     

Hemmung von Adenyl-Cyclase-Präparationen aus der Rattenniere durch Calciumionen und verschiedene Diuretica

Summary Antidiuretic hormone (ADH) increases the permeability to water of certain epithelial membranes. This effect, found in the urinary bladder of the toad and in the distal tubules and the collecting ducts of kidney, is mediated intracellularly by adenosine 35-monophosphate (Ado-35-P). Calcium ions and the diuretic ethacrynic acid are known to inhibit the ADH-induced increase in water permeability of the toad bladder. In adenyl cyclase preparations from rat renal cortex and medulla, the influence of these substances as well as of other diuretics added in vitro has been studied. Adenyl cyclase activity has been determined, excepted as noted, by measuring Ado-35-P formed from 1 mM ¹⁴C-ATP in the presence of 10 mM Mg⁺⁺, an ATP regenerating system, and 5 mM unlabeled Ado-35-P to reduce the enzymatic degradation of the labeled Ado-35-P.Calcium ions reduced the rate of Ado-35-P formation by particles from renal cortex and medulla when the activity was measured in the presence of either Mg⁺⁺ or Mn⁺⁺. With 10 mM Mg⁺⁺, 1 mM Ca⁺⁺ decreased adenyl cylase activity by about 50%. Activities of cortical adenyl cyclase stimulated by parathyroid hormone, thyrocalcitonin or ADH and of medullary adenyl cyclase stimulated by ADH were also reduced by about 50% in the presence of 1 mM Ca⁺⁺. The inhibition was independent of the ATP concentration, but was influenced by the Mg⁺⁺ content of the incubation medium.Adenyl cyclase activities of cortical and medullary membrane preparations were reduced by about 50% by 0.2 mM ethacrynic acid. The extent of this inhibition was essentially the same whether the enzymatic activity was determined in the absence or presence of stimulating hormones. The inhibitory action of ethacrynic acid was partially prevented by simultaneous addition of dithioerythritol (DTE). A derivative of ethacrynic acid, L 589420-0-2, also inhibited renal adenyl cyclase, but its action was not influenced by the addition of DTE. Adenyl cyclase from both parts of the kidney was inhibited by about 90% by 0.2 mM mersalyl. This action was almost completely prevented by the addition of 1 mM DTE. The pharmacological significance of adenyl cyclase inhibition by these diuretics is still uncertain since the role of Ado-35-P in the regulation of sodium transport is as yet unclear.Other diuretics, hydrochlorothiazide, furosemide, mefruside, amiloride, and the non-diuretic benzothiadiazine, diazoxide, had essentially no effect on cortical and medullary adenyl cyclase preparations when they were added in 0.1–0.5 mM concentration.The methylxanthines, theophylline and caffeine, which are known to inhibit nucleoside 35-monophosphate phosphodiesterase, reduced the rate of Ado-35-P formation. The unstimulated and the hormone-stimulated adenyl cyclases were inhibited to the same extent by theophylline. When adenyl cyclases was stimulated by fluoride, however, we found only a very small inhibition by theophylline. Inhibition of the medullary adenyl cyclase was greater than that of the enzyme prepared from renal cortex. At a concentration of 1 mM these methylxanthines significantly inhibited the medullary enzyme, but the inhibition became asymptotic at about 50% when concentrations up to 20 mM were used. Therefore, it is likely that inhibition by these substances varies in different cell types and tissues.Instead of phosphodiesterase inhibitors, unlabeled Ado-35-P can be used in the assay of adenyl cyclase activity to reduce the degradation of enzymatically formed labeled Ado-35-P. This addition, though, can also influence adenyl cyclase activity. In a medullary enzyme preparation 0.2 mM Ado-35-P reduced the adenyl cyclase activity by 13%, 5 mM Ado-35-P by 35%.

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Abkürzungen Ado-35-P Adenosin-35-monophosphat - Guo-35-P Guanosin-35-monophosphat - ADH antidiuretisches Hormon, Vasopressin - PTH Parathormon - TCT Thyreocalcitonin - DTE Dithioerythrit - EDTA Äthylendiamintetraessigsäure Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.Über einen Teil der Ergebnisse wurde auf der 11. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft berichtet (Jakobs et al., 1970). Einige der vorliegenden Ergebnisse sind der Inauguraldissertation von K. H. J. (Medizinische Fakultät der Universität Heidelberg, 1971) entnommen.     

Pharmacological characterization of A1 adenosine receptors in isolated rat ventricular myocytes

Summary The aim of the present study was the characterization of adenosine receptors in isolated rat ventricular myocytes. The CAMP-levels of rat ventricular myocytes in the presence of 1 mol/l isoprenaline were reduced by up to 48% by adenosine analogues; the rank order of potency was: R-N⁶-phenylisopropyladenosine (IC₅₀ 60 nmol/1), 5-N-ethylcarboxamidoadenosine (IC₅₀ 360 nmol/l) and S-N⁶-phenylisopropyladenosine (IC₅₀ 16 ol/l). The adenosine receptor antagonist XAC (xanthine amine congener) antagonized the effect of R-N⁶-phenylisopropyladenosine in a concentration-dependent manner with a K_i-value of 20 nmol/l. The A₁ receptor-selective radioligand R-N⁶-¹²⁵I-p-hydroxyphenylisopropyladenosine bound to membranes prepared from rat ventricular myocytes in a saturable manner with a B _max of 17.7 fmol/mg protein and a K _D-value of 1.1 nmol/l. Adenosine analogues competed for the binding with the same rank order of potency as for the inhibition of the isoprenaline-induced cAMP-increase. GTP inhibited radioligand binding with an IC₅₀-value of 73 ol/l. These results suggest the presence of A₁ adenosine receptors on rat ventricular myocytes, which mediate an inhibition of adenylate cyclase. The receptors may be responsible for the effects of adenosine and its analogues on the heart.Abbreviations ¹²⁵I-HPIA R-N⁶-¹²⁵I-p-hydroxyphenylisopropyladenosine - PIA N⁶-phenylisopropyladenosine - NECA 5-N-ethyl-carboxamidoadenosine - XAC 8-4-[([(2-aminoethyl)aminocarbonyl]methyl)oxy]phenyl-1,3-dipropylxanthine (xanthine amine congener) - Ro 20-1724 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone - ScAMPTME 2-O-monosuccinyladenosine-3,5-cyclic monophosphate tyrosyl methyl ester - HEPES N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid - GTP guanosine-5-tri-phosphate Send offprint requests to D. Martens     

Trennung und Charakterisierung der Abbauprodukte von DPN,DPNH und TPN nach enzymatischer Hydrolyse durch Gehirnhomogenate

Summary The degradation of DPN, TPN and DPNH by homogenates of brain has been studied. The products are separated and identified.Nucleosidase of brain splits DPN in Nicotinamide and Adenosine-diphosphoribose (ARPPR). TPN has broken down to Nicotinamide and 2-Phospho-adenosine-diphosphoribose whereas DPNH is not metabolised by this enzyme.

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Mit 5 Textabbildungen     

Phenprocoumon metabolites in human plasma; characterization by HPLC and GC-MS

Summary Pooled plasma from patients receiving phenprocoumon anticoagulant therapy was extracted and the following substances were characterized: phenprocoumon, and its 7-hydroxy,4-hydroxy and 6-hydroxy derivatives; they were identified by HPLC and after methylation by quartz capillary GC-MS using the electron impact and selective ion monitoring modes. This is the first occasion when phenprocoumon metabolites have been identified in plasma; they were unconjugated and in much lower concentrations (43.2 and 2 ng/ml for the 7,4 and 6-hydroxy derivatives, respectively) than the original compound (2000 ng/ml).     

Inhibition by papaverine and eupaverin of 3′,5′-cyclic AMP phosphodiesterase from rabbit skeletal muscle

Summary Papaverine and eupaverin are potent inhibitors of 3,5-cyclic AMP phosphodiesterase from rabbit white skeletal muscle. These drugs inhibit more the activity associated with the particulate fractions than that associated with the soluble fraction.