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W Schunack

Publications and source records attributed to W Schunack.

At least 109 records · Page 6Linked to original sources
PubMed1995

Synthesis, X-ray crystallography, and pharmacokinetics of novel azomethine prodrugs of (R)-alpha-methylhistamine: highly potent and selective histamine H3 receptor agonists.

Since various neuroregulatory functions of the histamine H3 receptor have been proved during the last few years, the H3 receptor is of current interest. Azomethine derivatives of the highly potent histamine H3 receptor agonist (R)-alpha-methylhistamine (1) were prepared as lipophilic prodrugs to improve the bioavailability of the hydrophilic drug, particularly its entry into the brain. Additionally, azomethine derivatization provides protection against histamine methyltransferase, the major metabolizing enzyme in man, and thus efficiently enhances the bioavailability of 1. The molecular conformations of (R)-2(-)[[N(-)[1-(1H-imidazol-4-yl)-2-propyl]- imino]phenylmethyl]phenol (9a) and (R)-4-fluoro-2(-)[[N(-)[1-(1H-imidazol-4-yl)-2-propyl[imino]- (4-chlorophenyl)methyl]phenol (9p) were determined by X-ray structure analysis. An intramolecular hydrogen bond which is essential for the stability of these azomethines was thereby confirmed. Moreover, the pharmacokinetic parameters of the prodrugs were investigated in vitro as well as in vivo. The halogenated azomethines have an effect following peroral administration in mice, and some of them seem to be highly potent for the central nervous system (CNS) delivery of 1. At present the most potent prodrug of 1 is (R)-4-chloro-2(-)[[N(-)[1-(1H-imidazol-4-yl)-2-propyl]imino](4- chlorophenyl)methyl]phenol (9q), reaching by far the highest CNS level of 1 (Cmax = 71 ng/g). Prodrugs of this type are not only valuable pharmacological tools but may also become H3 histaminergic drugs for therapeutic use.

Animals↗
PubMed1995

Synthesis and histamine H1 receptor agonist activity of a series of 2-phenylhistamines, 2-heteroarylhistamines, and analogues.

New histamine derivatives characterized by a (substituted) aryl, heteroaryl, benzyl, or heteroarylmethyl substituent in the C2 position of the imidazole ring have been prepared from appropriate imidates or amidines, respectively, and 2-oxo-4-phthalimido-1-butyl acetate (1). The compounds were screened as potential H1 receptor agonists on the isolated guinea pig ileum. The 3-halogenated 2-phenylhistamines (halogen = Br (35) and I (36)) were equipotent with histamine, while 2-(3-(trifluoromethyl)phenyl)histamine (2-[2-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl]ethanamine (39)) was significantly more potent than histamine (39: pD2 = 6.81, relative activity = 128%). The 2-substituted histamine analogues were partial H1 receptor agonists on the endothelium-denuded isolated guinea pig aorta with pEC50 values generally smaller than observed on the guinea pig ileum, but the rank order of potency was found to be similar. The contractile effects on guinea pig ileum and aorta, respectively, could be blocked concentration-dependently by the H1 receptor antagonist mepyramine, yielding KB values for mepyramine in the nanomolar range. In vitro compounds 35 and 39 bound to [3H]mepyramine-labeled guinea pig cerebellar membranes with a pKi of 6.1 and 5.9, respectively. However, upon iv administration, 35 (3-100 mg/kg) and 39 (3-300 mg/kg) failed to inhibit the binding of [3H]mepyramine to mouse cerebral cortex in vivo, thereby indicating that these histamine derivatives are not able to penetrate the blood-brain barrier. In functional in vitro studies on histamine H2, H3, and other neurotransmitter receptors the selectivity of 39 was found to be 2138 (H1:H2), > 64 (H1:H3), 1000 (H1:M3), 105 (H1:alpha 1), 708 (H1:beta 1), and 71 (H1:5HT2A). Thus compound 39 is the most potent and selective H1 receptor agonist reported so far. These results make meta-substituted 2-phenylhistamines, especially 2-(3-(trifluoromethyl)phenyl)- and 2-(3-bromophenyl)histamine (39 and 35, respectively) valuable experimental tools for the selective stimulation of histamine H1 receptors and the study of H1 receptor-mediated functions.

Animals↗
PubMed1995

Histamine receptor-dependent and/or -independent activation of guanine nucleotide-binding proteins by histamine and 2-substituted histamine derivatives in human leukemia (HL-60) and human erythroleukemia (HEL) cells.

In dibutyryl cAMP-differentiated human leukemia (HL-60) cells, the potent histamine H1-receptor agonist, 2-(3-chlorophenyl)histamine, activates pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G-proteins) of the Gi-subfamily by a mechanism which is independent of known histamine receptor subtypes (Seifert et al. Mol Pharmacol 45: 578-586, 1994). In order to learn more about this G-protein activation, we studied the effects of histamine and various 2-substituted histamine derivatives in various cell types and on purified G-proteins. In HL-60 cells, histamine and 2-methylhistamine increased cytosolic Ca2+ concentration ([Ca2+]i) in a clemastine-sensitive manner. Phenyl- and thienyl-substituted histamines increased [Ca2+]i as well, but their effects were not inhibited by histamine receptor antagonists. 2-Substituted histamines activated high-affinity GTPase in HL-60 cell membranes in a PTX-sensitive manner, with the lipophilicity of substances increasing their effectiveness. Although HEL cells do not possess histamine receptors mediating rises in [Ca2+]i, 2-(3-bromophenyl)histamine increased [Ca2+]i in a PTX-sensitive manner. It also increased GTP hydrolysis by Gi-proteins in HEL cell membranes. All these stimulatory effects of 2-substituted histamine derivatives were seen at concentrations higher than those required for activation of H1-receptors. In various other cell types and membrane systems, 2-substituted histamine derivatives showed no or only weak stimulatory effects on G-proteins. 2-Substituted histamine derivatives activated GTP hydrolysis by purified bovine brain Gi/Go-proteins and by pure Gi2 (the major PTX-sensitive G-protein in HL-60 and HEL cells). Our data suggest the following: (1) histamine and 2-methylhistamine act as H1-receptor agonists in HL-60 cells; (2) incorporation of bulky and lipophilic groups results in loss of H1-agonistic activity of 2-substituted histamine derivatives in HL-60 cells but causes a receptor-independent G-protein-stimulatory activity; (3) the effects of 2-substituted histamine derivatives on G-proteins are cell-type specific.

Animals↗
PubMed1995

Synthesis and histamine H2-receptor antagonist activity of 4-(1-pyrazolyl)butanamides, guanidinopyrazoles, and related compounds.

A series of 4-(1-pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3-position of the pyrazole ring was prepared via 4-(3-nitro-1-pyrazolyl)butanenitrile (5) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a-d were prepared from the primary amines 8a-d which represent partial structures of the H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine-derived 4-(3-nitro-1-pyrazolyl)butanamide (9a) proved to be the compound with the highest H2-receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh-Schild rats 9a did not inhibit histamine-stimulated gastric acid secretion at a dosage of 0.1 mumol/kg i.v. Compounds 20a (the 3-(trifluoroethyl-guanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N-(4-[3-(trifluoroethylguanidino)-1-pyrazolyl]butyl)cyanogua nidine (29), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29: 74% inhibition at 0.025 mumol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.

Amides↗
PubMed1995

Azines and diazines as potential histamine H3-receptor antagonists.

In search of structure-activity relationships among histamine H3-receptor antagonists the imidazole ring of known H3-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, azines and diazines with ether (6-13) and carbamate (15-24) moieties as functional groups were synthesized. The obtained compounds did not show significant H3-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mice brain). The new compounds were also screened for H1-receptor antagonist activity on the isolated guinea-pig ileum and for H2-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors, H1 and H2.

Animals↗
PubMed1995

Pyrazoles as potential histamine H3-receptor antagonists.

In search of structure-activity relationships among histamine H3-receptor antagonists, the imidazole ring of known H3-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, pyrazoles with ether (4,5) and carbamate (6,7) moieties as functional groups were synthesized. Reaction of the hydrochloride of 4-(3-hydroxypropyl)pyrazole (1) with phenyl or benzyl isocyanates mainly gave the carbamates 6 and 7, whereas a similar reaction with 1 as the free base furnished the N-carbamoylpyrazoles 8 and 9. The bifunctional pyrazoles 10 and 11 were formed as by-products. The compounds obtained did not show significant H3-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mouse brain). These results demonstrate the importance of the imidazole moiety for H3-receptor antagonists. The new compounds were also screened for H1-receptor antagonist activity on the isolated guinea-pig ileum and for H2-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors H1 and H2.

Animals↗
PubMed1995

Effects of iodoproxyfan, a potent and selective histamine H3 receptor antagonist, on alpha 2 and 5-HT3 receptors.

We determined the affinity and/or potency of the novel H3 receptor antagonist iodoproxyfan at alpha 2 and 5-HT3 receptors. Iodoproxyfan and rauwolscine (a reference alpha 2 ligand) (i) monophasically displaced 3H-rauwolscine binding to rat brain cortex membranes (pKi 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with 3H-noradrenaline (pEC50 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA2 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3 mumol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD'2 5.24). Tropisetron (a reference 5-HT3 antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA2 7.84). In conclusion, the affinity/potency of iodoproxyfan at H3 receptors (range 8.3-9.7 [1]) exceeds that at alpha 2 receptors by at least 1.5 log units and that at 5-HT3 receptors by at least 3 log units.

Animals↗
PubMed1995

Effect of probenecid on the distribution and elimination of ciprofloxacin in humans.

OBJECTIVE: Probenecid-sensitive anion transport systems may be involved in distribution and elimination processes of anionic drugs. The aim of this study was to determine the effect of multiple probenecid treatment on the pharmacokinetic disposition of the zwitterionic fluoroquinolone ciprofloxacin in 12 healthy volunteers. METHODS: A single intravenous dose of 200 mg ciprofloxacin was given with and without multiple oral administration of probenecid in a randomized crossover fashion. Serial plasma, urine, saliva, tear, and sweat samples were drawn and analyzed for ciprofloxacin and its 2-aminoethylamino-metabolite (M1) by reversed-phase HPLC. RESULTS: Plasma area under the concentration-time curve and elimination half-life of ciprofloxacin were increased (p < 0.05), and urinary recovery and total and renal clearance decreased (p < 0.05) in the presence of probenecid. Nonrenal clearance and volume of distribution did not differ significantly with and without coadministration of probenecid. Peak plasma concentration, plasma area under the concentration-time curve, and elimination half-life of M1 were increased (p < 0.05) because of the higher amount of M1 formed and the reduced renal clearance (p < 0.05) of the metabolite. Saliva, tear, and sweat exposure were elevated (p < 0.05), but the alterations can be attributed primarily to the different kinetics of ciprofloxacin in plasma. CONCLUSIONS: Coadministration of probenecid altered the renal excretion and hence the plasma concentrations of ciprofloxacin. Metabolite kinetics and distribution into saliva, tears, and sweat were affected accordingly, but there was no direct effect of probenecid on these processes. This type of drug-drug interaction might be of clinical relevance when ciprofloxacin is combined with drugs eliminated by the organic anion transport system in the kidney tubules.

Adult↗
PubMed1995

Distribution kinetics of enoxacin and its metabolite oxoenoxacin in excretory fluids of healthy volunteers.

The distribution kinetics of enoxacin and its main metabolite oxoenoxacin in excretory fluids was investigated in 11 healthy volunteers. A single intravenous dose of 428 mg of enoxacin was given as a 1-h infusion. Serial samples of plasma, urine, saliva, nasal secretions, tears, and sweat were drawn and analyzed for enoxacin and oxoenoxacin by reversed-phase high-pressure liquid chromatography. Large differences in the concentration-time profiles of the excretory fluids analyzed were observed. Nasal secretions exhibited the highest enoxacin exposure, as assessed by the area under the concentration-time curve. Excretory fluid/plasma area under the concentration-time curve ratios were found to be 1.67 +/- 0.36 for nasal secretions, 0.76 +/- 0.28 for saliva, 0.25 +/- 0.07 for sweat, and 0.23 +/- 0.11 for tears. The elimination half-life of enoxacin from sweat (8.27 +/- 2.63 h) was significantly longer than that for plasma (5.10 +/- 0.46 h). Oxoenoxacin was detected in urine and saliva and exhibited a higher renal clearance and a lower saliva exposure than the parent compound. In contrast to that of the metabolite, distribution of enoxacin in saliva was found to be time and pH dependent. In conclusion, our study revealed considerable differences in the distribution kinetics of enoxacin among various excretory sites. Because of distinct acidic and basic properties, the anionic oxometabolite significantly differs from the zwitterionic parent compound in its distribution characteristics.

Adult↗
PubMed1995

The class III antiarrhythmic drug amiodarone directly activates pertussis toxin-sensitive G proteins.

The class III antiarrhythmic drugs amiodarone and bretylium tosylate are cationic/amphiphilic, and various substances with these physico-chemical properties are known to directly activate heterotrimeric regulatory G proteins. We asked the question of whether class III antiarrhythmic drugs are also direct G protein activators, using HL-60 leukemic cells and purified bovine brain G proteins as model systems. In HL-60 cell membranes, aminodarone increased high affinity GTP hydrolysis with an EC50 of 7.5 microM. The stimulatory effect of amiodarone on GTP hydrolysis was inhibited by pertussis toxin. Amiodarone stimulated binding of guanosine-5'-O-(3-thio)triphosphate to, and incorporation of GTP azidoanilide into, Gi protein alpha subunits in HL-60 membranes. The drug increased the cytosolic Ca2+ concentration in HL-60 cells in the presence but not in the absence of extracellular Ca2+. Amiodarone-induced increases in the cytosolic Ca2+ concentration were reduced by pertussis toxin and by a blocker of non-selective cation channels, SK&F 96365. Amiodarone activated the GTPase of reconstituted Gi/G(o) proteins and G12 with EC50 values of 20 microM and 50 microM, respectively. Bretylium tosylate did not increase GTP hydrolysis in HL-60 membranes or with Gi/G(o) proteins. Our data suggest that amiodarone but not bretylium tosylate is a direct activator of Gi and G(o) proteins and that amiodarone activates nonselective cation channels in HL-60 cells via Gi proteins and independently of Ca2+ mobilization from intracellular stores. Future studies will have to test the hypothesis that direct G protein activation by amiodarone contributes to its toxic and/or therapeutic effects.

Amiodarone↗
PubMed1994

Lipophilic beta-adrenoceptor antagonists and local anesthetics are effective direct activators of G-proteins.

We studied the effects of various beta-adrenoceptor (beta AR) antagonists and local anesthetics (LAs), i.e. substances possessing one basic and one lipophilic domain each, on activation of regulatory heterotrimeric guanine nucleotide-binding proteins (G-proteins). In membranes of differentiated HL-60 cells, propranolol activated high-affinity GTP hydrolysis with a half-maximal effect at 0.19 mM and a maximum at 1 mM. There was a close correlation between the log Q values (logarithm of the octanol: water partition coefficient) of beta AR antagonists and the logarithm of their effectiveness at activating GTPase (EC 3.6.1.-) in HL-60 membranes. The lipophilic LA, tetracaine, was also an effective activator of GTPase in HL-60 membranes, whereas more hydrophilic LAs were less stimulatory (bupivacaine and lidocaine) or even inhibitory (procaine). Propranolol and tetracaine also stimulated binding of guanosine 5'-O-[3-thio]triphosphate (GTP[gamma S]) to HL-60 membranes, but their stimulatory effects on GTP[gamma S] binding were smaller than on GTP hydrolysis. The stimulatory effects of propranolol and tetracaine on GTPase and GTP[gamma S] binding were inhibited by pertussis toxin. Propranolol and tetracaine effectively activated GTP hydrolysis of a reconstituted mixture of bovine brain Gi/Go-proteins, but the concentrations of substances needed for GTPase activation were higher than in HL-60 membranes. Procaine showed stimulatory effects on the GTPase of Gi/Go-proteins. Our data show that beta AR antagonists and LAs activate pertussis toxin-sensitive G-proteins, presumably through interaction with the C-terminus of their alpha-subunits. Apparently, the lipophilic domain of beta AR antagonists and LAs is more important for G-protein activation than the basic domain. We discuss the possibility that activation of nucleoside diphosphate kinase by beta AR antagonists and LAs contributes to their stimulatory effects on GTP hydrolysis in HL-60 membranes.

Adrenergic beta-Antagonists↗
PubMed1994

[Synthesis and combined H1-/H2 antagonist activity of mepyramine, pheniramine and cyclizine derivatives with cyanoguanidine, urea and nitroethenediamine partial structures].

Compounds with combined histamine H1- and H2-receptor antagonist activity were synthesized by connecting H1- and H2-receptor substructures via cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H1-receptor activity compared to single reference compounds. At the guinea-pig right atrium (H2-receptor model) compounds with mepyramine or cyclizine structure are also less active than the single references tiotidine, ranitidine, or lamtidine. Nevertheless substances with a pheniramine like partial structure proved to be potent histamine H2-receptor antagonists at the atrium model (about 27 times more active than cimetidine).

Animals↗
PubMed1994

Unknown effects of clinically used drugs as bias in clinical trials: antihistaminergic activity of the antihypertensive fixed-dose combination Betathiazid.

In a controlled clinical trial on histamine release in anaesthesia, it was suspected that the antihypertensive fixed-dose combination drug Betathiazid masked clinical signs of histamine release. By structure analysis of its constituents (propranolol, triamterene and hydrochlorothiazide), hydrochlorothiazide was considered to be most likely an H1-antagonist. An aqueous solution of the whole drug tablet (2 x 10(-4) M propranolol, 2.9 x 10(-5) M triamterene, 1.7 x 10(-5) M hydrochlorothiazide) and of the individual substances (1 microM each) was tested in the classical H1-receptor assay using the guinea pig ileum. Betathiazid in total suppressed the contraction to histamine (78% inhibition), but not to carbachol. Propranolol and triamterene had depressive effects (14% and 38% inhibition), but hydrochlorothiazide potentiated the contractions to histamine (75% potentiation). In all cases, the type of antagonism was not competitive. Although different mechanisms may account for the modulatory effects of Betathiazid, they have to be considered in the interpretation of clinical studies, especially for relating mediator concentrations with clinical signs.

Animals↗
PubMed1994

Inhibition of IgE- and non-IgE-mediated histamine release from human basophil leukocytes in vitro by a histamine H1-antagonist, desethoxycarbonyl-loratadine.

Loratadine, a new nonsedating histamine H1-antagonist, has been shown to inhibit immunologic release of inflammatory mediators in addition to its H1-receptor blocking properties. After oral administration, the agent is metabolized primarily to desethoxycarbonyl-loratadine (DCL). The basic piperidine, DCL, is readily soluble in water, whereas the nonbasic urethane, loratadine, is insufficiently soluble in water for some in vitro investigations. Therefore we used the metabolite, DCL, to study its influence on in vitro leukocyte histamine release (LHR) in 24 allergic and 22 nonallergic subjects. IgE-mediated and calcium ionophore A23187-induced LHR were inhibited by DCL in a dose-dependent fashion (values of drug concentration to induce 30% inhibition after stimulation with inhalant antigen, anti-IgE, concanavalin A, and calcium ionophore A23187 were 6, 8, 5, and 11 mumol/L, respectively). Higher concentrations of DCL caused mediator release in all subjects (n = 45, 30 mumol/L DC: 11% +/- 2% LHR, 100 mumol/L DCL: 35% +/- 1% LHR), abolishing any inhibitory effect of the drug. Rapid onset of inhibition by 10 mumol/L DCL was found in kinetic studies (n = 10). The inhibition of anti-IgE-induced histamine secretion was synergistically increased by simultaneous preincubation of DCL with the potent histamine H2-agonist, FRA-19. Additional data indicate that the inhibition of LHR by DCL might involve biochemical events that occur after cellular Ca++ influx because LHR induced by N-formyl-methionyl-leucyl-phenylalanine or the phorbol ester, 12-O-tetradecanoyl phorbol-12-acetate, was not significantly affected by DCL.

Basophils↗
PubMed1994

The selective histamine H1-receptor agonist 2-(3-trifluoromethylphenyl)histamine increases waking in the rat.

The effects of the selective histamine H1-receptor agonist, 2-(3-trifluoromethylphenyl)histamine, were studied in rats implanted with electrodes for chronic sleep recordings. 2-(3-Trifluoromethylphenyl)histamine (80-120 micrograms) injected into the left lateral ventricle increased wakefulness, whereas slow wave sleep was reduced. Pretreatment with pyrilamine (2.0 mg/kg) prevented the effects of the H1-receptor agonist on wakefulness and slow wave sleep. Our results further support the involvement of histamine in the modulation of the waking state.

Animals↗
PubMed1994

Novel histamine H3 receptor antagonists: affinities in an H3 receptor binding assay and potencies in two functional H3 receptor models.

1. We determined the affinities of ten novel H3 receptor antagonists in an H3 receptor binding assay and their potencies in two functional H3 receptor models. The novel compounds differ from histamine in that the aminoethyl side chain is replaced by a propyl or butyl chain linked to a polar group (amide, thioamide, ester, guanidine, guanidine ester or urea) which, in turn, is connected to a hexocyclic ring or to an alicyclic ring-containing alkyl residue [corrected]. 2. The specific binding of [3H]-N alpha-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the ten compounds at pKi values ranging from 7.56 to 8.68. 3. Inhibition by histamine of the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]-noradrenaline was antagonized by the ten compounds and the concentration-response curve was shifted to the right with apparent pA2 values ranging from 7.07 to 9.20. 4. The electrically induced contraction in guinea-pig ileum strips (which was abolished by atropine) was inhibited by the H3 receptor agonists R-(-)-alpha-methylhistamine (pEC50 7.76), N alpha-methylhistamine (7.90) and imetit (8.18). The concentration-response curve of R-(-)-alpha-methylhistamine was shifted to the right by thioperamide (apparent pA2 8.79) and by the ten novel compounds (range of pA2 values 6.64-8.81). 5. The affinities and potencies were compared by linear regression analysis. This analysis was extended to thioperamide, the standard H3 receptor antagonist, which is also capable of differentiating between H3A and H3B sites. Comparison of the apparent pA2 values in the two functional H3 receptor models yielded a regression coefficient of 0.77 (P<0.02). When the pA2 of the drugs in the mouse brain cortex were compared to the pXj for H3 sites (ten novel compounds) and for H3A sites (thioperamide), a significant correlation (r = 0.87; P<0.001) was obtained. There was, however, no significant correlation when the pKi of thioperamide for H3B sites was used instead (r = 0.52). In a similar manner, comparison of the pA2 in the guinea-pig ileum with the pKi in the binding assay yielded a significant correlation(r = 0.70, P <0.05) only when the pKi of thioperamide for H3A sites was used but not when its pKi forH3B sites was considered (r = 0.17, NS).6 On the basis of these results, structure-activity relationships for the novel H3 receptor antagonists,and the nature of the H3 receptors in the guinea-pig ileum and mouse brain, are considered.

Animals↗
PubMed1994

Effect of an antacid containing magnesium and aluminum on absorption, metabolism, and mechanism of renal elimination of pefloxacin in humans.

The effects of an antacid containing magnesium and aluminum hydroxide on the pharmacokinetics of pefloxacin in 10 healthy volunteers were investigated. In a randomized crossover design, each subject received an oral dose of 400 mg of pefloxacin either with or without multiple doses of the antacid. The concentrations of pefloxacin and its metabolites in plasma and urine were determined by high-performance liquid chromatography assays. We found that coadministration of magnesium and aluminum hydroxide caused a decrease of levels of pefloxacin in plasma and urine. The area under the plasma concentration-time curve decreased significantly (P < 0.001), suggesting impaired absorption of pefloxacin from the gastrointestinal tract. The relative bioavailability of pefloxacin after the antacid treatment was 44.4% +/- 23.8%, compared with that after a single administration. The underlying mechanism of this drug interaction is the formation of chelate complexes and probably also physical adsorption to the aluminum hydroxide gel. The metabolism of pefloxacin was not altered by the antacid treatment. Renal clearance was found to depend on urinary pH. Terminal half-life was significantly shorter after the antacid treatment, probably because of an increase in nonrenal clearance. In conclusion, pefloxacin should be given at least 2 h before the antacid to ensure sufficient therapeutic efficacy of the quinolone.

Adult↗