Influence of cimetidine,ranitidine and imidazole on the behavioral effects of (±) N-n-propylnorapomorphine in male rats

Cimetidine injected IP 15 min before (±) N-n-propylnorapomorphine (NPA) antagonized in dose-dependent fashion the penile erections (PE) and stretching and yawning (SY) induced by this typical dopaminergic agonist in male rats. Ranitidine, which acts on H₂ histamine receptors in much the same way as cimetidine despite its lack of an imidazole ring, failed to produce the same effect. On the other hand, imidazole itself was similar to cimetidine in antagonizing PE and SY induced by (±) NPA, whether injected IP or ICV. Neither imidazole nor cimetidine antagonized the stereotyped behaviour (SB) induced by (±) NPA. Indeed, imidazole reduced the latency of this response. A mechanism which may underly these effects is discussed, as well as the possible preclinical use of this test in animals.     

Effect of imidazole on prostaglandin and thromboxane accumulation in urate arthritis

High concentrations of prostaglandins E₂ and F₂ and much lower concentrations of thromboxane B₂ occur in joint washes of chicken 1–3 h after intra-articular injection of urate crystals. Pretreatment with 200 mg/kg imidazole i.v. reduced the concentration of prostaglandons and of thromboxane B₂ in the joint washes significantly. Simultaneously, leucocyte invasion was delayed and development of oedema was inhibited. The results suggest that in urate crystal arthritis the effect on prostaglandin and thromboxane accumulation at the site of inflammation contributes to the anti-inflammatory activity of imidazole.     

Increased intestinal absorption in the rat caused by sodium lauryl sulphate,and its possible relation to the cAMP system

Summary The increases in the absorption of ouabain, phenolsulphonphthalein and pralidoxime caused by 17 mM sodium lauryl sulphate (SLS) from jejunal loops of anaesthetized rats were significantly reduced if sodium and chloride (Briseid et al., 1974) or chloride and bicarbonate were replaced by other ions in the loop fluid. Separate substitutions of sodium, chloride or bicarbonate did not significantly alter the SLS-caused absorption, except that the substitution of choline for sodium reduced the absorption of pralidoxime, both in the presence and in the absence of SLS.The increases in the absorption of phenolsulphonphthalein and pralidoxime caused by SLS were potentiated by theophylline (25 mM) and reduced by imidazole (25 mM). The addition of dibutyryl cyclic AMP (2.5 mM) to the loop fluid increased the absorption of the test substances. This effect was reduced by imidazole, but under the experimental conditions it was not potentiated by theophylline.Determinations of cyclic AMP in the rat intestinal mucosa showed that the level of this substance was significantly higher in the presence than in the absence of SLS. The experimental conditions were as described for the absorption experiments. It is concluded that the data obtained support the idea of an increased level of cyclic AMP as the main basis for the effect of SLS on the absorption.     

Receptor-specific functional efficacies of alkyl imidazoles as dual histamine H3/H4 receptor ligands

Histamine H₃ and H₄ receptors are highly related G protein-coupled receptors. Preclinical and clinical data strongly suggest the potential therapeutic application of selectively acting histamine H₄ receptor ligands to inflammatory conditions but also hint at a certain interference of the two receptors in diseases attended with itch and pain. The aim of this investigation was to identify dual acting ligands as pharmacological tools. Receptor binding profiles of ω-(1H-imidazol-4-yl)alkyl derivatives structurally defined as amides, carbamates, esters, ethers, ketones and ureas were evaluated with respect to their potencies at histamine H₃ and H₄ receptors. A two-step screening method based on in vitro radioligand binding studies and functional [³⁵S]GTPγS binding experiments was performed. The examined series of imidazole-containing compounds displayed both, selective histamine H₄ receptor and dual acting histamine H₃/H₄ receptor ligands. Slight structural modifications caused major differences in selectivity profiles and on functional properties at the human histamine H₄ receptor. N-(3-(1H-Imidazol-4-yl)propyl)-2-cyclohexylacetamide 11 was identified as most potent and selective human histamine H₄ receptor ligand in this series (K_i = 45 nM). Amide- and ether-containing structures consistently exhibited partial agonist efficacies, whereas ureas, ketones, esters and carbamates mainly acted as antagonists and inverse agonists. We identified novel dual acting histamine H₃/H₄ receptor ligands with varying efficacies at the histamine H₄ receptor subtype, whereas histamine H₃ receptor antagonism was kept constant, e.g. 3-(1H-imidazol-4-yl)propyl (cyclohexylmethyl)carbamate 19 or 4-(3-(3-phenylpropylthio)propyl)-1H-imidazole 30. These compounds state valuable pharmacological tools in studies of diseases, in which histamine H₃ and H₄ receptor signalling contributes to pathophysiological conditions.     

观察ICU危重患者机械通气中咪唑安定与芬太尼的临床作用

目的观察ICU危重患者机械通气中咪唑安定与芬太尼的临床镇静作用及效果。方法对我院59例ICU收治的危重需行机械通气的患者进行镇静药物的分组临床观察,29例患者在机械通气中使用芬太尼,30例患者在机械通气中使用咪唑安定。观察两组患者用药后的起效时间以及神志恢复时间,并观察两组患者呼吸以及血氧饱和度(SaO2)、动脉血氧分压(PaO2)、动脉血二氧化碳分压(PaCO2)等指标。结果芬太尼均让患者达到Ramsay氏分级标准3~4级的时间明显短于咪唑安定,而平均药物起效时间以及术后神志恢复时间,芬太尼组亦明显短于咪唑安定组。另外,两组患者呼吸以及SaO2、PaO2、PaCO2等指标上均较使用前有明显的改善(P<0.01),组间进行比较并无统计学意义(P>0.05)。结论 ICU危重患者机械通气中使用咪唑安定或芬太尼均有较好的镇静作用,临床可根据具体情况进行选择。     

Evaluation of the Skin Retention Time of Imidazole Derivative/Die Bewertung der Verweildauer von Imidazolderivaten in der Haut

Summary: The evaluation of prophylactic antifungal effect expressed as drug retention time, or as time required for the onset of an experimental mycotic infection in pre-treated guinea-pigs, has shown some imidazolederivatives capability to exert this activity even 48 and 72 hours after a single application. The long-term intracutaneous activity and powerful fungicidal activity of one of the tested drug, fenticonazole, suggest that a single daily administration can be adequate for the treatment of human dermatophytosis.
Zusammenfassung: Studien zur Bewertung der prophylaktischen, antimyzetischen Wirkung, ausgedrückt als Verweildauer des Antimykotikums oder als die zum Angehen einer experimentellen Infektion in vorbehandelten Meerschweinchen benötigte Zeit, zeigen einen solchen Effekt bei einigen Imidazolderivaten nach 48 und 72 h nach einmaliger Applikation. Die langanhaltende und starke, intrakutane, fungizide Aktivität eines der geprüften Antimykotika, des Fenticonazols, legt nahe, daß eine jeweils einmalige Anwendung pro Tag für die Behandlung einer Dermatophytose ausreichen dürfte.     

Formation and antimycotic effect of cyclodextrin inclusion complexes of econazole and miconazole

The stability constants between β-cyclodextrin (β-CD) and the two antimycotic imidazole derivatives, miconazole and econazole were measured. Increased ionization of the imidazole derivatives decreased the size of the stability constants. The same phenomenon was observed for miconazole and hydroxypropyl-β-cyclodextrin. In addition, the type of solubility diagram obtained was dependent on the degree of ionization of the imidazole derivatives. A type Bs solubility diagram was obtained for econazole and β-CD in buffer solution, pH 7.1. An econazole β-CD complex with a molar ratio of 1:1 was isolated. In a fluid medium the antimycotic effect of the econazole β-CD complex against a strain of Candida albicans was superior to the effect of a physical mixture of the two compounds. A small inhibitory effect of β-CD on the growth of the test organism was observed.     

Effects of methylxanthines and imidazole on the contractions of guinea-pig ileum induced by transmural stimulation.

Methylxanthines (10(-5) to 10(-3)M) were found to increase the amplitude of contractions of guinea-pig ileum induced by transmural stimulation but to inhibit those induced by acetylcholine or histamine. The order of the abilities of methylxanthines to augment the contractile responses was theobromine greater than caffeine greater than theophylline. When the contractions were completely suppressed by reduction of the calcium content in the medium or by addition of cyclic AMP, methylxanthines restored the responses effectively, just as does addition of calcium. Methylxanthines also accelerated the release of acetylcholine from the ileum associated with stimulation. Imidazole (3 X 10(-5) to 10(-3) M) had an essentially similar effect to methylxanthines in potentiating the contractile responses and in augmenting the release of acetylcholine. The present results indicate that the potentiating effects of methylxanthines and imidazole are due to an action on the nerve terminals, not on the postsynaptic membranes or contractile elements. Therefore, it si concluded that theit potentiating actions are due to facilitation of the movement of calcium in the nerve terminals on excitation, resulting in increased release of acetylcholine, and are not due to the effect of cyclic AMP formed as a result of their inhibitory actions on phosphodiesterase.     

The inhibition of thromboxane synthesis has no influence on HgCl2-induced acute renal failure in the rat

Renal function parameters and urinary thromboxane B2-excretion were studied in the rat in HgCl2-induced acute renal failure. Studies were performed before and 3 h after the inhibition of thromboxane synthesis alone, after HgCl2 alone, or after the combination of HgCl2 and thromboxane-synthesis inhibition. Thromboxane-synthesis inhibition alone by indomethacin (5 mg/kg i.v.), imidazole (25 and 50 mumol/kg per min i.v.) and dazoxiben (5 mg/kg i.v.) had no effect on glomerular filtration rate (GFR) or para-aminohippuric acid clearance (CPAH), whereas urinary thromboxane excretion was suppressed. Only the administration of the selective blockers imidazole and dazoxiben resulted in a marked increase in urinary volume (V) and fractional sodium excretion (FENa). HgCl2 alone (2 mg/kg i.v.) caused a decrease in GFR and CPAH with -38% (P less than 0.01), and urinary thromboxane B2 excretion increased from 20.3 +/- 1.5 to 30.6 +/- 2.6 pg/min. (P less than 0.01). The administration of indomethacin, imidazole (50 mumol/kg per min) and dazoxiben prevented the increase in thromboxane B2 excretion 3 h after HgCl2 to values of 3.3 +/- 1.2, 6.9 +/- 0.6 and 13.0 +/- 1.6 pg/min respectively (P less than 0.01 versus control for all values). Despite this, the decrease in GFR and CPAH after HgCl2 could not be prevented. A decrease of GFR with -44, -54, -57 and -32% and of CPAH with -37, -49, -57 and -27% were observed for indomethacin, imidazole 25 and 50 mumol/kg per min and dazoxiben respectively. This evolution was not significantly different from what was observed with mercury alone. Selective thromboxane synthesis inhibition resulted in a decrease of serum free ionised calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and antiplatelet activity of new imidazole-4-carboxylic acid derivatives

1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an additional secondary amino group were synthesized and identified as antiplatelet agents in a low micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary amino function, slight structural modifications are able to shift the pattern of activity among the above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC(50) = 1 microM and COX-1 inhibition (IC(50) = 0.4 microM). The carboxamide 6c shows ADP antagonistic properties (IC(50) = 2 microM). Compound 6g is as well PAF antagonistic (IC(50) = 4 microM) and a COX-1 inhibitor (IC(50) = 1 microM). The derivative 6i shows a strong antiadrenergic (IC(50) = 0.15 microM) and PAF antagonistic (IC(50) = 0.66 microM) effect.