摘要:

Summary—In the last ten years, the widespread increase inPlasmodium falciparumresistance to chloroquine has prompted research into antimalarial 4‐aminoquinolines, empirically used up to now. The mechanism of action of 4‐aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine‐resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four‐aminoquinolines are extensively distributed in tissues and characterized by a long elimination half‐life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4‐aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse‐effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance ofPlasmodium falciparumbetween chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine‐

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00774.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—We have already proposed a “Global Association Function” to represent the global affinity of proteins to a drug; it was first applied in the case of independent binding sites. In this paper, we show that this same function can also be used to assess interactions between sites by varying the number of interacting sites and their co‐operativity level. The resulting curves in two application cases are given together with the corresponding Scatchard plot: i) in a system with one single class of identical and interacting sites, ii) in a system with two classes of sites in which either primary or secondary are interacting; unexpectedly, in this latter case we also observed that sometimes positive co‐operativity occasionally resulted in a concave‐up Scatchard plot which is unusually admitted. In addition, as described in one example, our function is assumption free; this might be an advantage over usual methods, such as discrete parameter methods, because they require additional and empirical hypotheses on their related bi

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00775.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—The effects of the dihydropyridine calcium antagonist nicardipine on the concentration‐response curves of relaxant compounds acting through the adenylate‐cyclase/cAMP system (isoprenaline, forskolin, adenosine and theophylline) or by the cGMP pathway (sodium nitroprusside) were studied on human isolated bronchus and guinea‐pig isolated trachea. These effects were compared with those of nifedipine (a dihydropyridine derivative) and theophylline (a non‐selective phosphodiesterase inhibitor). Nicardipine, in the range of 0.01 to 1 μM, significantly potentiated the relaxant effects of isoprenaline, forskolin, adenosine and theophylline, whereas the effects of sodium nitroprusside were significantly potentiated at 10 μM only. These results suggest that nicardipine behaves as an inhibitor of phosphodiesterases III and IV. One such effect may be involved in the potentiation of the isoprenaline relaxation of human and guinea‐pig iso

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00776.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Isolated rabbit basilar (BA), middle (MCA) and posterior (PCA) cerebral arteries mounted in an isometric Mulvany myograph and stretched to a given level of resting tension, developed a spontaneous slow‐rising contraction. This tone presented the main features of a classical myogenic tone since it was not suppressed by repetitive washings, was not dependent on the presence of endothelium and was markedly influenced by the concentration of extracellular calcium. In addition, we observed that the occurrence of myogenic tone was dependent on the pH of the medium buffer. Decreasing pH of the Krebs solution from 7.54 to 6.81 by lowering NaHCO, concentration from 25 to 5 mM. reduced the amplitude of the myogenic tone developed by the arteries. We investigated the influence of such changes of pH on the contractile response to potassium chloride (KCl) and to 5‐hydroxytryptamine (5‐HT). We demonstrated that the contractile response to KCl (124 mM) was not affected by the pH of the organ bath whereas the maximum contraction to 5‐HT (10 μM) was significantly affected in BA but not in MCA and PCA. Furthermore, we found that three consecutive concentration‐response curves to 5‐HT were reproducible when obtained at pH 7.15 and 7.30 for BA and MCA. In PCA, 5‐HT‐induced responses were reproducible at pH 7.30 whereas the sensitivity of the repeated response curves to 5‐HT was reduced at pH 7.15. We also noted a larger variability of the response to 5‐HT for the three arteries at this pH. Thus, it appeared that bathing rabbit cerebral arteries in a buffer medium at pH 7.30 is suitable for studying their reactivity to 5‐HT. These results highlight the importance of controlling the pH of medium buffer when studyingin vitrothe reactivity of rabbit cerebral arteries. In addition, they define appropriate conditions to minimize the myogenic tone and to allow vigorous and reproducible contractile response

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00777.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Previous results have shown that the contractile response to norepinephrine (NE) was enhanced in isolated aortae from SHR and normotensive Wistar parathyroidectomized rats. In this work we sought to characterize the contribution of endothelium‐derived relaxing factor (EDRF) release to this effect which is not linked to hypertension. Parathyroidectomy (PTX) was performed by surgery on 5 week‐old male Wistar rats. Five weeks later intact (E+) and rubbed (E–) aortic rings were mounted in an organ chamber for isometric tension recording. KCl‐induced contractions were potentiated in PTX E+ aortae compared to sham operated (SO), (P<0.05), but not in denuded E‐ aortae. Similarly NE (1.nM‐ 10 μM) induced a potentiated contractile response in PTX E+ (P<0.01), but not in PTX E‐ rings; nevertheless the sensitivity did not change. After removal of endothelium, the expected enhanced contraction and sensitivity observed in SO rats was not present in PTX. The NO synthase inhibitor L‐NAME (20 μM), enhanced sensitivity to NE in SO but not in PTX E+ aortic rings. In addition, hemoglobin (Hb, 10 μM) enhanced NE contraction in SO (P<0.01) aortic rings, but to a lesser extent in PTX rat aortae. Moreover, in the presence of L‐NAME or Hb, SO and PTX aortae displayed a similar contraction. Superoxide dismutase (SOD, 150 U/ml) diminished the NE contraction since NO was protected from degradation but the difference was still present between SO and PTX rat aortae, ruling out the possible implication of superoxide anions in the hyperreactivity of PTX aortae. On the other hand, A23187, which induces EDRF release, reduced the level of NE contraction as expected, but suppressed the PTX enhancing effect and in calcium‐free solution the enhancement of contraction after PTX was not observed. These experiments extend to the rat the observations previously obtained in rabbit aorta: extracellular calcium is a major determining factor in NO production. Acetylcholine and A23187 (cumulative doses) produced an endothelium‐dependent relaxation which was not significantly modified in NE‐pre‐contracted PTX aortae compared to SO aortae. L‐arginine (100 μM), reversed the L‐NAME inhibitory effect and induced an attenuated endothelium‐dependent relaxation in PTX vessels (P<0.01). In conclusion, in rat isolated aortae the enhancing effect of parathyroidectomy on norepinephrine and KCl contractions is due to a diminished endothelial nitric oxide production. This might ariseviaa decrease of the constitutive NO synthase activity in an e

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00778.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—To investigate the involvement of nitric oxyde (NO) derived from endothelial cells in the control of vascular tone in the rat mesenteric vascular bed, the effects of different procedures known to interfere with the NO‐cyclic GMP pathway were evaluated both on the basal tone and on the vasodilatory responses to four muscarinic agonists. To this aim, rat isolated mesenteric vascular beds were perfused at constant pressure. Water infusion significantly increased the resting perfusion pressure whereas L‐NOARG, L‐NAME and methylene blue were devoid of effect. In noradrenaline‐preconstricted vascular bed, the perfusion pressure was significantly increased after water or L‐NAME infusion. The vasodilator response induced by subsequent addition of acetylcholine in bolus was not significantly modified by pre‐treatment with indomethacin but was significantly reduced by water infusion. Reponses to acetylcholine and to three other muscarinic agonists ‐carbachol, oxotremorine or McNeil A 343‐ were assessed. Incubation with L‐NAME did not modify the initial peak falls of the agonists except for Mc Neil A 343, whereas it significantly reduced the area under the pressure trace for all the substances. The latter effect was reversed after a subsequent incubation with L‐Arginine. Finally, L‐NAME strongly and significantly increased the drop in perfusion pressure and the area under the pressure trace following bolus of glyceryl trinitrate. These results suggest that in the mesenteric arterial bed of the rat, which can be considered as a resistant arteries preparation, basal tone appears to be controlled by a factor other than NO. Moreover, the vasodilator responses of muscarinic agonists are affected by L‐NAME in their second late sustained phase only, which probably relies on ade novosynthesis of endothelium derived‐NO. Finally, endothelium derived‐NO exerts inhibitory effects both on the sensitivy of the vascular smooth muscle to glyceryl trinitrate and on the magnitude of its contraction in the presence of noradrenaline, two types of effects

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00779.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—In anaesthetized animals, systemic injection of ET1at doses from 3 to 100 ng·kg−1provoked only a transient hypotensive effect. At 300 ng·kg−1we observed the classical biphasic effect, consisting of a transient lowering of the arterial pressure followed by a long‐lasting hypertensive effect. Direct injection of the peptide into the vertebral artery of anaesthetized animals only affected arterial pressure (AP) when the blood‐brain barrier was permeabilised. Under these conditions, a dose‐dependent decrease in AP was observed, which was not associated with a significant effect on the heart rate. Micro‐injections of the peptide in the medullary nucleus reticularis lateralis area (NRL), a medullary vasopressive centre, at doses of 30 to 60 ng·kg−1led to a significant reduction in mean arterial pressure (MAP) (17 ± 4% and 36.5 ± 6%) respectively without a significant change in heart rate. These effects lasted less than 2 hours. These results suggest a possible role of ET1as a neuromodulator involved in the central regulation of vasomotor ton

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00780.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Neuropeptide gamma (NPγ) induced a contractile response of the human isolated bronchus which was potentiated by the neutral endopeptidase inhibitor, phosphoramidon, but was not modified by atropine and indomethacin. NPγ was 3.31‐fold more potent than NKA. Contractile response curves to NPγ were shifted to the right and maximal responses reduced by the non‐peptide NK2‐receptor antagonist, SR 48968. The pKBof SR 48968 (8.94 ± 0.18,n= 15), calculated according to Kenakin (1987) was very close to that reported for [Nle10]‐NKA (4–10), a specific agonist of neurokinin NK2‐receptors (8.86 ± 0.13,n= 13), suggesting that the contractile effects of NPγ on the human isolated bronchus were mediated thr

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00781.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Drug metabolism in the liver may be decreased during liver diseases. However, the extent of impairment of specific isozymes of cytochrome P450 is largely unknown. We have studied the debrisoquine hydroxylation capacity of 17 patients with acute viral hepatitis and 106 unrelated healthy subjects. Debrisoquine metabolic ratio was increased in extensive metabolizers (EM) with acute viral hepatitis as compared with healthy EMs (median metabolic ratio: 1.20vs0.84,P<0.05). However, there was no difference in phenotype prevalence between patients and controls. Our results suggest that acute viral hepatitis only has a marginal effect on the activity of CYP2D6 and that substrates of this enzyme may be given in normal therapeutic doses to this category of patient

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00782.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—The effects of two single oral doses (5 mg and 20 mg) of a new angiotensin I‐converting enzyme inhibitor, imidapril, on a) systemic hemodynamics (arterial pressure, heart rate, cardiac output), b) brachial and common carotid arteries' hemodynamics (diameter and blood flow, pulsed Doppler technique), c) cerebral hemodynamics (middle cerebral artery mean blood flow velocity, transcranial Doppler technique), and d) biological parameters (plasma converting enzyme activity, active plasma renin, plasma aldosterone, catecholamines, and atrial natriuretic factor) were investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double‐blind, cross‐over study performed in six healthy volunteers. Imidapril induced a strong, dose‐dependent and sustained inhibition of plasma converting enzyme activity and at the 20 mg dose an increase in active plasma renin. Other investigated biological parameters were not drug‐affected. Imidapril, whatever the dose, did not significantly affect systemic hemodynamic parameters. Imidapril, 20 mg, significantly increased common carotid artery blood flow and diameter and brachial artery diameter. Brachial blood flow also tended to increase but this was not significant. The middle cerebral artery mean blood flow velocity investigated in only five volunteers, underwent spontaneous variations after placebo, and these variations were not affected by imidapril, suggesting that imidapril, whatever the dose, does not influence cerebral blood flow. Thus, imidapril's vasodilating properties apparently affect only the muscular (brachial artery) and cutaneous (external carotid artery) territories, but do not influence the cerebral v

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00783.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY