Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Converting enzyme inhibitors (CEIs) are widely used in treatment of essential hypertension. Large-scale clinical studies have shown that CEIs are well tolerated and cause fewer side effects than most other antihypertensive agents. The latter observation is fundamental for compliance with long-term treatment. There do exist, however, some side effects which although rare are not negligible. It is necessary though to distinguish between side effects linked to the class of therapeutic agents and those associated with particular structural features. Three types of side effects have been seen: 1) manifestations linked to inhibition of angiotensin II with systemic vasodilation (hypotension, vertigo) and decreased glomerular pressure (functional renal impairment) with preferred onset in renovascular hypertension; 2) potentiation of the bradykinin-prostaglandin system which causes cutaneous eruptions and for reasons still poorly understood a cough which may justify discontinuance of treatment: 3) side effects for which the sulfydryl group is essentially responsible (rash, dysgeusia, neutropenia, proteinuria) and which basically appear to be linked to the use of high doses of captopril. In general terms, and bearing in mind the frequently dose-dependent character of the side effects, it is advisable to prescribe low doses of CEIs, and this therapeutic approach is strengthened by the possibility of concomitant use of a thiazide diuretic allowing improved antihypertensive effects, coupled to better reciprocal tolerance of the drugs. The end result is a better quality of life for the hypertensive subject, and hence improved compliance with long-term treatment.
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PMID:[Quality of life of patients with hypertension treated with converting enzyme inhibitors]. 218 15

1. The characteristics of N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced oedema formation were investigated in vivo in rabbit skin. 2. FMLP injected intradermally alone induced a small increase in plasma leakage, but marked synergism with prostaglandin E2 (PGE2) in producing oedema responses was observed. In the presence of PGE2, FMLP was equiactive with C5a des Arg and 100-1000 times more active than histamine in terms of permeability-increasing activity. The response to FMLP was not dependent on endogenous histamine release. 3. FMLP-induced responses were of long duration (t1/2 approximately 40-50 min) when compared with bradykinin (t1/2 approximately 4-5 min). 4. The activity of a range of N-formyl peptides in increasing vascular permeability in skin correlated well with their activity as neutrophil stimulants in vitro. 5. Intravenous infusion of zymosan-activated plasma (ZAP) resulted in transient neutropenia and inhibition of oedema formation induced by FMLP and C5a des Arg in the skin. Responses to bradykinin were unaffected by the infusion of ZAP. 6. Intravenous injection of the non-steroidal antiinflammatory drug, ibuprofen, resulted in an inhibition of FMLP-induced, but not histamine-induced, oedema formation. This effect was independent of cyclo-oxygenase inhibition and the drug did not induced neutropenia. 7. Intravenous injection of the microtubule blocking agent colchicine inhibited FMLP-induced oedema formation. Responses to bradykinin were unaffected. When colchicine was administered after intradermal FMLP, subsequent plasma leakage was abolished. 8. The inference that receptors have evolved to bacterial secretions (i.e. FMLP) and products of the interaction of bacterial cell walls with tissue fluid (i.e. C5a des Arg), is consistent with the hypothesis that oedema formation is fundamentally a functional process concerned with regulating microbial lysis and opsonisation in an infected tissue.
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PMID:Characteristics of oedema formation induced by N-formyl-methionyl-leucyl-phenylalanine in rabbit skin. 249 23

A new synthetic compound, L-652,731 (trans-2,5-(3,4,5-trimethoxyphenyl) tetrahydrofuran), which has been demonstrated by Hwang et al. to be a potent and specific platelet-activating factor (PAF) receptor antagonist causes 100% inhibition of 1 microM PAF-induced neutrophil degranulation at 50 microM, but has no effect on neutrophil degranulation induced by precipitating immune complexes (323 micrograms/ml), fMet-Leu-Phe (10(-7) M), or the calcium ionophore A23187 (10(-5) M). Intravenous infusion of 1 mumol L-652,731 results in almost 100% inhibition of hypotension induced by PAF but not that induced by isoproterenol, histamine, bradykinin, or acetylcholine. With the use of this novel PAF receptor antagonist, the in vivo mediator role of PAF in the soluble immune complex-induced hypotension, extravasation, vascular lysosomal hydrolase secretion, and neutropenia in rats was determined. The hypotension, extravasation, and lysosomal hydrolase release induced by immune complex infusion take 2 to 10 min longer to occur than the same responses elicited by PAF infusion. The neutropenia response is immediate with both stimuli. L-652,731 when orally administered to rats (20 mg/kg, 1.5 hr before PAF infusion) inhibited PAF-induced hypotension (69%), extravasation (76%), vascular lysosomal hydrolase release (79%), and neutropenia (73%). The same L-652,731-dosing regimen inhibited immune complex-stimulated hypotension (87%), extravasation (77%), and vascular lysosomal hydrolase release (31%). The initial and complete neutropenia induced by immune complex infusion was not inhibited in L-652,731-pretreated rats, but the rate of return of neutrophils to the blood was faster in the latter rats. Rats with blocked circulation to the liver still exhibited extensive extravasation and vascular lysosomal hydrolase release in response to PAF, but there was no extravasation and greatly reduced hydrolase release in response to immune complexes. Thus PAF is indicated to be a major mediator of soluble immune complex-induced hypotension and vascular permeability and a minor mediator of immune complex-induced lysosomal hydrolase release in rats. PAF probably does not mediate the initial and complete neutropenia stimulated by immune complexes. The liver is probably the major site for PAF production in response to circulating immune complexes.
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PMID:Platelet-activating factor (PAF) mediation of rat anaphylactic responses to soluble immune complexes. Studies with PAF receptor antagonist L-652,731. 301

1 The mechanisms by which agents modulate the induction of kinin B1-receptors were investigated by studying the effects of kinins in vitro, by use of the rabbit isolated aorta, and in vivo by measuring the blood pressure of anaesthetized rabbits. 2 The contractile response of the rabbit isolated aorta to kinins increased in a time-dependent manner in vitro. This effect was abolished by continuous exposure to the protein synthesis inhibitor cycloheximide (71 microM). 3 Several substances were found to increase specifically the rate of sensitization to des-Arg9-bradykinin (des-Arg9-Bk), when applied continuously in vitro to tissues isolated from normal animals: bacterial lipopolysaccharide (LPS; 1 micrograms ml-1), muramyl-dipeptide (MDP; 2 micrograms ml-1), phorbol myristate acetate (PMA; 320 nM), epidermal growth factor (EGF; 100 ng ml-1) and endothelial cell growth factor (150 micrograms ml-1). 4 The protease inhibitors phenylmethylsulphonyl fluoride and aprotinin, a non-adjuvant isomer of MDP, rabbit purified leukocyte interferon, fibroblast growth factor and the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) did not have this effect. 5. It has been demonstrated that LPS induces B1-receptors in rabbits enabling des-Arg9-Bk to act as a hypotensive agent. In these experiments neutropenia induced by nitrogen mustard, did not prevent the in vivo effect of LPS. MDP (300 micrograms) and PMA (100 micrograms) were also found to induce a state of responsiveness to des-Arg9-Bk in vivo. FMLP (1 mg i.v.) induced a temporary decrease in blood neutrophil counts but had no effect on the induction of responses to des-Arg9-Bk. 6. The development of responses mediated by the B,-receptor in the two experimental systems seems to be unrelated to the activation of neutrophil leukocytes, but may be related to the activation of tissue macrophages. Approximately 3% of cultured adherent cells derived from rabbit aorta strips following protease digestion were stained for non-specific esterase, supporting such a possibility.
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PMID:Studies on the induction of pharmacological responses to des-Arg9-bradykinin in vitro and in vivo. 367 93

Platelet activating factor (PAF) has many proinflammatory properties. It is a polymorphonuclear leukocyte chemotactic factor, it aggregates platelets, increases vascular permeability, and is generated by inflammatory cells. To determine the possible in vivo role of PAF in inflammation, we examined the effects of the PAF antagonist and structural analogue, CV3988 on acute inflammatory responses in the skin of rabbits. Initial experiments indicated that CV3988 (10 mg/kg) was a specific inhibitor of PAF responses in vivo since it abolished neutropenia and thrombocytopenia induced by intravenous (iv) PAF infusion without effecting the response to f-met-leu-phe. In dermal inflammation, 125I-albumin, 111In-labeled platelets, 51Cr-labeled leukocytes, and 86RbCl were used to simultaneously quantitate protein exudation, platelet deposition, leukocyte accumulation, and blood flow in the lesions. CV3988 inhibited inflammatory responses to intradermal injection of PAF by 65 to 85% but it did not inhibit thrombin-induced platelet deposition or bradykinin and histamine-induced protein exudation. CV3988 treatment inhibited by 60 to 80% (p less than 0.01) the platelet deposition occurring at the peak of the reaction (1 1/2 hours) induced by the intradermal injection of zymosan, zymosan activated plasma, endotoxin, and the reversed passive Arthus reaction. Protein exudation was inhibited by 67 to 85% (p less than 0.1) and leukocyte accumulation was inhibited by 24 to 35% (p less than 0.05), but only in the zymosan and reversed passive Arthus reactions, respectively. Inflammatory hyperemia (increases blood flow) was not affected by CV3988 treatment. We conclude that in certain inflammatory reactions, PAF may mediate platelet deposition and protein exudation. The marginal effect of CV3988 on leukocyte accumulation suggests that the leukotactic activity of PAF is relatively less important in vivo.
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PMID:Evidence that platelet activating factor may mediate some acute inflammatory responses. Studies with the platelet-activating factor antagonist, CV3988. 395 Nov 99

Captopril (Capoten; Squibb) is a specific orally active antagonist of peptidyl-dipeptide carboxyhydrolase, the enzyme which converts angiotensin I to angiotensin II and which inactivates bradykinin. Captopril therefore reduces blood pressure in a variety of animal models of hypertension. In 96 studies on 1570 patients, captopril has been shown to be superior to placebo and equivalent to either propranolol or a diuretic in the treatment of essential hypertension. In the management of severe treatment-resistant hypertension, the response to captopril (alone or in combination with a diuretic and/or propranolol) was better than the response to standard triple therapy. Captopril, with digitalis and a diuretic, also improved the haemodynamic and clinical status of patients with refractory congestive heart failure. Side-effects include skin rashes (15%), proteinuria (1,1%, or 0,4% of patients with no prior renal disease) and the nephrotic syndrome (0,9%, or 0,3% of patients with no prior renal disease). Nearly all patients with the nephrotic syndrome in whom renal biopsies were performed were found to have membranous glomerulopathy. Neutropenia (total white cell count less than 1,000/microliter) was found in 33 of over 6,000 patients (0,4%), but in all cases there were other possible causes for this. Captopril is the first of an important group of antihypertensive and afterload-reducing drugs; its major indications are likely to be in the treatment of refractory severe hypertension or congestive heart failure.
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PMID:Captopril--an overview. 621 58

In congestive heart failure, acute administration of the converting enzyme inhibitor captopril leads to a decrease in arterial pressure, systemic vascular resistance, left ventricular filling pressure, and the end-diastolic volumes of both ventricles, as well as to an increase in cardiac index, stroke volume index, right and left ventricular ejection fractions. The mechanism of action appears not only attributable to a decrease in angiotensin II but, possibly, may also be accounted for by central and peripheral sympathicolytic effects diminished degradation of bradykinin and an increase in synthesis of vasoactive prostaglandins. During continued treatment with captopril over three months a further decrease in left ventricular filling pressure and an increase in cardiac output can be observed. While the exercise tolerance is not meaningfully affected at the beginning of treatment, a significant increase may be seen during long-term use. After three months of therapy an increase in the acutely-lowered mean arterial pressure can be noted. As compared with placebo-treated control patients, a more favorable clinical course was seen in those receiving captopril. There does not appear to be a relationship, however, between the initial hemodynamic effects and the clinical response. On combined use of captopril and hydralazine, as compared to treatment with captopril only, there is a greater increase in cardiac output and stroke volume without marked additional fall in pulmonary capillary pressure and a further decrease in systemic arterial pressure, incurred without symptomatic hypotension in the majority of patients. The adverse effect is hypotension which precludes long-term treatment in about 10% of patients. Proteinuria, neutropenia and renal insufficiency occur only rarely, usually in patients who are maintained on daily dosages above 300 mg or who have preexisting renal disease. Skin rashes and taste alterations are more common but are frequently well-tolerated and, generally, do not warrant discontinuation of treatment.
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PMID:Converting-enzyme inhibitor therapy for chronic heart failure. 634 10

Exposure of human blood polymorphonuclear leukocytes (PMN) to purified active plasma kallikrein resulted in PMN aggregation when kallikrein was present at concentrations ranging from 0.4 to 0.6 U/ml (0.18-0.27 microM). Kallikrein-induced PMN aggregation was not mediated through C5-derived peptides, because identical responses were observed whether or not kallikrein had been preincubated with an antibody to C5. Moreover, kallikrein was specific for aggregating PMN, because no aggregation was observed with Factor XII active fragments (23 nM), Factor XIa (0.6 U/ml or 15nM), thrombin (1.6 microM), plasmin (2 microM), porcine pancreatic elastase (2 microM), bovine pancreatic chymotrypsin (2 microM), or bradykinin (1 microM). Bovine pancreatic trypsin (2 microM) aggregated PMN, but to a lesser extent than kallikrein (0.18 microM). Kallikrein was a potent aggregant agent for PMN because similar responses were observed with kallikrein (0.5 U/ml or 0.23 microM) and an optimal dose (0.2 microM) of N-formyl-methionyl-leucyl-phenylalanine. In addition, PMN incubation with kallikrein resulted in stimulation of their oxidative metabolism as assessed by an increased oxygen uptake. Neutropenia and leukostasis observed in diseases associated with activation of the contact phase system may be the result of PMN aggregation by plasma kallikrein.
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PMID:Purified human plasma kallikrein aggregates human blood neutrophils. 691 55

Two antifibrinolytic drugs, tranexamic acid (TXA) and aprotinin (APR), are used to improve the recovery of patients following cardiac surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. To investigate their possible mechanisms of action during cardiopulmonary bypass, we examined (i) the effects of TXA and APR on bradykinin (BK) induced vascular permeability (VP) in conscious rats, (ii) the roles of platelets and neutrophils in this reaction, and (iii) the effects of TXA or APR on BK responses in platelet- or neutrophil-depleted rats. Evans blue dye (EB) was used as the marker of extravasation. The animals were treated with antiplatelet serum for platelet depletion or with methotrexate for neutrophil depletion. In normal rats, BK increased VP in most tissues. Thrombocytopenia and neutropenia also increased basal VP. TXA had no significant effect whereas APR decreased basal VP. In the second series of experiments, APR significantly attenuated BK-induced increases in VP, whereas TXA was completely ineffective. Platelet depletion did not affect BK-induced increases of VP, except for a massive plasma exudation in the lung parenchyma. Neutrophil depletion also had no effect on BK-induced increases of VP, except for an attenuation in the duodenum. In the third and last series of experiments, TXA potentiated the effect of BK in the upper and lower bronchi of platelet-depleted rats, compared with the effects of TXA on BK in normal animals, except in the lung parenchyma, where TXA blocked the increase of VP induced by BK. APR also potentiated the effect of BK in the lower bronchi of platelet-depleted rats. Overall, the inhibitory effect of APR on the VP induced by BK in normal rats was attenuated in platelet-depleted rats. Like TXA, APR blocked the increase of VP induced by BK in the lung parenchyma of platelet-depleted rats. In neutrophil-depleted rats, TXA did not affect the permeabilizing response to BK. In those rats, the inhibitory effect of APR against BK increases of VP was attenuated. These results show that the beneficial effect of APR, but not TXA, following cardiac surgery may be attributed to the inhibition of plasma exudation mediated, in part, by BK. In addition, platelets and neutrophils do not appear to be involved in BK-mediated plasma exudation. However, both cell types are essential for the regulation of basal VP. Finally, the mechanism underlying the protective inhibitory effect of APR on BK-induced increases of VP involves, at least in part, platelets and neutrophils, since the inhibitory effect of APR is attenuated in thrombocytopenic and neutropenic rats. Both cell types are not involved in the action of TXA on VP. Therefore, maintaining platelet and neutrophil counts following cardiopulmonary bypass could enhance the protective effect of APR.
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PMID:Aprotinin, an antifibrinolytic drug, attenuates bradykinin-induced permeability in conscious rats via platelets and neutrophils. 927 58

Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types. Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-methyltaxol C; 5-20 microM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives. The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction. The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects.
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PMID:Differential effects of paclitaxel and derivatives on guinea pig isolated heart and papillary muscle. 945 98


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