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PubMed1990

Action of corticosteroids on beta-adrenergic receptors. Clinical aspects.

Inhaled beta 2-stimulants are the most effective drugs for acute asthma attacks. This is probably due to functional antagonism against a large variety of possible asthma mediators. A defect in beta-receptor function is not the cause of asthma but treatment with beta 2-stimulants induces a down-regulation of beta-receptors and beta-receptor function outside the lung. There is, however, no convincing evidence that tachyphylaxis of clinical importance to the bronchodilating effect occurs in asthmatics receiving normal doses of beta 2-receptor stimulants. A slight rebound increase of bronchial hyperreactivity has, however, been demonstrated 12 to 23 h after stopping regular treatment. This may be due to slight tachyphylaxis not visible in normal lung function tests. Inhaled steroids should be given to all asthmatics needing regular inhaled beta 2-agonist treatment, at least to adults. Steroids not only seem to reduce bronchial inflammation and hyperreactivity, and thereby the distribution of inhaled drugs, but also attend to reverse beta 2-receptor subsensitivity.

Adrenergic beta-Agonists↗
PubMed1978

Inhibition of experimental immediate hypersensitivity reactions by a novel xanthone, RU 31156.

RU 31156, the tris-(hydroxymethyl)-aminomethane salt of 7-(S-methylsulphonimidoyl)-5-(n-hexyl)-xanthen-9-one-2-carboxylic acid has been found to be a potent inhibitor of experimental immediate hypersensitivity reactions in vivo. In the IgE-mediated rat PCA test, RU 31156 had an ED50 of 0.0046 (00037--0.0057) mg/kg which compared to a figure of 1.21 (1.04--1.42) mg/kg for disocium cromoglycate (DSCG), both compounds being administered intravenously. RU 31156 was also active when administered orally, having an ED50 of 0.19 (0.07--0.30) mg/kg when given 10 min before antigen. RU 31156 partially inhibited an IgG-mediated PCA reaction in the rat. Both RU 31156 and DSCG inhibited anaphylactic bronchoconstriction in the rat, giving bell-shaped dose-response curves. From the upward part of the curves, approximate ED30 values of 0.02 and 2.0 mg/kg were obtained for RU 31156 AND DSCG respectively. Anaphylactic bronchoconstriction in the guinea-pig was not affected by RU 31156 and pinnal anaphylaxis was inhibited at only relatively high doses of 1--10 mg/kg i.v. The effects of both histamine and 5-hydroxytryptamine in the mouse pinna were not affected by RU 31156. In PCA experiments, RU 31156 showed self-tachyphylaxis following both intravenous and oral administration. It also showed cross-tachyphylaxis with DSCG, indicating that these compounds are likely to share a similar mode of action.

Anaphylaxis↗
PubMed1989

Prevention and treatment of endotoxin and sepsis lethality with recombinant human tumor necrosis factor.

Tumor necrosis factor (TNF) is a macrophage product released in response to endotoxin that has been implicated as a cause of the toxicity and lethality seen in septic shock. Previous work suggests that tolerance to nutritional and lethal effects of TNF occur after repeated exposure to recombinant tumor necrosis factor (rTNF). In this study pretreatment of rats with a single low intravenous dose of rTNF prevented subsequent death when a lethal dose of rTNF was administered 24 hours later (tolerance or tachyphylaxis). Pretreatment with rTNF also afforded protection against the lethal effects of either endotoxin or cecal ligation and puncture when rats were challenged 24 hours later. Recombinant TNF injected 6 hours after cecal ligation and puncture initially resulted in a significant survival advantage for treated animals. When this experiment was repeated with a different lot of rTNF, however, the therapeutic benefit of rTNF was not obtained until the dose was decreased by a factor of 10. Protection against the lethal effects of cecal ligation and puncture did not occur when rTNF was given 24 hours after the insult. A single low dose of rTNF can result in tolerance or tachyphylaxis to the lethal effects of TNF. The results suggest that the early administration of low-dose rTNF may be useful in the prevention and treatment of the lethality of sepsis.

Animals↗
PubMed1986

Oral beta 2-selective adrenergic bronchodilators.

Oral beta 2-agonists (carbuterol, pirbuterol, procaterol, bitolterol, clenbuterol) are drugs widely used as bronchodilators. The efficacy and selectivity of bronchodilators drugs depend on their intrinsic pharmacological properties and on the route of administration. The characteristics of the oral route are easy usage, precise dosage and assured effects. Consequently, disadvantages (delayed onset of action, more frequent side-effects) and the indications, (patients with severe chronic airways obstruction, nocturnal asthmatic attacks, and children and elderly subjects) are clearly evident. The most recent beta 2-agonists have an efficient and prolonged bronchodilating action with well-known side-effects. In order to control drug efficiency in a large population and identify type and degree of adverse reactions, a post-marketing surveillance study was programmed for clenbuterol. The results available confirms that long-term treatment with oral clenbuterol is an effective and safe therapeutical approach. During long-term treatment, tachyphylaxis (a diminished responsiveness) develops. This complex biological phenomenon can be studied, in several ways i.e. functional response of target-organ, appropriate biochemical-metabolical indices, and functional evaluation of the cellular beta-receptors in vitro. Also in the light of evaluation of serum levels of cyclic nucleotides (cyclic adenosine and guanosine monophosphates) it appears that the clinical importance of tachyphylaxis is mild and that chronic therapy with beta 2-agonists is safe and effective when used in selected patients.

Administration, Oral↗
PubMed1981

Treatment with xylometazoline (Otrivin) nosedrops over a six-week period.

Twenty healthy subjects were treated with xylometazoline 1 mg/ml for six weeks in order to study the occurrence of tachyphylaxis and rhinitis medicamentosa. Each subject instilled 0.15 ml of xylometaxoline nose-drops into each nostril three times a day. Posterior rhinomanometry was performed before the trial started, after 1, 2, 4 and 6 weeks treatment and 20, 27, 40 and 48 hours after the subject had taken the nose-drops for the last time. With rhinomanometry it was possible in this study to show that the same dose was adequate during the whole six-week period, i.e. no tachyphylaxis was observed. No reactive congestion was observed after the trial was finished.

Adult↗
PubMed1984

Compartmentation and hemodynamic effects of nicotine in isolated, perfused guinea pig hearts.

Tachyphylaxis with respect to the positive inotropic and positive chronotropic effects of nicotine in isolated perfused hearts of guinea pigs was found to persist for 3 and 10 min, respectively, after discontinuation of intracoronary infusion of nicotine (5 X 10(-5) M). The longer duration of chronotropic tachyphylaxis correlated with a slower release of nicotine from the tissue of the right atrium in comparison to the washout from the ventricular myocardium. A similar disparity in washout between atrial and ventricular tissue was found for inulin. Thus, greater perfusion of the ventricular tissue, not a difference in affinity for nicotine, seems to account for the more rapid recovery of the inotropic response to nicotine. The apparent volume of distribution of nicotine in both atrial and ventricular myocardium was about 2 ml/g wet weight; uptake and release of nicotine was rapid. Kinetic analyses of coronary venous washout yielded four components, indicating that nicotine is distributed in at least four (kinetically defined) compartments within the ventricular myocardium. Washout from the largest tissue compartment was controlled by the rate of perfusion of the vascular space, as demonstrated by comparison with washout of erythrocytes, inulin, sucrose, and urea from the heart. Hexamethonium reduced the nicotine content of this fast-emptying compartment from 85-57 nmol/g (prelabeling concentration of nicotine 5 X 10(-5) M), giving an upper estimate for the number of specific nicotine binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Nitrate tolerance and dependence. A critical assessment.

Tolerance and cross-tolerance to nitrates has been known since 1900 but the actual clinical importance of this phenomenon is unclear. Vasodilator treatment of congestive heart failure has provided an important new role for long-acting nitrates. The advent of high-dose nitrate regimens for both angina and heart failure raises the possibility that nitrate tolerance could be a potential detriment to therapy. A number of older studies have documented the development of tolerance and cross-tolerance to blood pressure and heart rate responses to nitrates as well as the rapid onset of tolerance to nitrate headaches in subjects given nitrates on a regular basis. Animal experiments also confirm the ready appearance of nitrate tachyphylaxis. Needleman has proposed a cellular mechanism for nitrate tolerance based on a chemical alteration of nitrate receptors in the vascular wall. In spite of these studies, there is considerable evidence that clinically relevant tolerance to nitrates is rare. Several recent investigations designed to look at this problem using high-dose isosorbide dinitrate (ISD) failed to demonstrate tachyphylaxis to the anti-anginal or hemodynamic effect of ISD. However, very recent work in patients with angina suggests that tolerance to high dose ISD does occur and may reduce the duration of action of long-acting nitrates. Overall, the bulk of current evidence does not support tolerance to be a major problem in nitrate treatment of cardiac diseases, although attenuated vasodilator responses may occur after several weeks of nitrate therapy.

Angina Pectoris↗
PubMed1982

Nicotine-induced antinociception in rats and mice: correlation with nicotine brain levels.

Nicotine was found to be potent in producing antinociception in mice and rats as measured by tail-flick latency but its action was of short duration. Nicotine's ED50 values (confidence limits) were 0.7 (0.4-1.1) and 2.0 (1.2-3.4) mg/kg in rats and mice, respectively, at the time of maximum effect. Brain levels of nicotine reached a maximum at 10 min, whereas antinociception was maximal within 2 min in rats. However, there was a good correlation between the time courses of antinociception and brain levels of nicotine in mice with both attaining maximal levels at 5 min. It was found that tachyphylaxis developed to the antinociception in rats within 10 min and lasted for up to 14 h, but tachyphylaxis did not develop to nicotine-induced antinociception in mice. The effect of nicotine appeared to be central in both rats and mice inasmuch as mecamylamine antagonized completely but hexamethonium (5 mg/kg) antagonized partially. Nicotine-induced antinociception was not blocked in either rats or mice by atropine in doses up to 10 mg/kg. Naloxone did not block nicotine in rats but did antagonize the antinociception in mice. In addition, yohimbine, a selective alpha-2 antagonist, blocked the antinociception in both species. These data implicate several different mechanisms in the antinociceptive action of nicotine.

Analgesics↗
PubMed1982

[Effects of intra-arterially administered capsaicinoids on vocalization in guinea pigs and medial thalamic neuronal activity in cats (author's transl)].

Algesic actions of capsaicinoids were investigated by utilizing vocalization in conscious guinea pigs and medial thalamic neuronal activity in gallamine triethiodide immobilized cats. Intra-arterial administration of capsaicin and dihydrocapsaicin evoked strong vocalization response, but other capsaicinoids, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, norcapsaicin, N-(4-hydroxy-3-methoxybenzyl)-6-methylheptamide, and N-(4-hydroxy-3-methoxybenzyl)-6-methylhept-trans-4-enamide, were weaker than capsaicin and dihydrocapsaicin. Similar results were obtained from medial thalamic nociceptive neurons in cats. Morphine (10 mg/kg s.c.) suppressed vocalization response evoked by intra-arterial administration of capsaicin and bradykinin. Aspirin (100 mg/kg i.p.) also suppressed the bradykinin-evoked response, but not the capsaicin-evoked response. Capsi-amide, a non-pungent substance of Capsicum annuum L., failed to suppress nociceptive response to capsaicin or bradykinin in guinea pigs and cats. Tachyphylaxis was elicited by repeated administration of capsaicin in vocalization. No cross-tachyphylaxis to bradykinin, acetylcholine, and dihydrocapsaicin could be observed.

Action Potentials↗
PubMed1986

Response to epinephrine in children receiving oral beta-agonists.

Physicians are sometimes concerned that the regular use of oral beta-agonists in the outpatient management of childhood asthma will result in decreased sensitivity or tachyphylaxis to these agents. While tachyphylaxis might not be clinically important during outpatient treatment, it could become significant during the emergency treatment of acute asthmatic attacks. We compared the increase in peak flow measurements before and 20 minutes after the injection of subcutaneous epinephrine hydrochloride in children with acute asthma and found no significant differences between those patients taking and those not taking oral beta-agonists.

Administration, Oral↗
PubMed1986

The vasoactive properties of ascitic fluid in acute pancreatitis in a porcine model.

The hemodynamic effect of pancreatic ascitic fluid was studied in a porcine model. Pancreatitis was induced by a low-pressure infusion of trypsin and taurocholate sodium into the pancreatic duct. The ascitic fluid that accumulated was then injected into the inferior vena cava of five pigs, with each pig receiving five infusions at 40-minute intervals. Mean arterial blood pressure and peripheral vascular resistance fell with each infusion, while pulmonary artery pressure increased. The magnitude of the drop in arterial blood pressure decreased with subsequent infusions, suggesting tachyphylaxis. The rise in pulmonary artery pressure increased with successive infusions. Anesthesia artifact and decay of the pancreatic ascitic fluid were ruled out as causes of the tachyphylaxis. Filtration separated the substances producing pulmonary effects and systemic blood pressure effects (0.2 to 11 microns vs 10,000 daltons to 0.2 micron). These data suggest that two mediators may produce the hemodynamic effects of pancreatic ascitic fluid.

Animals↗
PubMed1987

Effects of tumour necrosis factor and related cytokines on vascular endothelial cells.

Tumour necrosis factor (TNF) and related cytokines have been found to alter the phenotype of vascular endothelial cells so as to promote coagulation, inflammation and immunity. We have used recombinant human TNF, lymphotoxin (LT), interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta) to study and compare the effects of these molecules on cultured human endothelial cells (HEC). All four mediators cause HEC monolayers to reorganize from an epithelioid to a fibroblastoid morphology. Reorganization is slow (days), reversible upon cytokine withdrawal and enhanced by co-addition of immune interferon. Coincident with morphological change, TNF and LT (but not IL-1 alpha or IL-1 beta) cause a marked increase in HLA-A, B mRNA and antigen expression. TNF and LT also induce a slow increase in the mRNA levels and cell-surface expression of IL-1 species. All four cytokines have been reported to enhance HEC adhesiveness for lymphocytes and inflammatory leucocytes; these changes temporally coincide with a rapid (hours) and sustained increase in expression of intercellular adhesion molecule 1 (ICAM-1), and with a rapid but transient de novo expression of an endothelial-leucocyte adhesion molecule (detected by antibody H4/18), respectively. TNF and LT induce reciprocal tachyphylaxis for the reinduction of H4/18 binding but do not inhibit induction by IL-1 alpha and IL-1 beta; similarly, IL-1 alpha and IL-1 beta induce reciprocal tachyphylaxis but do not inhibit TNF or LT. We have used the binding of H4/18 to explore the mechanism of action of TNF. Tumour-promoting phorbol esters, but not agents which increase cytoplasmic calcium concentrations, were found to induce binding, suggesting a possible involvement of the protein kinase C pathway in the response of HEC to TNF. Cells pretreated for 24 hours with phorbol esters cannot be reinduced to express H4/18 binding by phorbol esters yet retain full responsiveness to TNF. Thus TNF also appears to act on HEC through a pathway independent of protein kinase C activation. Collectively, these effects of TNF and related cytokines may be understood as examples of endothelial cell activation.

Blood Coagulation↗
PubMed1986

Attenuation of protection with repeated cromolyn dosing before exercise challenge in subjects with asthma.

Though cromolyn sodium exhibits tachyphylaxis in laboratory models of allergy, this pattern has not been identified in clinical use or in human asthma provocation models. We looked for it using a treadmill exercise challenge scheme that had previously confirmed cromolyn's protective effect. Twelve exercise-sensitive asthmatic volunteers received in random order, 12 20-mg cromolyn inhalations, 12 placebo inhalations, and 11 placebo inhalations with a final 20-mg dose of cromolyn. Each regimen was given over a three-day period, with the final dose administered 30 minutes before exercise. Subjects' respiratory functions were measured before and repeatedly after exercise with body plethysmography and peak flow rates. Beginning six minutes after the end of exercise, parameters measured after single-dose cromolyn and placebo administration differed in all endpoints at most of the measurement intervals. Results with 12-dose cromolyn pretreatment were significantly different from those seen with placebo only at 40 minutes after exercise, whereas single- and multiple-dose cromolyn results differed at 20 and 30 minutes. Cromolyn accelerated recovery from exercise-induced falls in lung function; this effect was attenuated with multiple dosing. These results are consistent with development of tachyphylaxis.

Aged↗
PubMed1987

Cardiovascular differences between phenylpropanolamine and its related norephedrine isomers in the rat.

Various studies have confused the norephedrine and norpseudoephedrine isomers with phenylpropanolamine (PPA, d,l-norephedrine). This confusion has led us to investigate the pharmacological activity of the norephedrine (NOR) and norpseudoephedrine (NORP) isomers in the cardiovascular system of the urethane:chloralose anesthetized rat. Following intravenous administration, in a cumulative-dose fashion, l-NOR and PPA were the most potent compounds at increasing arterial blood pressure, while d-NOR, d-NORP, and l-NORP were relatively inactive at the doses tested (0.31-10 mg/kg). Prior reserpinization did not significantly shift the cumulative dose-response curves for l-NOR and PPA. Repetitive injections of PPA and l-NOR (1 mg/kg, 4 doses at 5-min intervals) failed to produce tachyphylaxis to the pressor response. On the other hand, when d-NORP was administered in a similar fashion, tachyphylaxis to the second and subsequent doses was observed. These studies demonstrate that significant mechanistic differences exist between these norephedrine isomers.

Animals↗
PubMed1988

Phase II study of recombinant beta interferon in patients with advanced non-small-cell lung carcinoma.

Eighteen patients with advanced non-small-cell lung cancer (NSCLC) received recombinant beta interferon, 90 million units three times weekly. No complete or partial responses were seen. Five patients had stable disease for several months. Most patients experienced some toxicity, most commonly fever and chills. No dose reduction of interferon had to be made due to toxicity. Tachyphylaxis to symptoms of fever and chills occurred in most patients. While 33% of patients developed beta-interferon-binding antibodies, the incidence of interferon-neutralizing activity was 0%. This dose and schedule of beta interferon did not result in significant anti-tumor effects in advanced NSCLC. Stabilization of disease for up to 9 months in patients with previously progressive disease was of interest. Tachyphylaxis of symptoms should allow for dose escalation within patients. A dose-escalating study has been initiated to evaluate the efficacy of beta interferon when given at each patient's maximally tolerated dose.

Adult↗
PubMed1980

Timolol eye drops: bradycardia or tachycardia?

26 eyes of 14 patients--8 with primary open angle glaucoma, 6 glaucoma suspects--were treated for at least 6 months with either twice daily timolol 0.25% in both eyes or twice daily timolol 0.50% in one eye. None of the patients received concomitant local or oral drugs. Special attention was paid to tachyphylaxis and to blood pressure and pulse rate. We could detect a slight although not significant tendency to tachyphylaxis (1-2 mm Hg) after 1 week of timolol treatment. It takes at least 1-2 weeks to reach the initial I.O.P. level after withdrawal of timolol therapy. Blood pressure did not change significantly. The pulse rate showed a slight although not significant tendency to decrease (a few beats/minute), but we detected a reflex tachycardia (10 beats/minute) after withdrawal of timolol therapy which was very significant. This rebound phenomenon has not been referred to in the literature. It seems reasonable to conclude that one should take care in treating glaucoma patients with concomitant arrhythmias with timolol eye drops.

Adult↗
PubMed1989

Changes in residues 1 and 4 of angiotensin II affect differently its agonist and tachyphylactic properties.

Two series of angiotensin II analogues with modifications at positions 1 or 4 of the peptide chain were studied with respect to their tachyphylactic properties and to the kinetics of relaxation of the guinea-pig ileum after a contractile response to maximally effective concentrations. Tachyphylaxis was measured by the decrease in response amplitude after three successive treatments ("tachyphylactic index") and the relaxation rate was evaluated by the time taken for the tonus to reach half of its value at the moment of agonist washout ("half relaxation time"). A correlation between tachyphylactic index and half relaxation time was found for the series of position 1 analogues, but not for the position 4 analogues. For the two series, the half relaxation times of the tachyphylactic analogues decreased from the first to the third of a series of successive treatments. Bulky substituents at position 1, which did not greatly affect the agonist activity, suppressed the tachyphylactic property. The results provide evidence that the agonist and tachyphylactic properties of angiotensin II are due to its interaction, respectively, with an agonist site and a "tachyphylaxis" site on the receptor and that the structural requirements for binding to the two sites are different.

Angiotensin II↗
PubMed1989

Angiotensin II desensitization and Ca2+ and Na+ fluxes in vascular smooth muscle cells.

The role of ion fluxes in angiotensin II (AII) desensitization (tachyphylaxis) was investigated by studying Na+ and Ca2+ translocation in cultured vascular smooth muscle cells from the rat aorta. The effects of AII were compared to those of [1-sarcosine]-AII (Sar1-AII), an analogue which also induces tachyphylaxis, and [2-lysine]-AII (Lys2-AII), an analogue that does not show this property. Maximally effective concentrations of the three peptides induced a rapid and transient increase in 45Ca2+ efflux, a rapid and sustained decrease in total cell Ca2+ and an increased Na+ permeability. Repeated treatments, at short intervals, with either of the three peptides abolished the effect on Ca2+ efflux, and this desensitization was slowly reversible. A 30-min rest period was sufficient for full recovery of the response of cells that were desensitized by Lys2-AII, whereas the recovery from AII or Sar1-AII-desensitization was still not complete after 60 min. Our results suggest that the difference in the behaviour of the "tachyphylactic" AII and Sar1-AII and the "non-tachyphylactic" Lys2-AII lays not in the production of different signals upon binding to the receptor, but in a difference in the hormone-receptor interaction itself.

Angiotensin II↗