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PubMed2005

Tachyphylaxis in unipolar major depressive disorder.

BACKGROUND: Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis. METHOD: The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis. RESULTS: For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval. CONCLUSIONS: Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

Adult↗
PubMed1990

Tachyphylaxis to repeated challenges with inhaled adenosine in asthmatic subjects.

Adenosine, when administered as an aerosol to asthmatic subjects, provokes a prompt dose-dependent bronchoconstriction. The aim of this study was to establish whether tachyphylaxis in response to repeated inhalations with adenosine occurs in asthmatic subjects. Eight asthmatic patients were studied on three separate days (days A, B, and C) at the same time of day for each subject. Three inhalation tests were performed, separated by one hour, on each study day. The study was conducted in a double-blind fashion and performed in random order. On day A, three adenosine inhalation tests were performed to assess adenosine tachyphylaxis. On day B, a saline inhalation test was carried out between two adenosine challenges to assess the time course of the adenosine tachyphylaxis. On day C, three methacholine inhalation tests were performed to confirm that tachyphylaxis does not occur to methacholine. Repeated inhalation with adenosine, but not methacholine, produced a progressive loss of responsiveness to the nucleoside, which was particularly manifest with the third challenge.

Adenosine↗
PubMedDate not supplied

[Significance of tachyphylaxis induced by repeated bradykinin inhalation in bronchial asthma].

Bradykinin (Bk) is a potent bronchoconstrictor agent which may contribute to the pathogenesis of bronchial asthma. Recently we have shown that repeated bronchial challenge with this agonist in asthmatics produced a specific loss of responsiveness. In vitro studies suggest that this phenomenon may be due to generation of protective prostaglandins. In this study we investigated whether flurbiprofen (F) pretreatment inhibited Bk tachyphylaxis. The efficacy of F was demonstrated by the total suppression of whole blood TxB2 formation. In addition, a time-course study of the tachyphylactic response was carried out. Refractoriness in response to inhaled Bk occurred in all subjects. The mean PC20 Bk increased from 0.07 to 0.41 mg/ml with consecutive inhalation tests after placebo. Even in the presence of demonstrable cyclooxygenase inhibition, no effect of F was observed in inhibiting Bk tachyphylaxis the mean PC20 Bk still increasing from 0.10 to 0.47 mg/ml. Tachyphylaxis was still present at 6 h, but not in all subjects at 24 h. This study demonstrated that release of protective prostaglandins in the airway after Bk stimulation does not account for the loss of responsiveness following repeated exposure to Bk. At least 24 h should separate Bk inhalations to avoid tachyphylaxis. A possible mechanism of this phenomenon is discussed.

Administration, Inhalation↗
PubMed1985

[Beta-mimetics and tachyphylaxis].

This study covers current knowledge concerning the risks of tachyphylaxis induced by prolonged use of beta-mimetics in the asthmatic. The organization of the adrenergic membrane system is reviewed, as well as the various mechanisms which may lead to desensitization. Experimental evidence of the latter is described. The most extensive studies have involved circulating cells and, more precisely, lymphocytes and polynuclear neutrophils. Clinical trials are then dealt with. Studies concerned with bronchomotility and the possible loss of sensitivity of the bronchi after a therapeutic sequence using a sympatho-mimetic. No definite conclusion concerning this aspect can be made by review of the literature, because of contradictory results, and this regardless of the beta-mimetic used. However, it would seem that relative tachyphylaxis may develop in the bronchi. Nevertheless, the latter would not seem to be sufficiently marked in order to have clinical manifestations. Studies concerned with lymphocytes and polynuclears. Published studies are more in agreement here, demonstration of tachyphylaxis by measurement of cellular cyclic AMP or measurement of the density of receptors after impregnation by a beta-adrenergic being constant. The practical consequences of this risk is discussed, but cannot yet be accurately fixed. Therapeutic deductions from the findings described are then discussed. The protective role of corticosteroid therapy and of Ketotifen against the risk of tachyphylaxis is emphasized in particular.

Adrenergic beta-Agonists↗
PubMed1985

Kinetics of tachyphylaxis to mediators of acute inflammation.

The kinetics of vascular leakage and tachyphylaxis induced by histamine and bradykinin were examined in rabbit skin and were compared with the kinetics of tachyphylaxis of neutrophil accumulation in lesions induced with the chemotaxin formylmethionyl-leucyl-phenylalanine (FMLP). Maximal leakage of 125I-human serum albumin occurred during the first 5 min after injection of bradykinin and from 10 to 20 min after injection of histamine. Tachyphylaxis developed within 30 min of injection of bradykinin and 1 hr after injection of histamine. For both agents, there was a linear regression of sensitivity with time from 8 hr to 4 days, with normal sensitivity estimated to return at 4.6 days for bradykinin and 4.7 days for histamine. Marked cross-desensitization occurred between the two agents, and lesions initiated with the chemotaxin FMLP were desensitized to restimulation with a mixture of histamine and bradykinin. Initiation of lesions with histamine and bradykinin did not diminish the accumulation of neutrophils when lesions were restimulated with FMLP. The kinetics of tachyphylaxis of neutrophil accumulation in lesions stimulated with FMLP exhibited a linear regression of sensitivity on time between 4 days and 10 days, with estimated resensitization at 11.9 days. Histamine and bradykinin induce enhanced vascular permeability when endothelial cells in post-capillary venules contract following stimulation of their membrane receptors for these agents. We have recently proposed that the migration of neutrophils into acute inflammatory lesions is regulated by a mechanism coupled to chemotaxin receptors which may be similarly located on endothelial cells within the lesions. The present experiments indicate that expression of receptors for vascular permeability agents and the chemotaxin FMLP are independent events with distinct kinetics.

Animals↗
PubMed1980

Prostaglandin mediated histamine tachyphylaxis in subhuman primate tracheal smooth muscle.

The phenomenon of histamine tachyphylaxis previously observed in tracheal smooth muscle from canine species was investigated in isolated tracheal smooth muscle from subhuman primates. Tachyphylaxis to histamine was readily demonstrated by repetitive exposure to histamine. However, similar testing with acetylcholine did not indicate decreased responsiveness to this agent. The development of histamine tachyphylaxis could be prevented or reversed by inhibitors of prostaglandin synthesis (indomethacin, mefenamic acid, oxyphenbutazone). In indomethacin treated tissue, exogenous administration of prostaglandin E2 reduced the histamine response. It is concluded that the histamine tachyphylaxis which is present in subhuman primate tracheal smooth muscle is prostaglandin mediated.

Airway Resistance↗
PubMed1996

[Tachyphylaxis of airway response to inhaled bradykinin over several days].

Tachyphylaxis of airway responses has been described for a variety of pharmacological stimuli. A decrease in airway responsiveness to inhaled bradykinin has been reported when challenges were repeated within intervals of 60 minutes. Especially within the framework of drug studies, it is important to know whether tachyphylaxis persist over days. The aim of our study was to assess the occurrence of tachyphylaxis to inhaled bradykinin within several days. Thirteen patients with mild extrinsic bronchial asthma were included into the study. We performed two bradykinin inhalation challenges separated by an interval of three days and determined the provocative concentrations of bradykinin (PC20FEV1) which produced a 20% fall in FEV1. Geometric mean of PC20FEV1 was 0.033 mg/mL in the first and 0.105 mg/mL in the second challenge. These values were significantly different (p < 0.05). Our data demonstrate that tachyphylaxis of the airway response to bradykinin persists over a time period of three days.

Aerosols↗
PubMedDate not supplied

Alterations in ovine myometrial beta-adrenergic cascade do not mediate tachyphylaxis to ritodrine.

The purpose of this study was to determine in vivo the dose response relationship between beta-adrenergic receptor (BAR) agonist concentration and various elements of the BAR cascade: receptor density, hormone-stimulable adenylyl cyclase activity, and contraction inhibition. A previously described, chronically-catheterized ovine model was used. Ritodrine was infused continuously over 24 h in 22 mixed-breed sheep. Each animal received a single, constant infusion rate. Myometrial biopsies were obtained before and after the drug infusions. BAR density was determined using tritiated dihydroalprenolol. Adenylyl cyclase activity was determined using the Gilman competitive protein-binding assay. Intermittent oxytocin boluses were given into the maternal aorta and contractile response was determined. Infusion rates of 0.06-4.0 micrograms/kg/min yielded steady-state ritodrine serum concentrations of 5-168 ng/ml. No significant correlation was found between the ritodrine concentration and the magnitude of decrease in BAR density. Significant correlations existed, however, between the ritodrine concentration and both the magnitude of decrease in adenylyl cyclase activity and the loss of contraction inhibition. There was no correlation noted between the BAR cascade alterations and the loss of contraction inhibition. Despite significant reductions in receptor density (down regulation) and dose-related reductions in hormone-stimulable adenylyl cyclase activity (uncoupling), ritodrine at low concentrations was still able to inhibit oxytocin-induced contractions, i.e., tachyphylaxis did not occur. Tachyphylaxis appeared to correlate only with the serum ritodrine concentration. Hence, alterations in the BAR cascade do not necessarily equate with a loss of end-organ response (tachyphylaxis). Previous concepts based on in vitro studies about the interaction of the BAR agonist with its receptor, the subsequent generation of intracellular messengers, and the resultant end-organ response may not apply in the intact animal.

Adenylyl Cyclases↗
PubMed1991

Repeated provocation tests in asthmatic children for testing tachyphylaxis to histamine.

Tachyphylaxis to histamine was investigated in 16 children, aged 7-15 years, with mild asthma. Three consecutive histamine challenges were performed at intervals of 24 hours and 1 hour, respectively. No significant differences in IVC, FEV1, and PC20-histamine values between the three measurements were observed. After a 24 hour interval there was no difference in percentage fall of FEV1, but there was a slight (not significant) decrease in fall of FEV1 after a 1 hour interval. The PC20-histamine values showed good reproducibility with a 24 hour as well as with a 1-hour period between the tests (geometric mean PC20, 2.04 mg/mL +/- 3.50 %SD, 1.96 mg/mL +/- 4.37 %SD, 2.17 mg/mL +/- 4.12 %SD; correlation coefficients for a 24 hour interval, r = 0.87 and for a one-hour interval, r = 0.94 (P less than 0.01]. We conclude that in children there is no strong evidence for tachyphylaxis to histamine. Our results differ from studies on tachyphylaxis in adult asthmatics. Possibly different mechanisms exist in children and in adults.

Adolescent↗
PubMed1988

Role of sodium ions in angiotensin tachyphylaxis in the guinea-pig ileum and taenia coli.

We have examined the responsiveness of the guinea-pig ileum and taenia coli to angiotensin (ANG) analogues that were previously shown to be either able ([1-sarcosine]-ANG, Sar1-ANG) or unable ([2-lysine]-ANG, Lys2-ANG) to induce tachyphylaxis in the ileum. The taenia coli, in which tachyphylaxis had not been previously shown to occur, was strongly tachyphylactic to Sar1-ANG, but not to Lys2-ANG. The contractile responses of the ileum, as well as the contractile and electrical (sucrose-gap) events in the taenia coli, in response to the two ANG analogues, were used to investigate the tachyphylactic phenomenon and the role of Na+ in the manifestation. Relaxation of the ileum and repolarizations of the taenia coli were faster after treatment with Lys2-ANG than after Sar1-ANG. In the tachyphylactic state, relaxation and repolarization after Sar1-ANG became as fast as after Lys2-ANG. In "low-Na+" (80 mmol/l) medium, as well as in ouabain-treated preparations, the responses of the ileum to ANG analogues were similar to those of tissues in the tachyphylactic state. Addition of Ca2+ to taenia coli preparations previously treated with the two ANG analogues in Ca2+-free medium, caused contractile and electrical responses only in the case of Sar1-ANG. It is proposed that ANG tachyphylaxis is due to changes at the level of the receptor causing increased Na+ permeability which leads to a decreased Na+ gradient across the cell membrane.

Angiotensin I↗
PubMed1981

Allergen tachyphylaxis of guinea pigs in vivo; a prostaglandin E mediated phenomenon?

Ovalbumin (OA) sensitized guinea pigs were repeatedly challenged with 1% OA in saline nebulized ultrasonically at the 0, 10, 20, 60 and 70th min. The intensity of bronchial obstruction was measured by body plethysmography. The first three challenges (0. 10, 20 min) caused strong asthmatic reactions in all animals, the last two (60, 70 min) only mild one in 10 out of 15 animals. The development of this "tachyphylaxis" was markedly reduced by pretreatment of the animals with cyclooxygenase inhibitors (indomethacin 10 mg/kg intraperitoneally resp, acetylsalicylic acid 10 mg/kg orally 2 h before tests). The effect of both inhibitors (i.e. inhibition of tachyphylaxis) was abolished by supplementing prostaglandin E2 as aerosol simultaneously to the allergen (100-200 ng per inhalation). The results suggest that allergen tachyphylaxis we have observed in vivo might be due to synthesis of cyclooxygenase products, e.g. prostaglandin E.

Aerosols↗
PubMed1979

Cross-tachyphylaxis of the pressor response to angiotensins in conscious rabbits.

The effect of tachyphylaxis to angiotensin II amide on the pressor potency of angiotensin I, II and III and noradrenaline was investigated in conscious rabbits with indwelling cannulae. No significant difference was observed between the reduction in responses to angiotensin II (58 +/- 4%) and angiotensin III (42 +/- 6%) but angiotensin I (15 +/- 5 %) and noradernaline (17 +/- 10%) responses were less markedly inhibited. If all angiotensin I pressor activity was mediated through its conversion to angiotensin II one would expect an equivalent degree of cross-tachyphylaxis to occur with the two peptides. Our results suggest that angiotensin I may have significant inherent pressor activity of its own, independent of conversion. This compound is already known to have activity at other target tissues. The absence of a significant difference in the degree of tachyphylaxis with angiotensin II and III may indicate they have substantially common pathways as pressor agents.

Angiotensin I↗
PubMed1992

Tachyphylaxis to capsaicin-induced cough and its reversal by indomethacin, in patients with the sinobronchial syndrome.

Cough reflex testing with capsaicin has been used to study the pathophysiology of the cough reflex and the antitussive effects of various drugs. Although the reproducibility of capsaicin-induced cough has been well established in normal subjects, it is not known if prior challenge with capsaicin reduces the subsequent cough response to inhaled capsaicin in patients with the sinobronchial syndrome, a condition characterized by chronic upper and lower airway inflammation. Measurement of the capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was repeated four times at intervals of 15, 30 and 60 min in eleven patients with the SBS and ten normal subjects. The cough thresholds at 15, 30 and 60 min were greater than the initial value in patients with the SBS but not in normal subjects. In addition, we examined the effect of 4 days treatment with indomethacin (100 mg/day) on the cough thresholds measured twice at an interval of 15 min in eight patients with the SBS. Indomethacin increased the initial cough threshold and reduced the increment in the post-15 min cough threshold from the initial value compared with placebo, thus reducing the tachyphylaxis. These results indicate that chronic airway inflammation may be responsible for the decreased response (tachyphylaxis) to repeated inhalation of capsaicin, and suggest that cyclooxygenase products released by the airway inflammation may be involved in tachyphylaxis, cough receptor sensitivity to inhaled capsaicin, or both, in patients with the SBS.

Adult↗
PubMed1990

Lack of tachyphylaxis to histamine in both moderate and mild asthmatic subjects.

While some studies have clearly shown that tachyphylaxis occurs in asthmatic subjects when challenged consecutively with inhaled histamine, others were unable to demonstrate this phenomenon. There is reason to believe that these conflicting findings may be related to the different degrees of bronchial reactivity in the subjects studied. We selected 2 groups of 10 asthmatics on the basis of their degree of bronchial reactivity: a group with PC20 less than 1 mg/ml (moderate asthmatics); and a group with PC20 greater than 2.5 mg/ml (mild asthmatics). Each subject underwent 3 successive histamine challenges, allowing recovery of FEV1 after each to within 5% of the baseline value prior to the first challenge. Test results were recorded as the provoking concentration of histamine needed to produce a 20% fall in FEV1 (PC20). No significant change in histamine reactivity occurred in either group. However, one moderate and two mild asthmatics appeared to develop some tachyphylaxis. We conclude that tachyphylaxis to histamine is not a general phenomenon in asthma.

Asthma↗
PubMed1996

Tachyphylaxis to furosemide in isolated airways of guinea pigs.

This in vitro study was conducted to determine whether tachyphylaxis of guinea pig airway to furosemide occurs under conditions that produce tachyphylaxis to the beta 2-adrenoceptor agonist, salbutamol. Isometric tension was measured in tracheal rings bathed in HEPES buffer from 4-6 d newborn guinea pigs of either sex, and 6 wk old males. Paired rings were first incubated with furosemide, 30 or 300 microM, or control for 60 min, washed, then constricted with 3 microM acetylcholine. At stable contraction, relaxation to furosemide (30 microM-1 mM) was measured. For comparison, similar experiments were performed with 10 microM salbutamol incubation for 30 min. 86Rb uptake, a marker for K+ transport and Na-K-Cl cotransport activity, was also measured in these airway segments. Pre-exposure to these airway relaxants did not affect contractile force generation by acetylcholine. Tracheal desensitization to both salbutamol and furosemide was observed. Partial recovery of furosemide induced relaxation was seen one hour after desensitization. Pre-exposure to 300 microM furosemide did not inhibit the decrease in 86Rb uptake normally observed with furosemide. In summary, we found that: 1) tachyphylaxis of guinea pig airway relaxation occurred with both salbutamol and furosemide under similar experimental conditions; however 2) inhibition of 86Rb uptake by furosemide was not affected by prior exposure. Taken together, these results suggest that furosemide induced airway relaxation could be affected by repeated or prolonged exposure, but this response may not be associated with changes in furosemide-sensitive Na-K-Cl cotransporter activity.

Albuterol↗
PubMed1989

Arteriolar vasoconstriction and tachyphylaxis with intraarterial angiotensin II.

Several aspects of the differences between the responses of the second- to fifth-order arterioles (A2 to A5) to intraarterial administration of angiotensin II (AII) were studied by intravital microscopy on an original preparation of rat cremaster muscle. Dose-response curves displayed a leftward shift when the arteriolar order increased. Doses inducing 50% vasoconstriction were 15.1, 0.51, and 0.08 micrograms for A3, A4, and A5, respectively. For A2, very small vasoconstriction was found even at the highest dose of angiotensin II. The dynamics of the response were also dependent on the arteriolar order. The duration of the peak of vasoconstriction increased from A3 to A5, and the interval between the contact of vascular wall with drug and the response was smaller in A4 and A5 than in A3. To understand the effect of diameter as a determinant of heterogeneity in the degree of arteriolar vasoconstriction, norepinephrine was administered under the same conditions as angiotensin II, and responses were measured on arterioles with the same morphological characteristics as those examined after angiotensin II. When comparing the regression curves for the percentage of vasoconstriction vs diameter, we found that this relationship was drug dependent. The significantly steeper slope for angiotensin II than for norepinephrine excluded the possibility that heterogeneity of the degree of vasoconstriction is solely due to differences between the morphological characteristics of the arterioles. Since tachyphylaxis to AII is considered to be a reflection of the drug-receptor interaction, we also studied the magnitude of this phenomenon from proximal to distal parts of the arteriolar network. We showed that the degree of partial tachyphylaxis after 1 microgram AII was dependent on the arteriolar order and a decreasing tachyphylaxis gradient was evidenced from A3 to A5 arterioles.

Angiotensin II↗
PubMed1977

Role of prostaglandins in the mediation of systemic tachyphylaxis to angiotensin II.

Angiotensin-induced prostaglandin release has been implicated in the deveolpment of tachyphylaxis to angiotensin in vitro. Based on these findings and evidence that prostaglandins modulate the angiotensin reposne locally, experiments were done to investigate the role of prostaglandins in the systemic tachyphylaxis to angiotensin. Rats were given intravenous infusions of 1-asparaginyl-5-valyl and 1-aspartyl-5-isoleucyl andiotensin II at two different doses. Using systemic blood pressure as a parameter, varying degrees of tachyphylaxis were produced and the aspartyl analog was found to be more tachyphylactic. When rats were given indomethacin, a prostaglading synthesis inhibitors, the response to intravenous infusion of aspartyl angiotensin was not significantly altered.

Angiotensin II↗
PubMed1988

The effect of ketotifen on bronchial beta-adrenergic tachyphylaxis in normal human volunteers.

The effect of ketotifen on bronchial beta-adrenergic tachyphylaxis was studied in healthy volunteers. In a 2-week pilot study, 19 volunteers inhaled 300 micrograms of salbutamol, four times a day. Ten subjects became tachyphylactic to inhaled salbutamol, assessed by a dose-response curve, before and after the 2 weeks of treatment from a metered-dose inhaler. These 10 subjects were then involved in a double-blind, crossover study comparing the effect of ketotifen, 1 mg in the evening during 1 week, and 1 mg, twice daily, during 3 weeks, and placebo on the bronchial beta-adrenergic tachyphylaxis induced by the concomitant administration during the last 2 weeks of each treatment period of 300 micrograms of salbutamol, four times a day, from a metered-dose inhaler. The end of the pilot study preceded the double-blind study by at least 1 month. However, the salbutamol dose-response curve at the beginning of the double-blind study was still significantly decreased, compared to the dose-response curve before the pilot study. During placebo treatment, a further decrease in bronchial beta-adrenergic sensitivity was observed. Treatment with ketotifen prevented the induction of further beta-adrenergic tachyphylaxis. Each 2 weeks of treatment with inhaled salbutamol increased significantly the baseline specific airway conductance; therefore, based on the present data, it is impossible to determine whether ketotifen also restores the sensitivity of an already desensitized beta-adrenergic system in the airways.

Administration, Inhalation↗