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PubMed2001

Structures of withanosides I, II, III, IV, V, VI, and VII, new withanolide glycosides, from the roots of Indian Withania somnifera DUNAL. and inhibitory activity for tachyphylaxis to clonidine in isolated guinea-pig ileum.

Seven new withanolide glycosides called withanosides I, II, III, IV, V, VI, and VII were isolated from an Indian natural medicine, Ashwagandha, the roots of Indian Withania somnifera DUNAL. (Solanaceae), together with four known compounds, withaferin A, 5 alpha,20 alpha(F)(R)-dihydroxy-6 alpha,7 alpha-epoxy-1-oxowitha-2,24-dienolide, physagulin D, and coagulin Q. The structures of withanosides I, II, III, IV, V, VI, and VII were determined based on chemical and physicochemical evidence. Principal constituents, withanoside VI (10 and 30 microM) and withaferin A (10 microM), attenuated the tachyphylaxis to clonidine on electrically stimulated guinea-pig ileum in vitro.

Adrenergic alpha-Agonists↗
PubMed2003

The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors.

Members of the R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11) are found in the mouse CNS. The expression of these proteins was effectively reduced in different neural structures by blocking their mRNA with antisense oligodeoxynucleotides (ODNs). This was achieved without noticeable changes in the binding characteristics of labeled beta-endorphin to opioid receptors. Knockdown of R7 proteins enhanced the potency of antinociception promoted by morphine and [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO)-both agonists at mu-opioid receptors. The duration of morphine analgesia was greatly increased in RGS9-2 and in RGS11 knockdown mice. The impairment of R7 proteins brought about different changes in the analgesic activity of selective delta agonists. Knockdown of RGS11 reduced [D-Ala(2)]deltorphin II analgesic effects. Those of RGS6 and RGS9-2 proteins caused [D-Ala(2)]deltorphin II to produce a smoothened time-course curve-the peak effect blunted and analgesia extended during the declining phase. RGS9-2 impairment also promoted a similar pattern of change for [D-Pen(2,5)]-enkephalin (DPDPE). RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects. A single intracerebroventricular (i.c.v.) ED(80) analgesic dose of morphine gave rise to acute tolerance in control mice, but did not promote tolerance in RGS6, RGS7, RGS9-2, or RGS11 knockdown animals. Thus, R7 proteins play a critical role in agonist tachyphylaxis and acute tolerance at mu-opioid receptors, and show differences in their modulation of delta-opioid receptors.

Animals↗
PubMed2004

RGSZ1 and GAIP regulate mu- but not delta-opioid receptors in mouse CNS: role in tachyphylaxis and acute tolerance.

In the CNS, the regulators of G-protein signaling (RGS) proteins belonging to the Rz subfamily, RGS19 (G(alpha) interacting protein (GAIP)) and RGS20 (Z1), control the activity of opioid agonists at mu but not at delta receptors. Rz proteins show high selectivity in deactivating G(alpha)z-GTP subunits. After reducing the expression of RGSZ1 with antisense oligodeoxynucleotides (ODN), the supraspinal antinociception produced by morphine, heroin, DAMGO ([D-Ala2, N-MePhe4,Gly-ol5]-enkephalin), and endomorphin-1 was notably increased. No change was observed in the effect of endomorphin-2. This agrees with the proposed existence of different mu receptors for the endomorphins. The activities of DPDPE ([D-Pen2,5]-enkephalin) and [D-Ala2] deltorphin II, agonists at delta receptors, were also unchanged. Knockdown of GAIP and of the GAIP interacting protein C-terminus (GIPC) led to changes in agonist effects at mu but not at delta receptors. The impairment of RGSZ1 extended the duration of morphine analgesia by at least 1 h beyond that observed in control animals. CTOP (Cys2, Tyr3, Orn5, Pen7-amide) antagonized morphine analgesia when given during the period in which the effect of morphine was enhanced by RGSZ1 knockdown. Thus, in naive mice, morphine tachyphylaxis originated in the presence of the opioid agonist and during the analgesia time course. The knockdown of RGSZ1 facilitated the development of tolerance to a single dose of morphine and accelerated tolerance to continuous delivery of the opioid. These results indicate that mu but not delta receptors are linked to Rz regulation. The mu receptor-mediated activation of Gz proteins is effective at recruiting the adaptive mechanisms leading to the development of opioid desensitization.

Adaptor Proteins, Signal Transducing↗
PubMed2001

T cells activate the tumor necrosis factor-alpha system during hemodialysis, resulting in tachyphylaxis.

BACKGROUND: The immunosuppressive state of hemodialysis (HD) patients is accompanied by activation of antigen-presenting cell-derived cytokines, for example, tumor necrosis factor-alpha (TNF-alpha), which are required for T-cell activation. To test whether an activated TNF-alpha system results in impaired T-cell response in these patients, we analyzed parameters of their antigen-presenting cell (APC) function (for example, TNF-alpha system) and T-cell function [for example, interleukin-2 (IL-2) system]. METHODS: By quantitative flow cytometry, the expression of the TNF-receptor 2 (TNF-R2 = CD120b) and the alpha and beta chain of the IL-2 receptor (IL-2R; CD25, CD122) was measured. Using reverse transcriptase-polymerase chain reaction, the mRNA for TNF-alpha, IL-2, and IL-2R were determined. Phyto-hemagglutinin (PHA)- and IL-2-stimulated proliferation and cytokine production were measured. Biological activity of soluble receptors was measured by adding recombinant cytokines to the patient's plasma. RESULTS: CD120b expression was significantly increased in HD patients, whereas CD25 and CD122 was comparable to controls. In contrast to mRNA for IL-2 and IL-2R, mRNA for TNF-alpha was increased in HD. This resulted in significantly increased TNF-alpha levels in HD patients. In peripheral blood of HD patients, high levels of soluble TNF-R (R1 and R2) and IL-2R were found. These receptors were capable of binding 40% of added TNF-alpha and 55% of added IL-2. PHA-induced TNF-alpha production by T cells from HD patients was significantly lower, while their PHA-stimulated IL-2 production and proliferation capacity by T cells were comparable to controls. CONCLUSIONS: We conclude that although the TNF-alpha system is activated during HD, the TNF-alpha production of T cells is impaired, suggesting that tachyphylaxis of T cells occurs for TNF-alpha, as their proliferative capacity and IL-2 production capacity do not imply an intrinsic T-cell defect.

Aged↗
PubMed1976

Self-antagonism: a possible mechanism of tachyphylaxis in suxamethonium-induced neuromuscular block in man.

Twelve adults receiving halothane-nitrous oxide anaesthesia for elective surgery were investigated during suxamethonium-induced neuromuscular block, using the train-of-four twitch for measurement of both the degree of block and the magnitude of fade (decrease in fourth-to-first ratio). The residual neuromuscular block resulting from prolonged exposure to suxamethonium could be antagonized by bolus injections of suxamethonium itself, in doses which increased the block in Phase I. When self-antagonism was demonstrated, larger doses were necessary to increase the residual block, but only after overcoming the self-antagonizing effect. A biphasic response, first antagonizing then increasing the block, was observed following injection of a single bolus of suxamethonium. The self-antagonizing effect was more obvious in the fourth twitch of the train-of-four, resulting in a marked decrease in train-fo-four fade (increase in train-of-four ratio). It was concluded that self-anatagonism may be an important cause of tachyphylaxis in suxamethonium-induced neuromuscular block in man.

Adult↗
PubMed1997

Hemodynamic effects of intracoronary VEGF delivery: evidence of tachyphylaxis and NO dependence of response.

Vascular endothelial growth factor (VEGF) has been utilized to improve blood flow in the setting of myocardial or peripheral vascular ischemia. In this investigation we studied the hemodynamic effects of intracoronary VEGF administration. Hemodynamic parameters and Doppler flow wire recordings from the left anterior descending coronary artery were measured after intracoronary infusion of VEGF (1, 10, and 100 micrograms) in 28 intubated pigs. Additional studies were performed using an in vitro isolated microvessel preparation. VEGF produced a highly significant dose-dependent increase in coronary blood flow (maximal 3.51 +/- 0.85-fold) in the absence of significant changes in epicardial artery diameter, a decline in mean arterial pressure (maximal 43%), and a decrease in left ventricular end-diastolic pressure (maximal 52%), all of which could be inhibited by pretreatment with NG-nitro-L-arginine. The increase in coronary flow seen with 10 or 100 micrograms VEGF was significantly greater than the maximal vasodilation achieved with serotonin or nitroglycerin and was equivalent to a maximal adenosine response. In summary, VEGF stimulates nitric oxide (NO)-dependent dilation of coronary microvessels, and repeat administrations of VEGF resulted in rapid development of tachyphylaxis to VEGF as well as serotonin, but not to nitroglycerin or adenosine, which appeared to be secondary to impaired NO production.

Adenosine↗
PubMed1988

Reversal of vascular tachyphylaxis to catecholamines and histamine in the feline lung.

The pulmonary vascular responses to histamine, epinephrine, and norepinephrine demonstrate tachyphylaxis following repetitive exposure in the isolated blood-perfused cat lung. In the present study, we tested the hypothesis that this phenomenon was related to a change in the balance of antagonistic receptor activity. The protocol consisted of 5 consecutive dose-response maneuvers (DR I to V) to 1 amine in each animal separated by 1 h. Once the loss of the initial vasoconstrictor activity had occurred (DR I to IV), the animal was given a receptor blocking agent, either the beta blocker propranolol or the H2 blocker cimetidine, prior to a final dose-response maneuver (DR V). The dose-response relationships were analyzed in terms of 3 parameters: maximum response, slope, and ED50. All the experiments with norepinephrine (n = 6), epinephrine (n = 10), and histamine (n = 25) demonstrated a progressive loss of vasopressor activity as shown by reductions in the maximum response and slope between DR I to IV. In addition, histamine demonstrated a significant increase in ED50 from DR I to IV, which suggested a loss of sensitivity. The loss of vasoconstrictor activity to histamine and the catecholamines was restored by the administration of propranolol prior to DR V. In contrast, cimetidine did not restore the initial vasopressor activity of histamine. The loss of reactivity to histamine was not secondary to changes in circulating catecholamine levels, because the plasma catecholamine levels before DR I and immediately following DR V in a subset of animals (n = 5) were within the reported normal range for this species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics.

High doses of inhaled salbutamol produce substantial improvements in airway response in patients with asthma, and are associated with dose-dependent systemic beta-adrenoceptor responses. The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol. Twelve asthmatic patients (FEV1, 81 +/- 4% predicted), requiring only occasional inhaled beta-agonists as their sole therapy, were given a 14-day treatment with high dose inhaled salbutamol (HDS), 4,000 micrograms daily, low dose inhaled salbutamol (LDS), 800 micrograms daily, or placebo (PI) by metered-dose inhaler in a double-blind, randomized crossover design. During the 14-day run-in and during washout periods, inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purposes. At the end of each 14-day treatment, a dose-response curve (DRC) was performed, and airway (FEV1, FEF25-75) chronotropic (HR), tremor, and metabolic (K, Glu) responses were measured at each step (from 100 to 4,000 micrograms). Treatment had no significant effect on baseline values. There were dose-dependent increases in FEV1 and FEF25-75 (p less than 0.001), and pretreatment with HDS did not displace the DRC to the right. DRC for HR (p less than 0.001), K (p less than 0.001), and Glu (p less than 0.005) were attenuated after treatment with HDS compared with PI. There were also differences between HDS and LDS for HR (p less than 0.001) and Glu (p less than 0.05) responses. Frequency and severity of subjective adverse effects were also reduced after HDS: tremor (p less than 0.001), palpitations (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis.

Salmeterol (SM) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients. In the present study, evaluating efficacy and possible development of tachyphylaxis after SM, 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15% to 200 micrograms salbutamol (SB) or 20% to 500 micrograms SB. At inclusion all patients were receiving treatment with inhaled beta 2-agonists, and 11 of the 12 patients were also receiving inhaled corticosteroids. The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day, following a double-blind, double-dummy, randomized design. The treatment periods were separated by a washout period of 1 wk. Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period. On each of these days, basal FEV1, tremor, heart rate, and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve. During the treatment periods, as well as during the washout week after each treatment, the patients recorded their morning and evening peak expiratory flow (PEF) each day before the inhalation of the study drug. Subjective asthma symptoms were monitored by a visual analog scale after each treatment period. The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments, but significant increases in basal FEV1 and FVC were seen after the SM period (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1995

Mechanism of tachyphylaxis on the inhibitory effect of manganese on agonist-induced contractions in the isolated vas deferens of the guinea pig.

In the isolated vas deferens of the guinea pig, the inhibitory effect of manganese (Mn2+) on contractions induced by norepinephrine decreased when the contractions were induced repeatedly in the presence of Mn2+. This phenomenon, "tachyphylaxis" to the inhibitory effect of Mn2+, was minimally observed when contractions were induced by acetylcholine. Contractions induced by acetylcholine as well as by norepinephrine in a Mn(2+)-free medium were augmented in preparations in which manganese had accumulated intracellularly by repetitive applications of high potassium in the presence of Mn2+. The magnitudes of their augmentation were dependent on the manganese contents of the preparations. The augmented contractions were remarkably resistant to the inhibitory effect of Mn2+ applied to the medium. These results suggest that intracellular manganese augments the contractions and this augmentation results in an apparent decrease in the inhibitory effect of Mn2+ in the medium.

Acetylcholine↗
PubMed2002

Tachyphylaxis associated with continuous cisatracurium versus pancuronium therapy.

STUDY OBJECTIVES: To compare dosing requirements over time among patients receiving continuous cisatracurium versus pancuronium therapy, and to identify factors that may account for changes in pancuronium versus cisatracurium infusion requirements over time. DESIGN: Retrospective, comparative cohort analysis. SETTING: A tertiary level 1 trauma center. PATIENTS: Forty-five consecutive adult patients who were admitted to intensive care units at our institution from January 1998-August 2000 and received continuous cisatracurium or pancuronium therapy for at least 48 hours. MEASUREMENTS AND MAIN RESULTS: Dosing requirements of patients treated with pancuronium or cisatracurium were recorded over time throughout the treatment period. Factors that could affect dosing requirements of a neuromuscular blocking agent (NMBA) were stratified as time invariant (admitting service, acute physiology and chronic health evaluation II score, duration of mechanical ventilation, pressure control ventilation, baseline hepatic or renal insufficiency, thermal injury, train-of-four assessment, and concurrent drug administration or disorders affecting neuromuscular transmission) or time variant (concurrent sedation and narcotic analgesia therapy; serum magnesium, potassium, and creatinine concentrations; arterial pH level; temperature; peak airway pressure; and partial pressure of oxygen:fraction of inspired oxygen ratio). Hierarchical linear modeling was used to compare the dosing requirements and to identify confounders affecting the relationship. The infusion rate escalation for the cisatracurium group was greater (0.39 microg/kg/min; 95% confidence interval [CI] 0.22-0.56; 23 patients) than for the pancuronium group (-0.06 microg/kg/min; 95% CI -0.24-0.12; 22 patients; p<0.001) and was associated with an average daily cost/patient significantly higher (p<0.001) with cisatracurium ($258+/-$114) than pancuronium ($11+/-$5). Confounder analysis revealed that only the admitting service and the number of times the NMBA infusion was suspended because no twitch was detected differed between groups. Neither of these confounders significantly affected the temporal relationship between cisatracurium and pancuronium infusion rates. CONCLUSION: Dosing requirements increase over time at a significantly greater rate for cisatracurium than pancuronium infusions. Tachyphylaxis with cisatracurium is associated with substantial drug-related costs and is not accounted for by various disease-, patient-, and therapy-related factors. Further investigation is required to elucidate the mechanisms and risk factors underlying this phenomenon.

Adult↗
PubMed1976

[Trials of controlled hypotension with sodium nitroprusside in ORL surgery. Resistance and tachyphylaxis].

Sodium nitropusside has been used to lower blood pressure during surgical operations on the ear, nose and throat when an operative field without bleeding was desired, e.g. surgery of the inner ear under microscope in particular. In our experience, with the preparation used, sodium nitropusside proved to be a powerful hypotensive agent, the effect of which comes on early but it is difficult to use owing to frequent tachyphylaxis, the possible causes of which are considered. No undesirable side-effects were noted on the main functions. From this limited personal experience, the efficacy of this technique of per-operative hypotension did not appear greater in the surgical field under consideration to those of the anaesthetic techniques used commonly, e.g. neuroleptanalgesia under artificial ventilation, which proved sufficient for reduction in operative bleeding and which had already caused the authors to abandon, some time ago, the use of hypotensive ganglioplegic drugs.

Adolescent↗
PubMedDate not supplied

Sumatriptan overuse in episodic cluster headache: lack of adverse events, rebound syndromes, drug dependence and tachyphylaxis.

This observational study was designed to examine the pattern of sumatriptan use in patients with cluster headache using more than the recommended daily dose of subcutaneously injected (s.c.) sumatriptan. Thirteen patients suffering from episodic cluster headache were asked to record the characteristics of their attacks and drug intake for 1 year. All reported a high daily frequency of attacks (more than 3 per day) and the related overuse of s.c. sumatriptan. The results show that the overall incidence of adverse events among patients receiving sumatriptan injections for the treatment of cluster headache is low. The extended administration of this drug in episodic cluster headache did not result in tolerance problems or tachyphylaxis. Only 4 patients experienced minor adverse events and recovered more slowly than the others. They suffered from migraine without aura and cluster headache, and showed a family history of migraine. Even though they must be viewed with caution, due to the observational nature of the study and the low number of patients included, these results suggest that the profile of sumatriptan may differ in cluster headache compared with migraine.

Adult↗
PubMed2001

Long-term efficacy of sildenafil and tachyphylaxis effect.

PURPOSE: We observed that patients who initially responded to sildenafil frequently became resistant to it with time. We evaluated the long-term efficacy of sildenafil. MATERIALS AND METHODS: A telephone survey was conducted of patients during the first year of sildenafil usage, and another one was completed 2 years later of the same group. RESULTS: During the first survey, the etiology of impotence included post radical prostatectomy in 25, arterial insufficiency in 26, diabetes in 19, neurogenic impotence in 12, suspected venous leak in 9, proved venous leak in 7, Peyronie's disease in 6 and unspecified in 47 patients. The overall improvement rate, which was defined as the ability to initiate and maintain erections for successful intercourse, was 74%. The dose necessary to achieve this response was 100 mg. sildenafil in 15% of patients, 50 mg. in 83% and 25 mg. in 2%. During the second survey, information was collected on 82 patients and only 43 (52%) had continued treatment. Of the 69 patients who reported an initial good response 41 (59%) were still using sildenafil, and of the 43 who were still using it 16 (37%) had to increase the dose by 50 mg. to achieve an adequate result. There was no significant relationship between the need to increase the dose and frequency of treatment per month. Reduction in efficacy ranged from 15% to 50% (mean 36 +/- 12%) and the time to loss of efficacy ranged from 1 to 18 months (mean 11 +/- 5). Of the 82 patients in the second surgery, 39 (48%) stopped using sildenafil. A total of 28 (74%) patients reported a good initial response on the first survey, and 6 had spontaneous erections and no longer needed treatment. However, 14 (50%) patients discontinued sildenafil because of the loss of efficacy. In this group 10 patients had side effects, mainly headache and flushing of the face and nose, and only 2 discontinued treatment because of them. CONCLUSIONS: Our data suggest that there is a possible tachyphylaxis effect with sildenafil. Of the patients who were followed for 2 years 20% had to increase the sildenafil dose to have the same effect and 17% discontinued use due to loss of efficacy.

Adult↗
PubMed2001

Tachyphylaxis following regular use of formoterol in exercise-induced bronchospasm.

BACKGROUND: Formoterol is a highly effective therapeutic agent in the prevention of exercise-induced bronchospasm (EIB). Regular use of beta-adrenergic drugs may result in a reduction in the protective effect afforded by these bronchodilators against bronchoconstrictor stimuli. It is unknown whether this effect extends to formoterol and exercise. METHODS: We performed a randomized, double-blind, parallel clinical trial in 19 patients with EIB. Each patient received inhaled formoterol or placebo twice daily during 4 weeks. Patients performed two exercise tests in a cycle ergometer on the 1st, 14th, and 28th study days separated 3 hours from each other. A dose of formoterol was given 30 min prior to the 2nd test. RESULTS: There were significant differences in bronchoprotection between days 1 and 14 (p = .012) and between days 1 and 28 (p = .012) in the formoterol group. No differences were found in the placebo group. The evolution of the bronchoprotection index was also significantly different between the formoterol and the placebo group (p = .002) from day 1 to 28. CONCLUSIONS: Tachyphylaxis developed to the protective effect of formoterol against EIB after 4 weeks of regular dosing. Tolerance was already found on day 14, though not progressive. Formoterol should be recommended only as needed in EIB.

Adrenergic beta-Agonists↗
PubMed1976

Vasopressin tachyphylaxis. A study in conscious man.

The effects of repeated intravenous constant infusion of lysine-8-vasopressin (LVP) in a series of 12 conscious patients with portal venous catheters were studied. The portal venous pressure fell, the arterio-portal venous oxygen difference and the systolic and diastolic blood pressures rose and the heart rate decreased. Although no signs of tachyphylaxis were seen in portal venous pressure, systolic blood pressure or heart rate, they were observed both in the arterio-portal venous oxygen difference, indicating a tachyphylactic reaction in the effects on splanchnic blood flow, and in the diastolic blood pressure.

Aged↗