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At least 19 recordsLinked to original sources
PubMed2006

Growth phase-dependent expression of drug exporters in Escherichia coli and its contribution to drug tolerance.

Drug exporters contribute to the intrinsic drug resistance in many organisms. Although there are at least 20 exporter genes in Escherichia coli, most of them apparently do not confer drug resistance in complex laboratory media except for the AcrAB, EmrE, and MdfA efflux systems. In this study, we comprehensively investigated the growth phase-dependent expression of drug exporter genes. The expression of acrAB, emrAB, emrD, emrE, emrKY, mdfA, and ydgFE is stable at moderate levels during any growth phase, whereas mdtEF promoter activity greatly increased with cell growth and reached the maximum level at the late stationary phase. The growth phase-dependent increase in mdtEF expression was also observed on quantitative reverse transcription-PCR analysis. As expected from the transporter expression, the stationary-phase cells actually showed MdtEF-dependent tolerance to drugs and toxic dyes. Growth phase-dependent elevation of mdtEF expression was found to be mediated by the stationary-phase sigma factor rpoS and the RpoS-dependent signaling pathway, Hfq, GadY, and GadX. The induction level was decreased by tnaAB deletion, suggesting that indole sensing stimulates this process.

Anti-Bacterial Agents↗
PubMed2005

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats.

RATIONALE: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations. OBJECTIVES: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops. METHODS: During an initial 3-h administration of 60% nitrous oxide (N(2)O), male Long-Evans rats were screened for N(2)O's hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N(2)O or placebo gas. Core temperature was measured telemetrically. RESULTS: Rats that exhibited a comparable degree of hypothermia during an initial N(2)O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N(2)O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N(2)O exposure, the II group breathing N(2)O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N(2)O exposures. CONCLUSIONS: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent-adaptive responses may mediate this relationship.

Animals↗
PubMed1989

Alternating sequential dosing with furosemide and ethacrynic acid in drug tolerance in the newborn.

Drug tolerance seems to develop rapidly after the administration of sequential doses of the same loop diuretic. We evaluated whether alternating different loop diuretics could achieve the same initial diuretic response in the newborn. In a randomized double crossover study, we examined the diuretic and saliuretic effects of alternating doses of furosemide and ethacrynic acid (1 mg/kg administered intravenously every 24 hours) in 10 newborns, who received the drugs in the following sequential order: (1) furosemide, (2) ethacrynic acid, and (3) furosemide (group 1, n = 5); and (1) ethacrynic acid (2) furosemide, and (3) ethacrynic acid (group 2, n = 5). Hourly urine specimens were collected for the determination of rates of urinary and fractional excretion of sodium, chloride, and potassium and of urinary flow, before and 6 hours after dosing. There were no differences between the groups at each dose for all parameters measured. A significant decrease in prediuretic and postdiuretic rates of urinary flow, in sodium and chloride excretion, and in the fractional excretion of these electrolytes was observed before and after dosing. The associated reduction in patients' weights suggested a depletion in plasma volume. In conclusion, consecutive alternation of furosemide and ethacrynic acid in the same newborn does not prevent the development of pharmacologic tolerance to loop diuretics, since diuresis, natriuresis, and chloriuresis decrease after successive sequential administration of these drugs.

Creatinine↗
PubMed1994

[Involvement of gene expression in drug tolerance and dependence].

The development of drug tolerance and dependence are thought to be associated with gene expression. Our studies showed that the binding activity of nuclear factors to several DNA sequences is altered by long-term treatment with methamphetamine, cocaine and morphine: 1) the binding activity of AP-1 increased markedly in the mouse brain after administration of methamphetamine and cocaine, 2) CRE-binding activity was decreased by chronic morphine treatment in the amygdala complex, cerebral cortex and hypothalamus of the mouse brain, and 3) the binding activity of single-stranded CRE binding proteins was decreased by chronic morphine treatment in the mouse cerebellum. These data suggest that the changes of DNA binding proteins can be involved in the development of drug tolerance and dependence.

Amphetamine↗
PubMed2004

A theory of drug tolerance and dependence I: a conceptual analysis.

A mathematical model of drug tolerance and its underlying theory is presented. The model extends a first approach, published previously. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behavior to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes. In addition, it establishes a relation between the drug dose at any moment, and the resulting drug effect and relates the magnitude of the reactions following withdrawal to the rate of tolerance and other parameters involved in the tolerance process. The present paper analyses the concept behind the model. The next paper discusses the mathematical model.

Adaptation, Physiological↗
PubMed2004

A theory of drug tolerance and dependence II: the mathematical model.

The preceding paper presented a model of drug tolerance and dependence. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The present paper discusses the mathematical model in terms of its design. The model is a nonlinear, learning feedback system, fully satisfying control theoretical principles. It accepts any form of the stimulus-the drug intake-and describes how the physiological processes involved affect the distribution of the drug through the body and the stability of the regulation loop. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes.

Adaptation, Physiological↗
PubMed2003

[Prevalence and drug tolerance of mycoplasma in patients with urogenital inflammation].

OBJECTIVE: To observe the prevalence and drug tolerance of mycoplasma(Ureaplasma urealyticum and Mycoplasma hominis) in patients with urogenital inflammation. METHODS: Three thousand and fifty-five patients with urogenital inflammation such as non-gonococcal urethritis(NGU), chronic prostatitis or pelvic inflammation from 1999 to 2003 were included. The results of mycoplasma culture and drug sensitivity test were analyzed. RESULTS: A total of 992(32.5%) cases were mycoplasma positive in the 3,055 patients, and there was no significant difference in the yearly positive percentage in the 5 years (P < 0.05). Among them, 701(70.7%) were infected with Ureaplasma urealyticum, 44(4.4%) with Mycoplasma hominis, and 247(24.9%) with both Ureaplasma urealyticum and Mycoplasma hominis, the Ureaplasma urealyticum infection rate being much higher than that of Mycoplasma hominis and mixed infection (P < 0.01). The high colony counting(> or = 10(4) cfu/ml) in Ureaplasma urealyticum infection patients accounted for 76.7%, while Mycoplasma hominis infection represented only 18.2%. The results of drug tolerance test showed a higher sensitivity to doxycycline, pristinamycin, josamycin and tetracycline (94.3%, 96.6%, 86.5% and 97.4% respectively), and a lower sensitivity to erythromycin and ofloxacin (54.8% and 29.4% respectively). CONCLUSIONS: Ureaplasma urealyticum and Mycoplasma hominis should be detected simultaneously and the drug tolerance test is needed for the selection of appropriate antibiotics.

Adolescent↗
PubMed1981

A prospective randomized study of adjuvant parenteral nutrition in the treatment of diffuse lymphoma: effect on drug tolerance.

Total parenteral nutrition (TPN) has been suggested as a useful addition to chemotherapy of malignant disease in the hope of decreasing drug toxicity and increasing drug tolerance. In this study, 17 of 36 patients given chemotherapy for advanced diffuse lymphoma were randomly selected to receive TPN. The dose of the chemotherapeutic agents to be administered was decreased according to predetermined toxicity guidelines. A comparison of drug dosage in the group receiving TPN and the group receiving standard nutrition is a measure of drug tolerance in these patients. Drug dosage was evaluable in 15 TPN and 18 standard nutrition patients. No difference in tolerance of any specific drug or total drug dose occurred when all patients in both groups were compared. Similar comparisons in subgroups of malnourished patients and responding patients also revealed no difference. A cycle-by-cycle analysis demonstrated no difference in any phase of therapy. The wbc count, platelet count, and albumin level, on the first day of each cycle, the nadir during cycles and the day of nadir were compared in TPN and standard nutrition patients. No differences were found. This study does not suggest improved drug tolerance in lymphoma patients as a result of TPN support. Further controlled studies are needed to determine which groups of cancer patients might benefit from TPN and how these benefits occur.

Antineoplastic Agents↗
PubMed1996

Pediatric phase I drug tolerance: a review and comparison of recent adult and pediatric phase I trials.

PURPOSE: We evaluated the ratio of pediatric to adult maximum tolerated doses (MTDs) from 70 Phase I studies conducted between 1975 and 1995. The aim of this study was to determine whether previously observed differences in drug tolerance between adult and pediatric Phase I patients have persisted over the 20-year period of this analysis. PATIENTS AND METHODS: Phase I trials of pediatric and adult patients with solid tumors as the predominant diagnosis and sharing similar dosing regimens were evaluated. For consistent comparison between Phase I studies, the MTD was defined as the drug dose one level below that yielding dose-limiting toxicity in >30% of patients. The ratio of pediatric to adult MTDs was calculated and plotted chronologically by year of pediatric study closure. Statistical evaluation of MTD ratios included regression and correlation analysis. The extent of therapy before Phase I study entry was also examined. RESULTS: Ninety-three Phase I studies were reviewed. Twenty-one drugs (70 studies) met our criteria for paired review of MTDs and analysis of the variation of ratio with time. The pediatric to adult MTD ratios ranged from 0.4 to 2.8, with a median of 1.2. Regression analysis of the ratio of MTD versus date of pediatric study closure supports a linear relationship of decreasing ratio with time (p<0.01). Analysis of the regression line predicts MTD ratios of 2.02 and 0.76 for 1974 and 1995, respectively. Of patients included in this analysis, 37.1% and 68.6% of adult and pediatric patients, respectively, were considered to have been heavily pretreated before study entry. A significant (p<0.001) downward trend with time was observed in the proportion of adult patients entering Phase I studies who had received both radiation and chemotherapy. CONCLUSIONS: The results of this review continue to show an equal or greater drug tolerance in the pediatric population when compared with adult patients for most drugs studied during Phase I trials. However, there appears to be significant trend of decreasing differences in drug tolerance between pediatric and adult Phase I patients with time, as defined by the descent of the MTD ratio toward values <1.0. Mechanisms to explain greater drug tolerance in children and the observation of decreasing maximum tolerated dose ratios with time are discussed. Limited data suggest that changes in degree of therapy before Phase I study entry may be influencing the MTD ratio.

Adult↗
PubMed1995

Contingent drug tolerance: differential tolerance to the anticonvulsant, hypothermic, and ataxic effects of ethanol.

The kindled-convulsion model of epilepsy was used to study contingent tolerance to ethanol's (1.5 g/kg; IP) anticonvulsant, hypothermic, and ataxic effects in adult male rats. In the present experiments, three groups of amygdala-kindled rats received a series of bidaily (one every 48 h) convulsive stimulations: one group received ethanol 1 h before each stimulation; one group received ethanol 1 h after each stimulation; and another group served as the saline control. Tolerance to ethanol's anticonvulsant effect (Experiments 1 and 2) was greatest in those rats that received ethanol before each convulsive stimulation; whereas, tolerance to ethanol's hypothermic (Experiments 1 and 2) and ataxic (Experiments 2) effects developed in both groups that received ethanol. These results were predicted on the basis of the drug-effect theory of drug tolerance: the theory that functional drug tolerance is an adaptation to the disruptive effects of drugs on concurrent patterns of neural activity, not to drug exposure per se.

Amygdala↗
PubMed2004

slo K(+) channel gene regulation mediates rapid drug tolerance.

Changes in neural activity caused by exposure to drugs may trigger homeostatic mechanisms that attempt to restore normal neural excitability. In Drosophila, a single sedation with the anesthetic benzyl alcohol changes the expression of the slo K(+) channel gene and induces rapid drug tolerance. We demonstrate linkage between these two phenomena by using a mutation and a transgene. A mutation that eliminates slo expression prevents tolerance, whereas expression from an inducible slo transgene mimics tolerance in naive animals. The behavioral response to benzyl alcohol can be separated into an initial phase of hyperkinesis and a subsequent phase of sedation. The hyperkinetic phase causes a drop in slo gene expression and makes animals more sensitive to benzyl alcohol. It is the sedative phase that stimulates slo gene expression and induces tolerance. We demonstrate that the expression level of slo is a predictor of drug sensitivity.

Animals↗
PubMed2001

Receptor regulation as a unitary mechanism for drug tolerance and physical dependence--not quite as simple as it seemed!

This review examines the development of the unitary hypothesis that both drug tolerance and the drug withdrawal syndrome arise from adaptive regulation of drug receptors in the brain. Although there is still considerable merit in this hypothesis, the author explains that careful evaluation of some of the changes that have been reported suggests that many of these are not good explanations for both aspects of drug dependence. In addition, modern developments in the understanding of receptor mechanisms show that the original hypothesis represents a gross oversimplification of the true situation. Adaptive changes in post-receptor mechanisms are now believed to be at least as important as alterations in the receptors themselves. Equally some receptor proteins, by altering their subunit composition, may be able to adapt to the presence of drugs without producing major changes in the action of the natural transmitter. In conclusion, receptor regulation still seems to play an important role in drug dependence but this role is more complex than was once believed.

Adaptation, Physiological↗
PubMed1995

[Influence of the intravenous nitroglycerin dose on the appearance of drug tolerance].

BACKGROUND: There are few studies on the influence of different doses of intravenous nitroglycerin (NTG) on the appearance of drug tolerance. METHODS: A controlled clinical trial was performed in 40 patients admitted to an ICU with the diagnosis of acute myocardial infarction (AMI). The patients were divided into two groups: group A with a continuous perfusion of NTG at 2 mg/h, and group B with 4 mg/h. At 30 minutes of the infusion, NTG was exchanged for a placebo in half of the patients of each group (subgroups A1 and B1) with the remaining patients continuing with NTG for 24 h (A2 and B2). The hemodynamic variables studied were central venous pressure (CVP), pulmonary capillary pressure (PCP), mean pulmonary artery pressure (PAP) and mean blood pressure (BP). RESULTS: The patients in group A showed a decrease in the hemodynamic effects in all the variables studied. At 24 h of infusion no differences were observed with respect to the previous NTG values for CVP and PCP, with significant differences being maintained for PAP and BP. In group B the hemodynamic effect was maintained for all the variables during the 24 hours studied. CONCLUSIONS: In patients with acute myocardial infarction, the dosis of nitroglycerin administered was found to have a determined influence in the appearance of drug tolerance with this fact being more evident on evaluation of the effect of nitroglycerin on the venous system.

Aged↗
PubMed1996

A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures.

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the "time-off seizure" effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological vulnerability factors.

Affect↗
PubMedDate not supplied

Drug tolerance.

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Drug Tolerance↗