Function Of Treatment Duration Research Articles

Time-dependent cost comparison and health economic impact analysis of second-line interventions for transplant-ineligible patients with relapsed or refractory diffuse large B cell lymphoma.

Novel interventions (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tafasitamab-lenalidomide [Tafa-L], polatuzumab-rituximab-bendamustine [pola-BR]) improve clinical outcomes in second-line (2 L) treatment of transplant-ineligible patients with early relapse or refractory (R/R) diffuse large B cell lymphoma (DLBCL). The costs vary depending on the respective treatment regimen and the treatment duration, difficult comparability in reimbursement decisions. The objective was to analyze the health economic impacts of novel 2 L interventions and conventional immunochemotherapies (bendamustine-rituximab [BR], rituximab-gemcitabine-oxaliplatin [R-GemOx]) from a German healthcare payer's perspective as a function of treatment duration. An economic model was developed to compare treatment costs of 2 L interventions depending on the treatment duration. Treatment duration was measured by progression-free survival (PFS), identified based on a systematic review. Total and average costs were calculated over 5 years to evaluate incremental costs at median PFS for each intervention. Average costs per month at median PFS ranged from €2846 (95% CI: 5067-1641) to €40 535 (95% CI: 91180-N/A) for BR and liso-cel, respectively. Incremental costs at the lowest median PFS (R-GemOx: 5.3 months) revealed -€664, €5560, €11 817, €53 145, and €67 745 for BR, Tafa-L, pola-BR, axi-cel, and liso-cel as compared to R-GemOx, respectively. Analyses uncovered a variation of incremental costs of 2 L transplant-ineligible DLBCL interventions as a function of time leading to amortization of high-priced interventions.

Too Much of a Good Thing: Extended Duration of Gut Microbiota Depletion Reverses Protection From Experimental Autoimmune Uveitis.

Using the model of experimental autoimmune uveitis (EAU) induced by immunization with a retinal antigen, two studies have reported contradictory results on disease development following oral antibiotic treatment (ABX). We showed that long-term ABX did not affect EAU, but another study showed that short-term ABX was protective. We therefore studied the effects of ABX on EAU, gut microbiota, and host immune responses as a function of treatment duration. EAU-susceptible mice were treated orally with broad-spectrum antibiotics starting at least 10 weeks (long-term) or 1 week (short-term) before immunization until termination of the experiment. Gut microbiota were characterized by 16S amplicon sequencing, and host gut immune elements were studied phenotypically and functionally. Long-term ABX had no effect, whereas short-term ABX delayed EAU, as previously reported by us and others, respectively. Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with the frequencies of CD4+CD8+ IELs. IELs suppressed antigen-specific activation of autoreactive T cells in culture. Gut microbiota may play dual roles in uveitis development: They promote EAU development but also help maintain IEL populations that have regulatory function against autoreactive T cells. We propose that the progressive loss of this population during long-term ABX reverses the EAU-ameliorating effects of microbiota depletion.

Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease.

SummaryBackgroundInflammatory bowel disease (IBD) is often managed with anti‐tumour necrosis factor‐α therapy (anti‐TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%‐21% per patient‐year).AimsTo assess whether the incidence of loss of response decreases with longer treatment durationMethodsThis was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti‐TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti‐TNFα discontinuation and dose escalation.ResultsWe included 844 anti‐TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti‐drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three‐fold higher than after four years of treatment (17.2% vs 4.8% per patient‐year, P < 0.001). The incidence of anti‐TNFα discontinuation (28.6% vs 14.0% per patient‐year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient‐year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10‐2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15‐2.46) and male sex (aHR 0.55, 95% CI 0.38‐0.78). Immunomodulators were protective against loss of response with anti‐drug antibodies (aHR 0.42, 95% CI 0.24‐0.74).ConclusionsPatients with sustained benefit to anti‐TNFα after 2 years are at low risk of subsequent loss of response.

Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can...

Adaptation Of Operational Parameters Of Cold Atmospheric Plasma And Their Role In Cancer Therapy

The evaluation of CAP in cancer treatment has been significantly fueled by the growing demand for more effective therapies. CAP has been reported as a selective treatment method with a higher affinity of inducing cell death in cancer cells while leaving normal cells unharmed. However, the extent of its effectiveness varies significantly per cancer type. Studies have revealed that different types of cancers exhibit different response to treatment when exposed to the same CAP conditions. Therefore, an understanding of the immediate effect of CAP on cancer cells may enable improvement of treatment outcomes [1]. We demonstrated that instantaneous CAP response can be monitored in real-time by RealTime-Glo Assay with results interpreted as cell viability. This creates the possibility for developing an adaptive CAP approach platform which could enable real-time modification of the plasma treatment condition. In particular, the composition of reactive oxygen and nitrogen species (RONS) and the intensity of CAP, which is effected by discharge voltage and length of treatment, can be optimized with a feedback system at regular intervals to minimize the predicted viability of cancer cells [1, 2]. In an in vitro proof-of-concept study conducted in glioblastoma and breast cancer cells, we showed that CAP reduced cell viability in a dose dependent manner as a function of treatment duration and plasma discharge voltage. In fact, a 30-60 second increase in treatment duration and/or a discharge voltage adjustment from 3.16 to 3.71 kV, was consistently accompanied with a significant reduction in cell viability. Therefore, these two operational parameters can be utilized for adjusting plasma composition and improving treatment outcomes. In addition to the cell viability findings, we determined that CAP inhibited cancer cell proliferation and triggered apoptosis via damage to the mitochondrial membrane and deregulation of the protein synthesis mechanism [2]. The work completed in this study will serve as the foundation for the development of the adaptive CAP platform. The novel platform will intend to propel CAP therapy forefront other well-established therapies associated with cancer treatment.

In vitro evaluation of antimicrobial agents on Acanthamoeba sp. and evidence of a natural resilience to amphotericin B

The free-living amoeba (FLA) Acanthamoeba sp. is an opportunistic pathogen that can cause amoebic keratitis (AK) or granulomatous amoebic encephalitis (GAE). While current treatments of AK are long with some relapses, no consensus therapy has been developed for GAE remaining lethal in 90% of the cases. In this context, efficient antiacanthamoebal drugs have to be identified. In this work, 15 drugs used in the treatment of AK or GAE or in other parasitic diseases were evaluated for their in vitro activity on A. castellanii. Hexamidine, voriconazole and clotrimazole exhibited the highest activities with IC50 values at 0.05 μM, 0.40 μM and 0.80 μM, respectively, while rifampicin, metronidazole and cotrimoxazole were inactive. Among 15 drug associations evaluated, no synergistic effect was observed, and one antagonism was determined between hexamidine and chlorhexidine. Interestingly, amphotericin B was the only drug presenting an increase of IC50 as a function of treatment duration. The amoebae susceptibility to amphotericin B cultured in the presence of 250 μM of the drug was similar to the one of a naive control, revealing that no resistant strain could be selected. However, the amoebae susceptibility always returned to an initial level at each passage. This natural and non-acquired adaptation to amphotericin B, qualified as resilience, was observed in several strains of A. castellanii and A. polyphaga. Using a pharmacological approach with effectors of different cellular mechanisms or transports, and an ultrastructural analysis of amphotericin B-treated amoebae, the involvement of several mitochondria-dependent pathways as well as multidrug resistant transporters was determined in amphotericin B resilience. Based on the observations from this study, the relevance of using amphotericin B in GAE treatments may be reconsidered, while the use of some other drugs, such as rifampicin or cotrimoxazole, is not relative to intrinsic antiacanthamoebal activity.

Bacterial inactivation by high-voltage atmospheric cold plasma: influence of process parameters and effects on cell leakage and DNA

This study investigated a range of atmospheric cold plasma (ACP) process parameters for bacterial inactivation with further investigation of selected parameters on cell membrane integrity and DNA damage. The effects of high voltage levels, mode of exposure, gas mixture and treatment time against Escherichia coli and Listeria monocytogenes were examined. 10(8) CFU ml(-1) E. coli ATCC 25922, E. coli NCTC 12900 and L. monocytogenes NCTC11994 were ACP-treated in 10 ml phosphate-buffered saline (PBS). Working gas mixtures used were air (gas mix 1), 90% N2 + 10% O2 (gas mix 2) and 65% O2 + 30% CO2 + 5% N2 (gas mix 3). Greater reduction of viability was observed for all strains using higher voltage of 70 kVRMS and with working gas mixtures with higher oxygen content in combination with direct exposure. Indirect ACP exposure for 30 s inactivated below detection level both E. coli strains. L. monocytogenes inactivation within 30 s was irrespective of the mode of exposure. Leakage was assessed using A260 absorbance, and DNA damage was monitored using PCR and gel electrophoresis. Membrane integrity was compromised after 5 s, with noticeable DNA damage also dependent on the target cell after 30 s. Plasma treatment was effective for inactivation of challenge micro-organisms, with a greater sensitivity of L. monocytogenes noted. Different damage patterns were observed for the different bacterial strains attributed to the membrane structure and potential resistance mechanisms. Using atmospheric air as working gas resulted in useful inactivation by comparison with high nitrogen or high oxygen mix. The mechanism of inactivation was a function of treatment duration and cell membrane characteristics, thus offering potential for optimized process parameters specific to the microbial challenge.

Treatment Outcome in Patients Receiving Assertive Community Treatment

In an observational study of severely mentally ill patients treated in assertive community treatment (ACT) teams, we investigated how treatment outcome was associated with demographic factors, clinical factors, and motivation for treatment. To determine psychosocial outcome, patients were routinely assessed using the Health of the Nation Outcome Scales (HoNOS). Trends over time were analyzed using a mixed model with repeated measures. The HoNOS total score was modeled as a function of treatment duration and patient-dependent covariates. Data comprised 637 assessments of 139 patients; mean duration of follow-up was 27.4 months (SD = 5.4). Substance abuse, higher age, problems with motivation, and lower educational level were associated with higher HoNOS total scores (i.e., worse outcome). To improve treatment outcome, we recommend better implementation of ACT, and also the implementation of additional programs targeting subgroups which seem to benefit less from ACT.

Field-scale constructability evaluation of underwater vacuum preloading

There is an ever-increasing demand for land to cope with the rapid economic development worldwide. As a result, new land is always reclaimed from the sea to meet the demand. The soft marine deposit in the seabed is often too weak to support the reclamation and the infrastructure to be built upon it. However, dredging of marine deposit has to be minimized to prevent ecological damage to the marine environment. In-situ improvement of the marine deposit is thus often required. Vacuum preloading is a proven technique to improve the engineering properties of soft clay onshore. However, the viability of applying the technique underwater is yet to be established. Practicality and constructability are important issues. The results of a field-scale constructability evaluation of underwater vacuum preloading are presented in the paper. Different techniques to install a membrane underwater to provide the required air-proof barrier were evaluated by monitoring the vacuum pressure underneath the membrane, pore pressure in the clay in the seabed, and ground settlement as a function of treatment duration.

A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: The empirical basis for U.S. clinical practice

For many years practitioners have had limited data from double-blind, placebo-controlled studies to guide the types of decision-making needed to optimally manage patients with insomnia in clinical practice. However, in recent years there has been a great increase in insomnia research studies that address issues of clinical importance. This body of work represents an increasingly useful empirical basis for making clinical practice decisions. The purpose of this article is to compile the body of work on the pharmacological management of insomnia to make it available in as accessible form as possible for optimal application in clinical practice with the hopes that doing so will decrease the gap separating the available research and the clinical management of insomnia and, thereby, improve the care of the many individuals who suffer from this condition. The review of studies consists of the following sections: 1) basic pharmacology; 2) double-blind, placebo-controlled trials in adults with primary insomnia; 3) double-blind, placebo-controlled trials in elderly patients with primary insomnia; 4) adverse effects reported in placebo-controlled trials in elderly primary insomnia patients; 5) double-blind, placebo-controlled trials in adults and the elderly as a function of treatment duration; 6) double-blind, placebo-controlled trials of the treatment of comorbid insomnia. Issues related to the application of these data to clinical practice are discussed in the text.

Influence of atmospheric pressure plasma treatment time on penetration depth of surface modification into fabric

In order to determine the relationship between the treatment duration of atmospheric pressure plasma jet (APPJ) and the penetration depth of the surface modification into textile structures, a four-layer stack of polyester woven fabrics was exposed to helium/oxygen APPJ for different treatment durations. The water-absorption time for the top and the bottom sides of each fabric layer was reduced from 200 s to almost 0 s. The capillary flow height for all fabric layers in the stack increased linearly with the treatment duration but the rate of increasing reduced linearly with the fabric layer number. A model for the capillary flow height as a function of treatment duration and the layer number was established based on the experimental data and the maximum penetration depth of the APPJ was predicted for the polyester fabric. The improved wettability of the fabrics was attributed to the enhanced surface roughness due to plasma etching and the surface chemical composition change due to plasma-induced chemical reaction as detected by scanning electron microscopy and X-ray photoelectron spectroscopy, respectively. The surface roughness and the surface chemical composition change diminished as the fabric layer number increased.

Estimating mean response as a function of treatment duration in an observational study, where duration may be informatively censored.

After a treatment is found to be effective in a clinical study, attention often focuses on the effect of treatment duration on outcome. Such an analysis facilitates recommendations on the most beneficial treatment duration. In many studies, the treatment duration, within certain limits, is left to the discretion of the investigators. It is often the case that treatment must be terminated prematurely due to an adverse event, in which case a recommended treatment duration is part of a policy that treats patients for a specified length of time or until a treatment-censoring event occurs, whichever comes first. Evaluating mean response for a particular treatment-duration policy from observational data is difficult due to censoring and the fact that it may not be reasonable to assume patients are prognostically similar across all treatment strategies. We propose an estimator for mean response as a function of treatment-duration policy under these conditions. The method uses potential outcomes and embodies assumptions that allow consistent estimation of the mean response. The estimator is evaluated through simulation studies and demonstrated by application to the ESPRIT infusion trial coordinated at Duke University Medical Center.

HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy.

To determine HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. Twenty-three consecutive HIV-infected patients (median age, 43 years; male:female ratio, 18:5; median CD4 cell count, 419 x 10(6)/l) undergoing Coleman's lipostructure were enrolled prospectively in this study. HIV-1 RNA and plasma concentration of antiretroviral drugs were determined blindly in plasma and adipocyte lysate samples. HIV-1 proviral DNA was detected by nested PCR in fresh frozen adipocytes. Mean plasma HIV-1 RNA was significantly higher than that in adipocyte lysate samples (this was below the limit of detection in all patients tested). HIV-1 proviral DNA was positive in two out of 18 adipocyte samples with a level between 2 and 5 copies; the distribution seemed to be specific and comparable within each therapeutic class--protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). NNRTI concentrations in adipocyte lysates were approximately 100-fold higher than those of PI. Efavirenz may accumulate in fat tissue as a function of treatment duration. Our results suggest that HIV does not replicate and does not integrate its genome in fat tissue in patients with fat redistribution abnormalities. In patients with effective nadir plasma concentrations of PI and NNRTI, determination of concentration in adipocyte lysates suggests that PI may diffuse in fat tissue with the same pattern of distribution for all structurally related components tested. NNRTI present a high affinity for fat tissue and may accumulate in this compartment.

Treatment and Analysis of a Paint Chip from “Water Lilies” a Fire Damaged Monet

ABSTRACTA museum fire in 1958 severely damaged a Monet “Water Lilies” (1916-1926) painting that was on display. The surface of the painting is very dark with areas of blistering and charring. Over the years, traditional techniques have been found to be ineffective at removal of the soot and char from the surface. The painting, which is now in the care of the New York University (NYU) Conservation Center of the Institute of Fine Arts, was the subject of a study to determine if atomic oxygen treatment could remove the soot and char without damaging the fragile painting underneath. For test purposes, a small chip of paint was removed from the edge of the painting by a conservator at NYU and supplied to NASA Glenn Research Center for atomic oxygen treatment and analysis. The diffuse spectral reflectance, at three locations on the paint chip, was monitored at intervals during the atomic oxygen treatment process. Photo documentation of the chip during treatment was also performed. The color contrast was calculated from the spectral reflectance data as a function of treatment duration. Results of the testing indicated that the contrast improved as a result of the treatment, and the differentiation of colors on the surface was significantly improved. Soot and char could be removed without visibly affecting the gross surface features such as impasto areas. These results indicate the feasibility for the treatment of the “Water Lilies” painting.

Calibrating Ultraviolet Irradiation of Fish Sperm

Milt collected from common carp, Cyprinus carpio, and bluegill, Lepomis macrochirus, was irradiated with ultraviolet (UV) light to evaluate the effects on sperm viability as a function of sperm concentration and UV dose. The optical density of milt samples was determined using UV spectrophotometry. Sperm viability was estimated, based on motility and fertilization of eggs following UV radiation. Sperm samples were diluted with 0.85% saline to reduce cell density. UV dose was measured using a Blak-Ray meter and varied as a function of treatment duration. The results of sperm motility examined in the context of high absorbance (optical density) of undiluted milt samples form a framework for explaining the Hertwig effect.

Plasma desorption time‐of‐flight mass spectrometric elucidation of the mechanisms of adhesion enhancement between plasma‐treated PEEK–carbon composite and an epoxyamine adhesive

AbstractPlasma desorption time‐of‐flight mass spectrometry (PD‐TOFMS) using accelerated argon ions (9 MeV) has been successfully used for characterizing the surface modifications induced at the surface of poly(ether etherketone) (PEEK) by cold plasma treatments. While the intact polymer structure leads to the emission of negative ions from fragmentation of the repeat unit, the degradation of such a structure under plasma exposure gives rise to production of oxidized fragments. It is demonstrated that this production is highest for a plasma using a mixture of O2 and N2 (20:80), and that as a function of treatment duration, the rate of oxidation of the modified surface layer correlates with adhesive strength, at least in a first step. PD‐TOFMS is used for analysis of the failure patterns of epoxyamine adhesive/PEEK/carbon composite in order to localize the fracture position. It is concluded that the increase of the cohesion of the interphase layer as a function of the plasma treatment duration leads to a shift from the interphase/PEEK interface to the bulk of the matrial.

Effects of amiodarone on the circadian rhythm and power spectral changes of heart rate and QT interval: Significance for the control of sudden cardiac death

Effects of chronic amiodarone therapy on the circadian rhythmicity and power spectral changes of heart rate and QT intervals from Holter recordings were evaluated in three groups of patients: group 1 baseline ( n = 10); group 2, treated for 3 to 6 months ( n = 11); and group 3, treated for >1 year ( n = 13). Amiodarone reduced heart rate, which reached steady state at 3 to 6 months; bradycardia was evident during the entire 24 hours. The corrected QT (QT c) interval increased as a function of treatment duration. It was 457 ± 39, 530 ± 28 ( p < 0.001), and 581 ± 36 ( p < 0.0002) msec for groups 1, 2, and 3, after 6 months, respectively. The circadian rhythmicity of QT c was abolished in group 3. Power spectral analysis showed a tendency for amiodarone to reduce both R-R and QT interval variabilities, suggesting inhibition of autonomic control on the heart by the drug. The effectiveness of amiodarone against ventricular arrhythmias may result in part from the sustained bradycardia in concert with continuous uniform prolongation of myocardial repolarization.

Interleukin-2-induced thyroid dysfunction is correlated with treatment duration but not with tumor response.

To analyze the putative relationship between immunotherapy-associated dysthyroidism and the probability of a tumor response. A total of 89 consecutive patients with advanced cancer were treated with interleukin-2 (IL2)-based immunotherapy in a prospective study. Twenty patients developed thyroid dysfunction. Repeatedly positive tests for thyroid antibodies developed in 28% of the patients. Twenty-two patients achieved a response. There was no relationship between the formation of antibodies and the probability of response. There appeared to be a trend toward a relationship between thyroid dysfunction and response (P = .23). A strong relationship was found between response on the one hand and cumulative dose of IL2 (P = .01) and treatment duration with IL2 (P = .025) on the other. The frequency of thyroid dysfunction was also significantly correlated with treatment duration (P = .001). After adjustment for cumulative dose of IL2 and treatment duration, no relationship between thyroid dysfunction and response remained (P = .99). There is no relationship between thyroid dysfunction and the probability of tumor response. Thyroid dysfunction is merely a function of treatment duration and cumulative dose of IL2.

Synergistic behavioural effects of dopamine D 1 and D 2 receptor agonists are determined by circadian rhythms

The effects of continuous subcutaneous infusions of rats for 336 h with vehicle, SKF 38393 (a dopamine D 1 receptor agonist), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a dopamine D 2 receptor agonist) or both D 1 and D 2 receptor agonists, on locomotor activity were investigated. Rats were maintained under constant lighting conditions, either continuous dark (dark:dark) or continuous light (light:light), before and during drug treatments in order to determine the influence of free-running circadian rhythms on drug responses. The D 2 receptor agonist initially increased locomotion in rats kept under dark:dark during both subjective night (period of maximum locomotion) and day (period of minimum locomotion), but had no effect in rats maintained in light:light throughout the 336 h of treatment. The motor stimulant effects of the D 2 receptor agonist on rats kept in dark:dark increased during the course of treatment during subjective night (sensitization), but decreased during the rats' subjective day (tolerance). The D 1 receptor agonist, SKF 38393, had no effect on its own regardless of the lighting conditions and the duration of treatment. However, the D 1 receptor agonist interacted synergistically with the D 2 receptor agonist in rats maintained under light:light, depending on the duration of treatment. Synergistic effects were also observed on initiation of treatment in rats dark:dark but only during subjective day. Tolerance to the synergistic effects of the receptor agonists occured as a function of treatment duration, but only during subjective day. The D 1 receptor agonist blocked the effects of the D 2 receptor agonist during the rats' subjective night after 100h of traatment, but not after 25 or 325 h. It is concluded that the motor stimulant effects of a D 2 receptor agonist, behavioural D 1/D 2 dopamine receptor interactions, and the development of sensitization and tolerance to the locomotor effects of a D 2 receptor agonist are determined by endogenous free-running circadian rhythms, lighting conditions and duration of treatment.

Onset of tolerance to discriminative stimulus effects of morphine

Experiments assessed the onset of tolerance to discriminative stimulus effects of morphine in rats treated repeatedly with twice daily doses of 10 mg/kg morphine. Saline and 3.2 mg/kg morphine were established as discriminative stimuli for food-reinforced fixed-ratio performances in several groups of rats, and initial ED 50 values were determined for stimulus and rate-altering effects of morphine. To assess onset of tolerance, training was halted and 10 mg/kg doses of morphine were administered repeatedly at 12-h intervals. In separate experiments, ED 50 values were redetermined after various treatment periods. One treatment with 10 mg/kg morphine did not alter the ED 50 for stimulus effects of morphine, whereas treatment for one or three days increased the ED 50 by approximately 2-fold. Comparisons with published data showed even greater tolerance when treatment lasted one or two weeks. Tolerance to stimulus effects of morphine generally was accompanied by tolerance to its rate-decreasing effects. Repeated treatment with morphine also produced cross-tolerance to morphine-like stimulus effects of methadone and buprenorphine. As with morphine itself, greater tolerance developed with longer treatment. These results suggest that tolerance to discriminateve stimulus effects of morphine develops gradually, with magnitude of tolerance increasing as a function of treatment duration.