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Results for “Tolerability”

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PubMed1982

Tolerance and cross tolerance with morphine resulting from physiological release of endogenous opiates.

Mice which had been exposed to a chronic schedule of warm water swimming showed the development of a significant tolerance to the antinociceptive response (tail-flick latency) and a significant, two-fold increase in the ED50 of morphine (tail-flick latency and abdominal constriction response). These results suggest the involvement of endogenous opiates during swim stress in mice and are consistent with the hypothesis that during chronic stress the opiate receptors are activated in a manner analogous to the repeated application of exogenous opiates producing tolerance, morphine cross tolerance and (as previously reported) withdrawal-like behaviour.

Animals↗

PubMed1983

Clonidine analgesia: tolerance and cross-tolerance to autoanalgesia.

Clonidine induced significant antinociception in rats, as assessed by radiant-heat tail-flick procedures. Continued administration of 0 5 mg/kg and 1.0 mg/kg of the drug for 7 days induced significant analgesic tolerance in a dose-dependent manner. Significant cross-tolerance to antinociception elicited by acute footshock or classical conditioning procedures was observed, with the greatest cross-tolerance being exhibited by the 1.0 mg/kg group. These data suggest similar noradrenergic mechanisms may subserve clonidine antinociception and autoanalgesia.

Analgesia↗

PubMed1983

Paradoxical release of growth hormone during oral glucose tolerance test in patients with abnormal glucose tolerance.

Oral glucose tolerance tests were performed on 24 patients characterized as having abnormal glucose tolerance (AGT) and on 27 control subjects. Serums for glucose, growth hormone and insulin determinations were serially obtained for 4 hr after glucose administration. As serum glucose declined 2 hr or more after glucose ingestion a rise in growth hormone, as has been previously described, was observed in 40% of control subjects and 12% of AGT patients. However, of interest was a paradoxical early increase in growth hormone levels noted in 44% of lean AGT subjects occurring during the first 2 hr of the test with glucose levels rising. This response was seen in only one of 8 obese patients with AGT and in none of the control subjects. An abnormality in the hypothalamic glucose receptors in the ventromedial nucleus is a possible explanation for the changes observed. It is possible that this early inappropriate increase in growth hormone release may in some nonobese subjects with AGT contribute to the abnormal oral glucose tolerance tests observed.

Administration, Oral↗

PubMed1984

Antinociceptive and gastrointestinal effects of opiates: an analysis of the nature of the involvement of mu and delta receptors of the central nervous system in morphine-tolerant and non-tolerant mice.

This study attempted to distinguish between mu (morphine) and delta [(D-Ala2-D-Leu5)-enkephalin; DADLE] receptors, with regard to both in vivo effects (analgesia and gastrointestinal motility) and the location of binding activity in the brain. Analgesia and motility are distinguishable both by dose (intracerebroventricular) and by ligand selectivity with mu ligands more potent for the former and delta for the latter. Tolerance and cross-tolerance are exhibited for both effects, with the relationships between mu and delta ligand potencies preserved. In vitro receptor binding revealed an affinity decrease for delta in medulla and an increase in medulla and diencephalon for mu receptors after tolerance development to morphine. The results indicate that the mu receptors in medulla and diencephalon mediate analgesia, while medullary delta receptors control motility.

Analgesia↗

PubMed1990

Tolerance and cross-tolerance to 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine and methylenedioxyamphetamine.

The effects of (+-)-3,4-methylenedioxymethamphetamine (MDMA) (0.62-20.0 mg/kg), (+)-methamphetamine (MA) (0.62-5.0 mg/kg) and (+/-)-3,4-methylenedioxyamphetamine (MDA) (0.62-5.0 mg/kg) on milk intake in rats were determined before and during a period of repeated daily administration of MDMA. Experimental sessions consisted of 15-min access to a sweetened milk solution each day, 5 days a week. After initial determination of the effects of MDMA, MA and MDA on milk intake, rats were injected daily with either MDMA (2.5-5.0 mg/kg) or saline. Two groups of rats were injected with MDMA, one group 15 min before, and the other group 15 min after the milk-drinking sessions. Two more groups of rats were injected with saline, one group 15 min before, and the other group 15 min after the sessions. During this repeated administration period the effects of MDMA, MA and MDA (injected 15 min prior to the session) were redetermined. In rats that had been injected with MDMA on a daily basis either before or after the milk-drinking sessions, the dose-response function of MDMA was shifted to the right, indicating that tolerance had developed. Cross-tolerance to MA appeared to develop only in the group of rats that had been injected with MDMA on a daily basis before the milk-drinking sessions. Cross-tolerance to MDA did not develop in any of the 4 groups of rats.

3,4-Methylenedioxyamphetamine↗

PubMed1988

Failure to support the validity of the Fagerstrom Tolerance Questionnaire as a measure of physiological tolerance to nicotine.

We tested the validity of the Fagerström Tolerance Questionnaire as a measure of physiological tolerance to nicotine. Both clinical and laboratory studies found neither the total questionnaire score nor the individual questionnaire items were related to physiological tolerance as measured by heart rate, skin conductance, blood volume pulse, and skin temperature responses to smoking a cigarette. We hypothesize the questionnaire measures behavioral dependence or perceived dependence rather than physical dependence.

Adult↗

PubMedDate not supplied

Neurobehavioral toxicity of 2,4-D-n-butyl ester (2,4-D ester): tolerance and lack of cross-tolerance.

Daily administration of 2,4-dichlorophenoxyacetic acid-n-butyl ester to rats (2,4-D ester, 150 mg/kg/day SC) initially produced depressions in photocell locomotor activity and increases in landing foot splay. Maximal tolerance developed to these effects following ten days of repeated exposure. By themselves, physostigmine sulfate (0.01-0.10 mg/kg) and (0.3-10.0 mg/kg) n-butanol produced locomotor activity depression in a dose-related manner. n-Butanol produced increases in landing foot splay while physostigmine had no effect at the doses employed. No cross-tolerance was observed between 2,4-D ester and physostigmine sulfate or n-butanol when locomotor activity was the dependent variable. Similarly, a lack of cross-tolerance was observed between 2,4-D ester and n-butanol when landing foot splay was measured. Unlike physostigmine, prior exposure to n-butanol tended to enhance its toxicity upon subsequent exposures, an effect which was blocked when 2,4-D ester was administered between n-butanol exposures.

1-Butanol↗

PubMed1993

Tolerance to the effects of diazepam, clonazepam and bretazenil on GABA-stimulated Cl- influx in flurazepam tolerant rats.

The effect of chronic flurazepam treatment on the GABA (gamma-aminobutyric acid) receptor/chloride channel complex was studied using GABA-stimulated 36Cl- influx into brain microsacs, and its potentiation by diazepam, clonazepam and bretazenil. Rats were given flurazepam for 1 week, then microsacs were prepared from cerebral cortices of rats that were still receiving flurazepam, and from those that had stopped treatment 48 h earlier. Diazepam and clonazepam produced concentration-dependent increases in GABA-stimulated 36Cl- influx while bretazenil produced a much smaller effect, which did not reach statistical significance in the tissue from control rats. There was no significant change in the basal or 10 microM GABA-stimulated 36Cl- influx between control and treated groups. Tolerance was shown by a significantly reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl- influx in the tissue prepared from non-withdrawn rats. However, for both diazepam and clonazepam, there was no tolerance 48 h after chronic treatment. The results suggest that changes in the GABA receptor/Cl- channel complex on cerebral cortical neurons contribute to cross-tolerance from flurazepam to other benzodiazepines.

Animals↗

PubMedDate not supplied

The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials.

Organ transplantation has become a standard life-saving therapy for many causes of end stage organ failure. Although valuable, it remains hampered by the requirement for, and complications of, immunosuppression to prevent immune rejection of the transplanted organ. It is now clear that rejection can be avoided in some experimental systems without a requirement of immunosuppressive medication, and these experimental concepts are now making their way into the clinic in the form of early transplantation tolerance trials. This manuscript will discuss the most promising techniques for tolerance induction, namely, costimulation blockade, lymphocyte depletion, and mixed chimerism. Seminal preclinical studies will be cited and the results of initial clinical trials will be reviewed. The data to date indicate that while tolerance remains elusive, immunosuppression minimization is a feasible near-term alternative.

Animals↗

PubMed2002

RB101(S), a dual inhibitor of enkephalinases does not induce antinociceptive tolerance, or cross-tolerance with morphine: a c-Fos study at the spinal level.

In behavioural tests, RB101 (N-[(S)-2-benzyl-3[(S)(2-amino-4-methyl-thio)butyldithio]-1-oxopropyl]-L-phenylalanine benzyl ester), a mixed inhibitor of enkephalin-degrading enzymes, induces antinociceptive effects without producing tolerance, or cross-tolerance with morphine. In the present experiments, the acute or chronic effects of enantiomer RB101(S) were examined on the response of spinal cord neurons to nociceptive inflammatory stimulation (intraplantar injection of carrageenin) using c-Fos studies in awake rats. The number of c-Fos immunoreactive nuclei was evaluated in the lumbar spinal cord 90 min after carrageenin. c-Fos-immunoreactive nuclei were preferentially located in the superficial (I-II) and deep (V-VI) laminae of segments L4-L5 (areas containing numerous neurones responding exclusively, or not, to nociceptive stimuli). In the first experimental series, acute RB101(S) (30 mg/kg, i.v.), morphine (3 mg/kg, i.v.), or respective vehicles were injected in rats chronically treated with RB101(S) (160 mg/kg/day for 4 days, s.c.). In chronically treated RB101(S) rats, both acute RB101(S) and morphine reduced the total number of carrageenin-evoked c-Fos-immunoreactive nuclei. In the second experimental series, acute RB101(S) (30 mg/kg, i.v.) reduced the total number of carrageenin-evoked c-Fos-immunoreactive nuclei with similar magnitude in naive and in morphine-tolerant (100 mg/kg/day for 3 days, s.c.) rats. These data provide further evidence that different cellular mechanisms occurred after chronic stimulation of opioid receptors by morphine or endogenous enkephalins.

Analgesics↗

PubMedDate not supplied

Effect of doxazosin therapy on glucose tolerance and lipid metabolism in hypertensive patients with impaired glucose tolerance.

The effects of long-term monotherapy with doxazosin, an alpha 1-blocker, or placebo on blood pressure (BP), glucose tolerance, and serum lipid levels were investigated prospectively in 43 hypertensive patients with impaired glucose tolerance. The levels of plasma glucose, serum lipids, fructosamine, and glycated hemoglobin A1c (Hb A1c) were determined before and during long-term (mean treatment period, 6.7 months) therapy with doxazosin (n = 23) or placebo (n = 20). A 75-g oral glucose tolerance test was performed before and during therapy. Significant decreases in both systolic and diastolic BP were maintained during doxazosin therapy; BP did not change in the placebo group. Neither fasting nor post-glucose-load venous plasma glucose levels were altered, and there was no significant change in the insulinogenic index in either group. Glucose intolerance was slightly improved with significant reductions in Hb A1c and fructosamine levels during doxazosin therapy. Serum total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels were significantly decreased, and high-density lipoprotein cholesterol levels were significantly increased in patients treated with doxazosin. Moreover, TC, LDL cholesterol, and apolipoprotein B levels were significantly decreased in patients with hypercholesterolemia (TC > or = 5.69 mmol/L). In contrast, there were no significant changes in Hb A1c, fructosamine, and lipid levels in the placebo group. These results suggest that long-term doxazosin therapy may improve glucose and lipid metabolism in hypertensive patients. Doxazosin appears useful as an antihypertensive agent for hypertensive patients with either impaired glucose metabolism or dyslipidemia.

Antihypertensive Agents↗

PubMed1995

The induction of skin xenograft tolerance in rat-to-mouse combination could be affected by DFR mediating cells and antibodies against rat bone marrow cells as well as NK cells in the cyclophosphamide-induced tolerance system.

We investigated whether the prolongation of skin xenograft survival was obtained by a tolerance-inducing method using cyclophosphamide (CY), by which long-lasting skin allograft tolerance could be induced. The long-lasting skin allograft survival could be obtained in the recipient C3H/HeN (C3H) mice which were given 100 micrograms of anti-CD4 mAb on day -3, 1 x 10(8) spleen cells (SC) plus 3 x 10(7) bone marrow cells (BMC) derived from C57BL/6 (B6) mice on day -2,200 mg/kg CY on day 0, and which were grafted with allogeneic B6 skin on day 14. When the C3H mice were treated with anti-CD4 mAb, 1 x 10(8) s.c. plus 5 x 10(7) BMC derived from F344 rat and CY, the F344 skin grafts survived slightly longer (about 15 days) than those in untreated recipients (about 8.4 days). Such a prolongation of skin xenograft survival was considered donor-specific because rejection of 3rd party skin grafts from BN rats occurred significantly earlier than that of F344 skin grafts. In the recipient C3H mice treated with anti-CD4 mAb, F344 s.c. plus BMC and CY, mixed chimerism in the periphery was detected for a few days after CY administration, although intrathymic chimerism was not detected throughout this study. In these recipient C3H mice, cytotoxic T lymphocytes (CTL) against F344 antigens were completely abrogated through the delayed footpad reaction (DFR) remained at a low but significant level. Moreover, though antibody (Ab) activity against F344 s.c. was completely abrogated, neither Ab activity against F344 BMC, which seemed to have a background common to natural Ab activity, nor NK activity were abrogated by this treatment. These results suggested that DFR mediating cells directly mediated skin xenograft rejection in the recipient mice treated with anti-CD4 mAb, F344 cells, and CY. Such cells may interfere with establishment of mixed chimerism and long-lasting skin xenograft tolerance, presumably in cooperation with CY-resistant Ab activity and NK cells.

Animals↗

PubMed1998

Genetics of immunological tolerance: I. Bidirectional selective breeding of mice for oral tolerance.

The polygenic nature of oral tolerance regulation was elucidated by the method of bidirectional selective breeding of mouse strains for tolerance susceptibility (TS) and resistance (TR) starting from a genetically heterogeneous population achieved by the equilibrated intercrossing of eight inbred mouse strains (A/J, DBA/2J, P/J, SWR/J, SJL/J, CBA/J, BALB/cJ and C57BL/6J). Seven days after intragastric administration of 5 mg OVA or BSA, mice were intraperitoneally immunized with 100 microg of the corresponding antigen. The individual antibody titres were measured by haemagglutination. The phenotypes at the highest and lowest extremes were selected for assortative mating, avoiding consanguinity. The second litter of each mating couple was intraperitoneally immunized only to evaluate the immunocompetence of the corresponding generation and to ascertain the non-selection of non-responder mice. A normal distribution of agglutinin titres ranging from 4 to 14 log2 was observed in the F0 population. In the F12 generation, TR and TS strains showed highly significant differences for agglutinin titres (TR=15.06+/-1.80 and TS=8.35+/-2.44), and IgG responses by ELISA. Up to the F12 generation, the mean realized heritability was 0.14+/-0.02. The response to the selection was 0.43 log2 and the selection differential 3.10 log2/generation. A provisional estimation indicated that oral tolerance may be influenced by eight or nine independent loci.

Administration, Oral↗

PubMed2001

Formation of morphine tolerance in offspring of morphine-tolerant animals: neurochemical and neuroimmune correlates.

We carried out a complex physiological, neurochemical, and neuroimmunologic study of the formation of tolerance to analgetic effect of morphine and analyzed enkephalinase A activity in different brain structures and serotonin antibodies in the serum. More early development of morphine tolerance and a sharp increase in serum antibody titer was found in the offspring of morphine-tolerant rats. This points to an imbalance in the neurotransmitter system and can serve as a diagnostic marker of endogenous opioid system pathology.

Analgesics, Opioid↗

PubMed1983

Conditioned morphine tolerance in the rat: absence of a compensatory response and cross-tolerance with stress.

In four separate experiments with rats as subjects, strong evidence was obtained that tolerance development to morphine analgesia occurs most rapidly when morphine delivery is paired with salient contextual cues. However, contextual cues previously paired with morphine did not elicit conditioned drug-compensatory responses when presented to nondrugged animals. These results were obtained by different analgesia assessments, with different drug-administration--analgesia-test latencies, and in environments differing with respect to stress level. Stress level did influence nociceptive response, as it was found that the combination of bright illumination, white noise, and a strong odor resulted in antinociception in the absence of drug. Moreover, rats that had a history of receiving morphine in this stressful context were tolerant to this stress-induced antinociception, but only when morphine was present in their systems. In the final two studies, this antinociception, which was cross-tolerant with morphine, was characterized with respect to naloxone reversibility and brain levels of met- and leu-enkephalin as determined by radioimmunoassay.

Animals↗

PubMed2002

Cellular mechanisms of opioid tolerance and the clinical approach to the opioid tolerant patient in the post-operative period.

The high prevalence of opioid use for recreational purposes in the USA and the European Union, as well as the use of opioids for the treatment of chronic non-malignant pain, has resulted in an increase in the number of patients with opioid tolerance who undergo surgery and require post-operative pain management. The approach to post-operative pain control in these patients is significantly different to the strategies used in opioid naïve patients. Fortunately, better understanding of the cellular mechanisms of opioid tolerance in animals has resulted in the transfer of concepts from the 'bench' to the clinical arena. This chapter describes the new developments in opioid tolerance and how this knowledge can be applied to clinical practice.

Adaptation, Physiological↗

PubMed1980

Induction of tolerance to 1-fluoro-2,4-dinitrobenzene contact sensitivity with hapten-modified lymphoid cells. II. Selective tolerance in F1 mice of T cell subsets recognizing 1-fluoro-2,4-dinitrobenzene associated with parental major histocompatibility complex antigens.

F1 animals were tolerized to 1-fluoro-2,4-dinitrobenzene (DNFB) contact sensitivity with parentally derived, in vitro hapten-modified spleen cells. This tolerant state was found, upon adoptive transfer to naive parental strain recipients, to affect only that T cell subpopulation that recognized the parental haplotype of the cell used as the tolerogen, and did not inhibit the ability of the remaining T cell subset to confer immunity. This demonstrates that this tolerant state involves the inactivation of a cell required for the expression of contact sensitivity by recognizing DNFB in association with self major histocompatibility complex gene products.

Animals↗

PubMed1993

Tolerance of CD8+ T cells developing in parent-->F1 chimeras prepared with supralethal irradiation: step-wise induction of tolerance in the intrathymic and extrathymic environments.

Tolerance of CD8+ cells was examined in parent-->F1 bone marrow chimeras (BMC) prepared with supralethal irradiation; host class I expression in the chimeras was limited to non-BM-derived cells. In terms of helper-independent proliferative responses in vitro and induction of graft-vs.-host disease on adoptive transfer, CD8+ cells from long-term chimeras showed profound tolerance to host antigens irrespective of whether the cells were prepared from the thymus or from spleen or lymph nodes. By limiting dilution analysis, cytotoxic T lymphocyte (CTL) precursors specific for host antigens were rare in the extrathymic lymphoid tissues. In the thymus, by contrast, host-specific CTL precursors were only slightly less frequent than in normal parental strain mice. These host-specific CD8+ cells survived when BMC thymocytes were transferred intravenously to a neutral environment, i.e., to donor strain mice. When transferred to further BMC hosts, however, most of the host-reactive cells disappeared. Collectively, the data suggest that tolerance of CD8+ cells in BMC hosts occurs in both the intrathymic and extrathymic environments. In the thymus, contact with host antigens on thymic epithelial cells deletes CD8+ cells controlling helper-independent proliferative responses and in vivo effector functions but spares typical helper-dependent CTL precursors. After export from the thymus, most of the CTL precursors are eliminated after contacting host antigens on stromal cells in the extrathymic environment.

Animals↗