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Results for “Tolerability”

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PubMed1995

Plasma oxidizability in subjects with normal glucose tolerance, impaired glucose tolerance, and NIDDM.

OBJECTIVE: Several lines of evidence support an atherogenic role for oxidized low-density lipoprotein (LDL). Studies on LDL oxidation in diabetes to date have examined LDL isolated from plasma, but have failed to evaluate the other pro- and antioxidant factors present in vivo, the balance of which could be crucial in determining the susceptibility of LDL to lipid peroxidation. RESEARCH DESIGN AND METHODS: We examined the oxidizability of plasma from Mexican-Americans in the San Antonio Heart Study. The oxidizability of plasma in 75 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and non-insulin-dependent diabetes mellitus (NIDDM) was studied after co-incubation with a free radical initiator, 2,2'-azobis-2-amidinopropane hydrochloride (AAPH). Lipid peroxide (LPO) levels were measured by a modified fluorimetric assay. RESULTS: Baseline LPO levels (mumol/l; means +/- SE) were similar in the three glucose tolerance categories (NGT, 1.99 +/- 0.07; IGT, 1.88 +/- 0.07; NIDDM, 1.97 +/- 0.07; P = 0.521). However, after incubation with AAPH (NGT, 4.30 +/- 0.20; IGT, 4.45 +/- 0.20; NIDDM, 5.35 +/- 0.20; P = 0.003), the diabetic plasma had significantly greater amounts of LPOs compared with the other two groups. There was no significant difference in LPOs between the NGT and IGT groups. The statistical significance of increased oxidizability of the diabetic plasma persisted after exclusion of patients who smoked cigarettes (n = 15) or who had vascular disease (n = 4). CONCLUSIONS: In conclusion, this study shows that the plasma of Mexican-American subjects with NIDDM is more prone to lipid peroxidation than that of non-Hispanic whites.

Amidines↗

PubMed2006

Impaired glucose tolerance of pregnancy is a heterogeneous metabolic disorder as defined by the glycemic response to the oral glucose tolerance test.

OBJECTIVE: Gestational diabetes mellitus (GDM), defined by two abnormal glucose values on a 3-h oral glucose tolerance test (OGTT), is associated with insulin resistance and a low serum concentration of adiponectin. The metabolic implications of impaired glucose tolerance (IGT) of pregnancy (i.e., a single abnormal value on an OGTT), however, are not well established. We sought to evaluate the metabolic phenotype of pregnant women with IGT in relation to the timing of their isolated hyperglycemia. RESEARCH DESIGN AND METHODS: A cross-sectional study was performed in pregnant women undergoing a 3-h, 100-g OGTT. The OGTT stratified participants into four groups: 1) GDM (n = 48), 2) 1-h IGT (single elevated value at 1 h) (n = 15), 3) 2-h/3-h IGT (single elevated value at either 2 or 3 h) (n = 23), and 4) normal glucose tolerance (NGT) (n = 93). Insulin sensitivity was measured by the validated insulin sensitivity index (IS(OGTT)) of Matsuda and DeFronzo. RESULTS: Measures of severity of glycemia (fasting glucose, area under the glucose curve from the OGTT, and glucose challenge test result) were highest in the GDM group, followed by the 1-h IGT, 2-h/3-h IGT, and NGT groups, respectively (each trend P < 0.0001). Consistent with this finding, IS(OGTT) was highest in the NGT group (5.1), followed by the 2-h/3-h IGT (4.6), 1-h IGT (3.8), and GDM (3.2) groups (trend P < 0.0001). Furthermore, on multiple linear regression analysis of IS(OGTT), both GDM and 1-h IGT were independently associated with reduced insulin sensitivity (whereas 2-h/3-h IGT was not). Mean adjusted adiponectin was highest in the NGT group (15.7 microg/ml), followed by the 2-h/3-h IGT (15.6 microg/ml), 1-h IGT (13.7 microg/ml), and GDM (12.0 microg/ml) groups (trend P = 0.0024). CONCLUSIONS: The metabolic implications of IGT in pregnancy vary in relation to the timing of the abnormal glucose value from the diagnostic OGTT. The metabolic phenotype associated with 1-h IGT resembles that of GDM, whereas the phenotype associated with 2-h/3-h IGT exhibits similarity to that of NGT.

Administration, Oral↗

PubMed1992

[The prevalence of diabetes mellitus and impaired glucose tolerance studied by 75 gram oral glucose tolerance test in a rural island population].

A mass health examination was performed to assess the glucose tolerance of inhabitants of the island of Ojika, in the Goto islands, Nagasaki prefecture Japan. There were 554 males and 820 females older than 34 years who participated in the mass health examination, a response rates of 42 percent and 52 percent for males and females respectively. Serum glucose levels after overnight fasting and at 2 hours after a 75 gram oral glucose tolerance were used with WHO criteria to classify individuals. Among these subjects, the prevalence of diabetes mellitus increased with age, with a prevalence of diabetes mellitus of around 10 percent in the older subjects. The prevalence for males was higher than that for females. Prevalences of impaired glucose tolerance were roughly in the 15-25 percent range and did not show clear differences among different age groups and sexes. From a questionnaire survey of all island inhabitants, it was considered that the degree of bias of the results was small, if any. The true prevalence for all the inhabitants may be a little larger than the observed prevalence of these subjects.

Adult↗

PubMed2005

[The mechanism of the recipient maternal-fetal immuno-tolerance induced by the transferred paternal antigen-tolerant T cells].

To study the effect of adoptive transfer of paternal antigen-tolerant T cells on recipient reactive T cells, CBA/JxDBA/2 mating was recruited as an abortion-prone model, and CBA/JxBALB/c mating as a successful pregnancy model. The abortion-prone CBA/J females mated with DBA/2 males were injected intraperitoneally with rat anti-mouse CD80 and CD86 mAb or rat isotype IgG at day 4 after gestation (time of implantation). The purified T cells were obtained from spleen of the pregnant CBA/J mice using magnetic beads at day 9 after gestation and labeled with CFSE in vitro. The CFSE-labeled T cells were intravenously injected into other CBA/J females mated with DBA/2 males at day 4 after gestation. The proliferation of recipient splenocytes in response to DBA/2 stimulator cells was evaluated at day 9 after gestation in vitro, and the expressions of intracellular cytokines and costimulatory molecules in CFSE +/- T cells were analyzed by flow cytometry. The results showed that adoptive transfer of either paternal antigen-tolerant T cells or T cells from BALB/c-mated CBA/J mice significantly suppressed the proliferation of recipient splenocytes in response to DBA/2 stimulator cells and resulted in lower frequency of cells positive for IL-2, IFN-gamma, CD28 and higher frequency of IL-10,CTLA-4-producing cells in both CFSE+ CD3+ population and CFSE- CD3+ population compared with adoptive transfer of T cells from isotype IgG-treated CBA/J mice, whereas the frequency of IL-4-producing cells did not appear significant change. Our findings suggest that paternal antigen-tolerant T cells transferred in recipient not only function as antigen-specific suppresser cells but also disable the recipient reactive T cells, which co-suppresses maternal rejection to the allogeneic fetus, thus resulting in the decrease of the embryo resorption rate of the abortion-prone mice to that of the normal pregnancy mice.

Adaptive Immunity↗

PubMedDate not supplied

Cross-tolerance to L-arginine-dependent guanylate cyclase activators in nitrate-tolerant LLC-PK1 kidney epithelial cells.

Recently, it was shown that in LLC-PK1 kidney epithelial cells hormones such as vasopressin or oxytocin increase cyclic GMP in a receptor-mediated and L-arginine-dependent manner. In the present study, the possible existence of cross-tolerance to vasopressin and oxytocin was investigated in nitrate-tolerant LLC-PK1 cells. Pretreatment with 1 mM glyceryl trinitrate for 3 h decreased cyclic GMP stimulation by 1 microM vasopressin and 1 microM oxytocin by 49% and 54%, respectively. Under the same conditions, cyclic GMP stimulation at 1 microM sodium nitroprusside was diminished by 56% whereas the cyclic GMP response to 100 microM glyceryl trinitrate was virtually abolished. Our results demonstrate that a substantial degree of cross-tolerance to L-arginine-dependent guanylate cyclase activators occurs in nitrate-pretreated nonvascular cells which may be due to glyceryl trinitrate-induced desensitization of soluble guanylate cyclase.

Animals↗

PubMed1990

Cyclophosphamide-induced chimera-type tolerance to allografts: an overview of drug-induced immunological tolerance.

A CP-induced tolerance induction method in mice that consists of donor spleen cell injection followed 2 days later by CP treatment was found useful for inducing permanent skin allograft tolerance. In order to regularly overcome fully allogeneic (major H-2 plus multiminor H) barriers, both a reduction of recipient T cells with anti-T cell antibody before tolerance induction and a supplement of the spleen cells with bone marrow cells were required. The reduction of recipient T cells was necessary because the antigen-stimulated-and-proliferating cell destruction with CP, which is considered to be the main mechanism of this system, is not completed due to the less proliferative quick maturation of T cells when a relatively large number of reactive T cells exist. The bone marrow cells were required probably because the establishment of stable mixed chimerism is necessary to ensure skin graft survival. This system is considered to be potentially applicable to human transplantation.

Animals↗

PubMed1990

Peripheral clinico-chemical parameters in experimentally naive versus morphine tolerant mice: evidence for development of clinico-chemical tolerance.

Changes in peripheral clinico-chemical parameters (packed cell volume (PCV), hemoglobin (HGB), serum glucose, carbamide nitrogen (CN), sodium, uric acid and creatinine) were investigated in mice during the development of acute morphine tolerance. Acute morphine treatment (in drug-naive organism) altered the PCV, HGB, serum glucose and CN levels in a naloxone-reversible manner. Acute tolerance developed in PVC, HGB, sodium and CN values. The data raise the possibility of a relationship between clinico-chemical and pharmacological tolerance.

Animals↗

PubMed1989

Long-term treatment with active vitamin D (alphacalcidol) in middle-aged men with impaired glucose tolerance. Effects on insulin secretion and sensitivity, glucose tolerance and blood pressure.

There are specific receptors for the active metabolite of vitamin D on the pancreatic beta cells and severe vitamin D deficiency can inhibit insulin secretion. In the present study 14 middle aged men with impaired glucose tolerance and low glucose-stimulated insulin values received 2 micrograms alphacalcidol daily for 18 months. On treatment there was a transient increase of both the peak and the late insulin response to intravenous glucose while neither intravenous nor oral glucose tolerance were consistently altered. Nor was the peripheral insulin sensitivity, measured by the euglycemic clamp technique, significantly affected. In the untreated state there was a positive relationship (r = 0.77) between the tissue insulin sensitivity and the serum concentrations of 25-hydroxyvitamin D. There was also an inverse relationship (r = 0.61) between systolic blood pressure and the serum levels of 1,25-dihydroxy vitamin D. Although the subjects were normotensive and not overweight, treatment with alphacalcidol tended to lower both systolic (6 +/- 12 mmHg) and diastolic blood pressures (5.8 +/- 9.1 mmHg) and there was a small reduction (0.9 kg) in body weight. In conclusion, subjects with impaired glucose tolerance without vitamin D deficiency do not benefit from vitamin D supplementation, which however has some hypotensive action also in normotensive individuals.

Blood Glucose↗

PubMed1987

Development of tolerance towards glyceryl trinitrate in vitro. Low concentration induced tolerance and changes in cyclic guanosine-3',5'-monophosphate metabolism.

Bovine mesenteric arteries were exposed to glyceryl trinitrate (GTN) in vitro for 2 and 8 h in a low concentration (0.1 nmol/l), that equals the plasma concentrations reached by using GTN-discs in patients with angina pectoris. After reexposure to GTN a significantly reduced relaxant response was observed. In the concentration range 1 pmol/l to 10 nmol/l a 10-fold right shift of the concentration-effect curve was noted as compared to control vessels not previously exposed to GTN. The reduced relaxant response was accompanied by a significantly impaired ability to form cyclic guanosine-3',5'-monophosphate (cGMP). The results are interpreted as a development of tolerance towards GTN at the level of the vascular smooth muscle cell. A concentration of GTN (0.1 mmol/l) previously used to induce tolerance in vitro, produced a much more pronounced shift to the right of the concentration-response curve, especially in the concentration range 10 nmol/l to 0.1 mmol/l. This might indicate that tolerance to GTN can be induced by 2 different mechanisms, which in turn might be interpreted as the existence of 2 mechanisms of action by GTN in inducing vascular smooth muscle relaxation.

Animals↗

PubMed1987

Tolerance induction in mice by conjugates of monoclonal immunoglobulins and monomethoxypolyethylene glycol. Transfer of tolerance by T cells and by T cell extracts.

The specific tolerance induced in mice by conjugates of human monoclonal IgG (HIgG) with monomethoxypolyethylene glycol (mPEG) was transferred to normal mice by spleen cells or a surface immunoglobulin negative (sIg-) Lyt-2+ subpopulation of these cells. Although transferable tolerance was demonstrable 6 to 14 days after treatment of the cell donors with tolerogen, the state of tolerance persisted in the treated mice for at least 43 days. Moreover, an extract prepared by freezing and thawing of the sIg- spleen cells obtained from mice 6 days after treatment with HIgG(mPEG)20 was capable of reducing (greater than 85%) the immune response of normal mice to heat aggregated HIgG. On the basis of these results, it is suggested that similar tolerogenic mPEG derivatives of xenogeneic monoclonal immunoglobulins (XIg) may prove to be useful therapeutic agents in man when administered before treatment with the unmodified XIg.

Animals↗

PubMed1987

Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors.

The tolerance effects of continuous intrathecal infusions of opioids at mu and delta receptors were studied in rats. These effects were compared to those of chronic systemic morphine. A chronic intrathecal infusion of the relatively selective delta agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), produced a larger degree of tolerance to DADLE than to the highly specific mu-activating morphiceptin analog [N-methyl-Phe3, D-Pro4]morphiceptin (PL017). The slope of the analgesic dose-response curve for the highly specific delta agonist, cyclic [D-Penicillamine2, D-Penicillamine5]enkephalin (DPDPE), was significantly different (flatter) from those of mu agonists or DADLE. High-dose infusion of PL017 induced a 61-fold parallel shift of the dose-response curve for PL017. This same treatment also induced a corresponding flattened, nonparallel change of the dose-response curve for DADLE. This altered curve for DADLE was very similar in slope to that of DPDPE. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine, caused a parallel rightward shift of the dose-response curve for PL017 but did not affect DPDPE activity. beta-Funaltrexamine treatment induced a nonparallel rightward shift of the dose-response curve for DADLE with a change of slope similar to that of DPDPE. These findings demonstrate a mixed mu-delta analgesic activity for the compound DADLE, which is often referred to as a prototypic delta agonist. These interactions differ from prior reports of none or minimal mu-ligand interactions with DADLE. Despite the cross-reactivity of DADLE to mu receptors, DADLE remains a more effective analgesic than do mu agonists in states of mu receptor tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1981

Tolerance and immunity in mice infected with herpes simplex virus: studies on the mechanism of tolerance to delayed-type hypersensitivity.

Tolerance to delayed-type hypersensitivity is produced in mice following an intravenous injection of herpes simplex virus. This form of tolerance is produced early on, following simultaneous injections of virus subcutaneously and intravenously, and is long lasting (greater than 100 days). The early tolerance mechanism is resistant to high doses of cyclophosphamide and is not transferable by serum or spleen cells taken after 7 days. However, spleen cells taken at 14 days onwards inhibit the induction of delayed hypersensitivity when transferred to normal syngeneic recipients. These cells are T lymphocytes and are specific for the herpes type used in the induction.

Animals↗

PubMed1978

Tolerance and cross-tolerance to cocaine and d-amphetamine.

The effects of cocaine (4.0-32 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) on milk intake of rats were determined before and during periods of repeated daily administration of each drug. Experimental sessions consisted of 15 minutes access to 50 ml of a sweetened condensed milk solution. After the determination of the disruptive effects of single injections of cocaine or d-amphetamine on milk intake, rats were injected daily with either 16 mg/kg of cocaine 15 minutes before the session, 16 mg/kg of cocaine immediately after the session, 2.0 mg/kg of d-amphetamine 15 minutes before the session or saline before the session. During the period of repeated administration when milk intake had stabilized in each group, dose-effect functions for cocaine and d-amphetamine on milk intake were redetermined. On selected days, test doses of either drug were substituted for the usual daily injection. Test doses were separated by at least 3 days of stable intake after injection of the appropriate drug or saline. During the period of repeated administration, milk intake returned toward control levels for animals receiving daily cocaine or daily d-amphetamine before the session. Further, when the dose-effect functions for cocaine and d-amphetamine on milk intake were redetermined, a shift to the right (i.e., toward larger doses) was observed in all groups that had received drug presession during the repeated administration. This indicates that the animals became tolerant to cocaine and d-amphetamine as well as cross-tolerant to both drugs. The development of tolerance to cocaine was contingent upon the relationship of the time of injection to milk availability. Animals that had received postsession injections of cocaine during repeated administration were more sensitive to the effects of cocaine and d-amphetamine on milk intake.

Animals↗

PubMed1983

The Bedford Survey: observations on retina and lens of subjects with impaired glucose tolerance and in controls with normal glucose tolerance.

After the Bedford Survey observations were made upon retina and lens in borderline diabetics (persons with impaired glucose tolerance) and in age and sex matched controls with normal glucose tolerance. Seven years after the Survey, the prevalence of retinal abnormalities ("microaneurysms" and "exudates") was similar in each group. Of 145 initially borderline diabetics examined 10 years after the Survey, 25 had worsened to diabetes. Only two of the total group had "micro-aneurysms" present and the maximum recorded in any eye was three. Lens opacities were of similar frequency in both groups shortly after the Survey and at the seven year follow-up examination. By contrast, 24% of 79 diabetics newly diagnosed during the Survey had "microaneurysms" recorded five years later. These results further justify the diagnostic category of impaired glucose tolerance, which, at least when discovered by population screening, carries no risk of clinically apparent eye disease for at least ten years after ascertainment.

Aneurysm↗

PubMed1981

Tolerance and immunity in mice infected with herpes simplex virus: simultaneous induction of protective immunity and tolerance to delayed-type hypersensitivity.

Unresponsiveness to delayed type hypersensitivity was induced in mice following an intravenous injection of herpes simplex virus. The principal tolerogens used were thymidine kinase-deficient virus mutants which grow poorly in vivo; u.v.-inactivated and to a lesser extent formalin-inactivated virus were also tolerogenic. The tolerance induced was specific for the virus type. Despite the tolerance to delayed hypersensitivity, anti-viral immunity is present as determined by the rapid inactivation of infectious virus. The mechanism of tolerance to herpes virus and the importance of these observations for the pathogenesis of viral disease is discussed.

Animals↗

PubMed1994

Ascorbic acid delays the development of tolerance to amphetamine induced anorexia but does not affect the reverse tolerance which develops to the locomotor activity.

Ascorbic acid (1 g/kg) accentuated anorectic and locomotor effects of amphetamine (5 mg/kg) and delayed development of tolerance to anorectic effect. On the contrary, it did not alter the pattern of reverse tolerance to increased locomotor activity. The results suggest that modulation of dopamine receptor sensitivity by ascorbic acid may be the reason for the delay in development of tolerance to amphetamine induced anorexia.

Amphetamine↗

PubMed1993

[The enkephalinase mechanisms of the resistance and tolerance to the analgesic effect of morphine in rats. Differences in the effects of the action of D-phenylalanine in morphine-sensitive, morphine-tolerant and morphine-resistant rats].

In morphine-sensitive (s.c. 1.5 mg/kg) Wistar rats (60%) i.p. inoculation of 300-600 mg/kg d-Phenylalanine (d-Pha) did not change the nociception (tail-flick test), but in morphine-resistant rats (40%) evoked a dose-dependent analgetic effect. In morphine-sensitive rats (40%) chronic morphine administration induced the tolerance and d-Pha injection evoked analgetic effect. Morphine injection just after d-Pha analgesia was over evoked analgetic effect in morphine-resistant and -tolerant rats. It is suggested that morphine-resistant rats have a congenital and morphine-tolerant rats an acquired high level of enkephalinase activity which blocked the morphine analgetic action.

Analgesia↗

PubMed1997

Tolerance to mu-opioid receptor agonists but not cross-tolerance to gamma-aminobutyric acid(B) receptor agonists in arcuate A12 dopamine neurons with chronic morphine treatment.

The present study examined the potential for cross-tolerance development between mu-opioid and gamma-aminobutyric acidB receptor agonists, in hypothalamic arcuate neurons, resulting from chronic morphine treatment. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. The mu-opioid receptor agonist D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin and the gamma-aminobutyric acidB receptor agonist baclofen produced dose-dependent membrane hyperpolarizations of arcuate neurons. The reversal potential for both agonist-induced hyperpolarizations was near -95 mV, indicative of the activation of an underlying K+ conductance. Coadministration of maximally effective concentrations of D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin and baclofen produced a response that was not additive, indicating a convergence onto a common K+ channel. In arcuate neurons, including a subset that was immunopositive for tyrosine hydroxylase, chronic morphine treatment for 4 to 7 days produced a 3.2-fold reduction in the potency, with no change in the efficacy, of D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin. In contrast, it affected neither the potency nor the efficacy of baclofen. Therefore, chronic morphine exposure does not produce cross-tolerance between mu-opioid and gamma-aminobutyric acidB receptor agonists in A12 dopamine neurons, suggesting that convergence upon a common effector is not a sufficient criterion for the development of cross-tolerance between receptor systems.

Animals↗