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PubMed1990

Corticosteroid sensitivity and cross-sensitivity. A review of 18 cases 1967-1988.

506 patients were suspected of being allergic to corticosteroid medicaments in our clinic during the 22 years from 1967 to 1988. Patch tests were performed in these patients. Scratch tests, intradermal tests, and challenge tests were also carried out in some cases. 69 patients showed positive reactions to corticosteroid products (as is). 18 were allergic to the corticosteroid itself and 44 were sensitive to vehicle components or other active ingredients. In 7 cases, the allergen could not be detected. Patients who were allergic to corticosteroids were tested for their cross-sensitivity with our corticosteroid patch test series. Cross-reactions tended to occur between members of the same corticosteroid type, and some of the combinations of different corticosteroid types cross-reacted with each other. Corticosteroid-sensitive cases have increased in number during these 22 years. Corticosteroid sensitivity is not as rare as formerly thought.

Adult↗
PubMed1998

Oral and epicutaneous desensitization in urushiol contact dermatitis in guinea pigs sensitized by 2 methods of different sensitizing potency.

This investigation was conducted to study the relationship between the different intensities of sensitization to urushiol induced by the maximization test method (MT) or by the ear-flank method (EF) in guinea pigs, and hyposensitization induced by repeated oral and/or epicutaneous administration of the allergen, and to compare the immune tolerance achieved between these routes of dosing. During the observation period of 10 weeks, both oral and epicutaneous administration produced hyposensitization to urushiol after weak sensitization by EF; however, only combined administrations via the oral and epicutaneous routes achieved hyposensitization after potent sensitization, while inadequate tolerance was induced by oral dosing and none by epicutaneous dosing. Thus, it is indicated that difficulty in establishing immune tolerance may increase with increasing intensity of primary sensitization, and that hyposensitizing potency tends to increase in the order epicutaneous, oral and combined (e.p.+p.o.) administrations of urushiol.

Administration, Cutaneous↗
PubMed1995

Ozone exposure decreases UVB sensitivity in a UVB-sensitive flavonoid mutant of Arabidopsis.

The impact of sequential exposure to ozone (O3) and UVB (290-320 nm) was studied using two genotypes of Arabidopsis thaliana differing in UVB sensitivity. The negative impact of UVB on dry matter production and photosynthetic pigments was absent in the ecotype Landsberg erecta (LER), while the negative impact of UVB was more pronounced when LER plants pre-exposed to O3 were irradiated with UVB. However, the growth of tt5 plants (a mutant virtually incapable of synthesizing flavonoids) was significantly affected by the UVB exposures, while the impact of UVB was significantly counteracted when tt5 plants pre-exposed to O3 were irradiated with UVB. These results suggest that pre-exposure to O3 decreased sensitivity of tt5 but increased sensitivity of LER to UVB. Concentrations of UV-absorptive compounds were almost the same in plants exposed to UVB alone or sequentially to O3 and UVB. Exposures of LER and tt5 to UVB enhanced both ascorbic acid and glutathione as well as their redox state compared to control plants. Pre-exposure to O3 enhanced the total ascorbic acid and glutathione as well as the redox state of ascorbate and glutathione in tt5 but decreased the redox state in LER. Irradiation of plants pre-exposed to O3 with UVB enhanced the redox state of ascorbate and glutathione slightly in tt5 but decreased it further in LER. The high redox state of ascorbate and glutathione in tt5 pre-exposed to O3 would have protected plants from UVB and decreased their sensitivity to UVB in spite of their inability to synthesize flavonoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Arabidopsis↗
PubMed1989

Partial reversion of conditional transformation correlates with a decrease in the sensitivity of rat cells to killing by the parvovirus minute virus of mice but not in their capacity for virus production: effect of a temperature-sensitive v-src oncogene.

The cytolytic effect of the autonomous parvovirus minute virus of mice, prototype strain (MVMp), was studied in cultures of ts 339/NRK rat cells that display a temperature-sensitive transformed phenotype as a result of their transformation with a Rous sarcoma virus strain matured in the v-src oncogene. A shift from restrictive (39.5 degrees C) to permissive (34.5 degrees C) temperature was associated with a marked sensitization of these cells to killing by MVMp. In contrast, ts 339/NRK cell derivatives supertransformed with a wild-type src oncogene were sensitive to MVMp at both temperatures, suggesting that the expression of a functional oncogene product may determine, at least in part, the extent of the parvoviral cytopathic effect. Although ts 339/NRK cells were quite resistant to parvoviral attack at 39.5 degrees C, they were similarly proficient in MVMp uptake, viral DNA and protein synthesis, and infectious particle production at both permissive and restrictive temperatures. Consistently, electron microscopic examination of infected ts 339/NRK cultures incubated at 39.5 degrees C revealed the presence, in the majority of the cells, of numerous full and empty virions that were predominantly located in autophagic-type vacuoles. Thus, in this system, the reversion of transformed and MVMp-sensitive phenotypes appears to correlate with the setting up of a noncytocidal mode of parvovirus production. These results raise the possibility that the physiological state of host cells may affect their susceptibility to parvoviruses by modulating not only their capacity for virus replication but also cellular processes controlling the cytopathic effect of viral products.

Animals↗
PubMed1981

Sequential cord-sensitive mutations in Aspergillus fumigatus. III. Mechanism of cold sensitivity.

The mechanism of cold sensitivity of Aspergillus fumigatus ON5, a 37 degrees C-sensitive mutant derived from A. fumigatus I-21 (ATCC 32722) by five sequential mutations, was investigated. The rate of in vivo protein synthesis by ON5 was not affected for 2 h following a shift from 45 to 34 degrees C, but the rate of in vivo RNA synthesis dropped almost immediately. The RNA polymerases 2 h following a shift from 45 to 34 degrees C, but the rate of in vivo RNA synthesis dropped almost immediately. The RNA polymerases of ON5 possessed wild-type activity in vitro at a nonpermissive temperature (34 degrees C) indicating that the reduction in the rate of in vivo RNA synthesis did not result from cold sensitivity in transcription, but was possibly a result of rapid feedback inhibition of transcription. Mutant ON5 was not able to produce ribosomes at a nonpermissive temperature as evidenced by the fact that no 3H-labelled amino acids were incorporated into the monosome, large ribosomal subunit, or small ribosomal subunit at 34 degrees C. Ribosomal subunit assembly or ribosomal RNA processing appears, therefore, to be the cold-sensitive cellular function in ON5.

Aspergillus fumigatus↗
PubMed2006

H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+ channels.

Hydrogen peroxide (H(2)O(2)) is a proposed endothelium-derived hyperpolarizing factor and metabolic vasodilator of the coronary circulation, but its mechanisms of action on vascular smooth muscle remain unclear. Voltage-dependent K(+) (K(V)) channels sensitive to 4-aminopyridine (4-AP) contain redox-sensitive thiol groups and may mediate coronary vasodilation to H(2)O(2). This hypothesis was tested by studying the effect of H(2)O(2) on coronary blood flow, isometric tension of arteries, and arteriolar diameter in the presence of K(+) channel antagonists. Infusing H(2)O(2) into the left anterior descending artery of anesthetized dogs increased coronary blood flow in a dose-dependent manner. H(2)O(2) relaxed left circumflex rings contracted with 1 muM U46619, a thromboxane A(2) mimetic, and dilated coronary arterioles pressurized to 60 cmH(2)O. Denuding the endothelium of coronary arteries and arterioles did not affect the ability of H(2)O(2) to cause vasodilation, suggesting a direct smooth muscle mechanism. Arterial and arteriolar relaxation by H(2)O(2) was reversed by 1 mM dithiothreitol, a thiol reductant. H(2)O(2)-induced relaxation was abolished in rings contracted with 60 mM K(+) and by 10 mM tetraethylammonium, a nonselective inhibitor of K(+) channels, and 3 mM 4-AP. Dilation of arterioles by H(2)O(2) was antagonized by 0.3 mM 4-AP but not 100 nM iberiotoxin, an inhibitor of Ca(2+)-activated K(+) channels. H(2)O(2)-induced increases in coronary blood flow were abolished by 3 mM 4-AP. Our data indicate H(2)O(2) increases coronary blood flow by acting directly on vascular smooth muscle. Furthermore, we suggest 4-AP-sensitive K(+) channels, or regulating proteins, serve as redox-sensitive elements controlling coronary blood flow.

4-Aminopyridine↗
PubMed1999

Altered contractile sensitivity of isolated bronchial artery to phenylephrine in ovalbumin-sensitized rabbits.

We tested the hypothesis that atopy and/or allergic lung inflammation enhances alpha1-adrenoceptor-mediated contractions of the bronchial artery. Bronchial arterial resistance vessels were isolated from rabbits that had undergone either systemic ovalbumin (OVA) sensitization followed by saline aerosol challenge (OVA/saline rabbits), or OVA sensitization followed by OVA aerosol challenge (OVA/OVA rabbits), or no sensitization followed by saline aerosol challenge (control rabbits). In OVA/OVA rabbits, bronchoalveolar lavage and lung histology revealed lymphocytic and eosinophilic inflammation. Arterial rings were contracted with phenylephrine (PE). In endothelium-intact arteries isolated from OVA/saline and OVA/OVA rabbits, PE responsiveness was enhanced compared with that of arteries isolated from controls. The nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester increased the contractile response to PE in all three experimental groups to a similar degree, suggesting that depressed NOS activity was not involved in the enhanced PE responsiveness in OVA/saline and OVA/OVA rabbits. After endothelium removal, arteries from OVA/saline and control rabbits showed similar PE responsiveness, indicating that the enhancement of PE responsiveness was endothelium dependent, possibly due to an endothelial constricting factor. In OVA/OVA rabbits, endothelium-denuded arteries showed decreased PE responsiveness compared with the other two groups; this difference was abolished by NG-nitro-L-arginine methyl ester. We conclude that systemic sensitization with OVA per se enhances PE-induced contractions of isolated bronchial arteries in rabbits by an endothelium-dependent mechanism and that allergic lung inflammation attenuates this effect by increased nonendothelial NOS activity.

Animals↗
PubMed2006

In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group.

PURPOSE: In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct association between in vitro and in vivo chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between in vitro sensitivity and therapy outcome. PATIENTS AND METHODS: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five drug combinations using an ATP-based luminescence viability assay. RESULTS: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all study end points (per protocol). The drug combinations used were gemcitabine+treosulfan, paclitaxel+cisplatin, paclitaxel+doxorubicin, and gemcitabine+cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and 31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients compared with 16.1% in chemoresistant patients (P=0.114); progression arrest (complete response+partial response+stable disease) was 59.1% versus 22.6% (P=0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients (P=0.041). CONCLUSION: In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.

Adult↗
PubMed1983

Decreased sensitivity and response of isolated tracheal muscle to methacholine and histamine without changing the activity of pulmonary muscarinic receptors in the egg albumin-sensitized guinea pig.

Guinea pigs were sensitized by daily intraperitoneal injections of 100 mg of egg albumin for 3 consecutive days and sacrificed at 30-35 days after the last injection. The in vitro sensitivity and response of the sensitized tracheal muscle to methacholine and histamine were significantly less than those of littermate controls. However, there was no difference between the dissociation constants and concentrations of pulmonary muscarinic receptor binding sites of the control and sensitized guinea pigs. We conclude that subsensitivity and hyporesponsiveness to methacholine and histamine occur in the airway muscle of this guinea pig model of experimental asthma and suggest that the decreased reactivity to methacholine might be due to defects beyond the receptor.

Animals↗
PubMed2003

Temporally sensitive trophic responsiveness of the adrenalectomized rat anterior pituitary to dexamethasone challenge: relationship between mitotic activity and apoptotic sensitivity.

Depending on timing and dose, exogenous glucocorticoids induce a wave of apoptosis in the adult rat anterior pituitary, a response that is enhanced by adrenalectomy. In this study, we show that the size of the glucocorticoid-sensitive apoptotic population progressively increases during the week following surgical adrenalectomy, plateaus for a further week, then spontaneously declines to levels seen in intact animals by 4 wk. Mitotic activity, in contrast, rises rapidly post adrenalectomy but returns to baseline within 2 wk. Increased mitotic activity precedes the increase in the population of cells that undergo glucocorticoid-induced apoptosis and the subsequent decline in mitotic activity precedes the decline in apoptotic sensitivity despite persistent elevation of hypothalamic CRH and pituitary proopiomelanocortin transcripts. If glucocorticoid exposure is delayed until 4 wk post adrenalectomy when the apoptotic response has returned to baseline, glucocorticoid withdrawal, by transiently increasing mitotic activity, again primes the formation of an expanded glucocorticoid-sensitive apoptotic cell population. These data suggest that apoptotic sensitivity is largely confined to cells that have recently entered the cell cycle. This observation is further corroborated by demonstrating an abrupt glucocorticoid-induced step-down in the bromodeoxyuridine-labeling index to basal levels in rats given daily injections of bromodeoxyuridine during the week following adrenalectomy.

Adrenalectomy↗
PubMed2004

Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity.

We investigated the metabolic actions of ghrelin in humans by examining the effects of acute administration of acylated ghrelin, unacylated ghrelin, and the combination in eight adult-onset GH-deficient patients. We followed glucose, insulin, and free fatty acid concentrations before and after lunch and with or without the presence of GH in the circulation. We found that acylated ghrelin, which is rapidly cleared from the circulation, induced a rapid rise in glucose and insulin levels. Unacylated ghrelin, however, prevented the acylated ghrelin-induced rise in insulin and glucose when it was coadministered with acylated ghrelin. Surprisingly, the injection of acylated ghrelin induced an acute increase in unacylated ghrelin and therefore total ghrelin levels. Finally, acylated ghrelin decreased insulin sensitivity up to the end of a period of 6 h after administration. This decrease in insulin sensitivity was prevented by coinjection of unacylated ghrelin. This combined administration of acylated and unacylated ghrelin even significantly improved insulin sensitivity, compared with placebo, for at least 6 h, which warrants studies to investigate the long-term efficacy of this combination in the treatment of disorders with disturbed insulin sensitivity.

Acylation↗
PubMed1984

The role of bestatin-sensitive aminopeptidase, angiotensin converting enzyme and thiorphan-sensitive "enkephalinase" in the potency of enkephalins in the guinea-pig ileum.

The role of each enkephalin-hydrolyzing peptidase in the inhibitory potency of exogenously added enkephalins in the myenteric plexus-longitudinal muscle preparation of guinea-pig ileum was studied by using the relatively specific inhibitor of each enzyme. Results showed that three distinct enzymes, bestatin-sensitive aminopeptidase(s), angiotensin converting enzyme, and thiorphan-sensitive "enkephalinase", played a critical role in the inactivation of enkephalins. Additionally, these enzymes are likely to be located close to opioid receptors, since they produce a significant concentration difference of enkephalin between the surrounding organ bath and the vicinity of opioid receptors. In contrast to these three enzymes, both L-tyrosyl-L-tyrosine-sensitive dipeptidyl aminopeptidase and D-phenylalanine-sensitive carboxypeptidase are indicated not to be involved significantly in the degradation of exogenously added enkephalins in the guinea-pig ileum.

Amino Acids, Sulfur↗
PubMed2006

Food-induced behavioral sensitization, its cross-sensitization to cocaine and morphine, pharmacological blockade, and effect on food intake.

Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity. Whereas the activity of this group increased with repeated testing, that of a group exposed to the runways but that received the food in the home cage (FH group), or of a group satiated by prefeeding before testing (SAT group), decreased. When exposed to the runways in the absence of food, the paired group was more active than the other groups (conditioned activity); no activity differences were seen in an alternative, non-food-paired, apparatus. Conditioned activity survived a 3-week period without runway exposure. Conditioned activity was selectively reduced by the opiate antagonist naltrexone (10-20 mg/kg) and by the noncompetitive AMPA receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] (5-10 mg/kg). The D1 antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] (15-30 microg/kg) and D2 antagonist sulpiride (25-125 mg/kg) reduced activity nonspecifically. A single intraperitoneal dose of cocaine (10 mg/kg) or morphine (20 mg/kg) increased activity compared with saline, the stimulant effect being larger in the FR group, suggesting "cross-sensitization" to these drugs. However, pretreatment with GYKI 52466 or naltrexone at doses that suppressed conditioned activity in FR animals suppressed cross-sensitization to cocaine. When allowed ad libitum access to food in the runway, FR mice consumed more pellets in a time-limited test. Thus, many of the features of behavioral sensitization to drugs can be demonstrated using food reward and may contribute to excessive eating.

Analgesics, Opioid↗
PubMedDate not supplied

Heat sensitization to cisplatin in two cell lines with different drug sensitivities.

Heat sensitization to cisplatin was studied in drug-sensitive Chinese hamster fibroblast (CH) and inherently drug-resistant hamster kidney (HaK) cells. Under normothermic conditions the slopes of the survival curves differed by a factor of 3.6, while the cellular uptake was higher in CH cells by a factor of 3. When heat and drug treatment were given simultaneously, both effects were increased in CH and HaK cells: thermal enhancement factors at 43 degrees C were 5.5 (CH) and 2.9 (HaK) for cytotoxic drug action and 3.9 and 2.2 for the increase in cellular drug content. Increase in cell sensitization was also obtained if the cells were heat pretreated (42.5-44 degrees C for various times) followed by drug exposure at 37 degrees C. It is concluded that thermal enhancement depends on the efficiency of cisplatin cytotoxicity, which in turn correlates with cellular drug uptake in both the sensitive and resistant cell line.

Animals↗
PubMed1989

Further characterization of drug-sensitivity and cross-resistance profiles of cloned cell lines of Adriamycin-sensitive and -resistant P388 leukemia.

The drug-sensitivity and cross-resistance profiles of cloned cell lines of Adriamycin-sensitive and -resistant P388 murine leukemia have been further characterized. A range of drug sensitivity that was more than 50,000-fold was observed for Adriamycin-sensitive cells; the most potent cytotoxic agent was the Adriamycin analog, 3'-(3-cyano-4-morpholinyl)-3'-deamino adriamycin, and the least active compound was vinblastine. Adriamycin-resistant cells, which express the multidrug resistance phenotype, were cross-resistant to the DNA topoisomerase II interactive drugs: actinomycin D, daunorubicin, mitoxantrone, etoposide, and 4'-(9-acridinyl-amino)methanesulfon-m-anisidide, to the vinca alkaloids: vincristine and vinblastine, and to colchicine but not to the Adriamycin analog, 3'-(3-cyano-4-morpholinyl)-3'-deamino adriamycin or the alkylating agent, melphalan. These findings are consistent with other studies suggesting that 3'-(3-cyano-4-morpholinyl)-3'-deamino adriamycin acts as an alkylating agent. Studies with DNA topoisomerase II interactive agents, including mitoxantrone, the DNA intercalator, and etoposide, the epipodophyllotoxin, showed that, as with Adriamycin, cytotoxicity correlated closely with the formation of DNA double-strand breaks.

Amsacrine↗
PubMed1998

[Sensitized photomodification of DNA with binary systems of oligonucleotide conjugates. III. Double-quantum sensitization].

Site-specific modification of single-stranded DNA by oligonucleotide derivatives of p-azido-O-(4-aminobutyl)tetrafluorobenzaldoxime sensitized by an oligonucleotide derivative of pyrenylethylamine was studied. Upon irradiation with the long-wave UV light (365-390 nm) of a DNA target-oligonucleotide reagent complementary complex, a considerable increase in the rate of sensitized photomodification at the G11 residue of the target relative to the direct photomodification was observed owing to the singlet-single energy transfer from the sensitizer onto the photoreagent. Upon simultaneous irradiation of the complex with UV and visible light in the region of the triplet-triplet absorption of pyrene (360-580 nm), an additional increase in the modification rate and a change in its site-direction (from the G11 to T13 residue) occurred through the two-photon triplet-triplet sensitization. The total extent of the structure photomodification amounted to 80%.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2000

[Acetylsalicylic acid effects on pain sensitivity to myocardial ischemia and skin sensitivity in patients with angina pectoris].

AIM: To clarify if pain-relieving action of acetylsalicylic acid (ASA) is associated with lowered sensitivity of anginal patients to pain due to myocardial ischemia. MATERIALS AND METHODS: A double blind randomized placebo-controlled trial enrolled 10 males aged 42-69 years with stable effort angina (EA) of functional class II-III. When exposed to exercise tolerance test (treadmill, stress-system Sicard 460S, computed ECG), the patients developed EA attack with at least 1 mm decline of ST segment on ECG. The exercise test was made before, 2 and 4 hours after administration of ASA and placebo. Sensitivity to ischemia was estimated by the total depth of the ST segment decline in 11 ECG leads (sigma ST) registered at the attack onset. Tactile and pain thresholds (TT and PT) were studied with a highly reproducible technique. TT and PT were measured before, 2 and 4 hours after ASA and placebo administration. RESULTS: 2 and 4 hours after intake of 100 mg of ASA, sigma ST and TT significantly rose compared to the baseline level and placebo. PT significantly rose vs the baseline level. CONCLUSION: ASA deteriorates sensitivity of anginal patients to myocardial ischemia, skin tactile and pain sensitivity and thus can deprive the EA patient of the pain attack signal. This leads to the risk of overexercising and emergence of painless myocardial ischemia.

Adult↗
PubMed2001

Differential sensitivity of Kv1.4, Kv1.2, and their tandem channel to acidic pH: involvement of a histidine residue in high sensitivity to acidic pH.

We studied the effects of acidic pH on the currents through voltage-gated K+ channels, Kv1.2, Kv1.4, and their tandem construct (Kv1.4-Kv1.2). Kv1.4 currents were inhibited considerably under acidic pH in a voltage-independent manner, whereas Kv1.2 currents were less inhibited in an apparently voltage-dependent manner. The apparent voltage-dependent block of Kv1.2 currents was mostly ascribed to the shift of activation voltage, which is probably due to surface charge effects of H+ ions. Mutagenesis analysis identified the histidine residue at 508 (H508) in the S5-H5 linker as a molecular determinant of pH sensitivity of Kv1.4. Currents through the tandem channel showed intermediate characteristics between the two parent channels in both sensitivity and voltage dependence of pH effects. Our results suggest that 1) the H508 plays a critical role in determining pH sensitivity of Kv1.4; and 2) the two parent channels, Kv1.2 and Kv1.4, are involved in determining pH sensitivity and apparent voltage dependence of the tandem channel.

Amino Acid Sequence↗