After a hundred years of using hormonal therapy for the treatment of breast cancer, and developments since 1942 in chemotherapy, combining the two modalities seemed a logical next step. However, trials using tamoxifen plus cyclophosphamide, methotrexate, and 5-FU, or dibromodulcitol and doxorubicin with tamoxifen showed no improvement in survival, and considerable toxicity. But it was learned from these trials that breast cancers exhibit cellular heterogeneity with regard to estrogen-receptor status and that hormonal therapy and chemotherapy have different actions and toxicity. Also, cell cycle specific agents are most effective against rapidly dividing cells. Further trials utilizing these concepts are warranted, although routine use of combined chemohormonal therapy is not yet recommended.
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The aim of this study was to establish whether fexofenadine hydrochloride, an antihistamine, modulates daytime sleepiness or performance.
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The hypoxic effects of salbutamol 200 micrograms (CAS 18559-94-9) and bitolterol mesilate 740 micrograms (Biterol, CAS 30392-41-7), both administered by pressurized aerosol, were assessed by transcutaneous pO2 monitoring in 18 asthmatic subjects and in 12 normal volunteers. Unlike the latter, the asthmatics showed a highly significant difference in ptcO2 time course after the two drugs. After bitolterol mesylate the decrease in ptcO2 was much more gradual and the maximal decrease showed a 10-min time lag vs. salbutamol, which may partly explain the well known chronotropic effect of bitolterol. The clinical importance of the beta 2-induced hypoxemia may be related more to the dynamics of the ptcO2 decrease than to its absolute magnitude, which is usually fairly moderate.
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Information reviewed included package inserts, data obtained from manufacturers, and articles published in MEDLINE (1966 to December 2001). Medications examined included presently available and potentially approved OTC antiinflammatory, gastrointestinal, and antihistamine drugs.
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The aim was to compare possible effects of verapamil, as a P-glycoprotein (P-gp) inhibitor, on the pharmacokinetics of each fexofenadine enantiomer, as a P-gp substrate.
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We developed an assay which permits measurement of aspartate carbamoyltransferase (ACTase) activity. Cytosol from human peripheral blood mononuclear cells was used as the enzyme source. Using [14C]carbamoyl phosphate as the radiolabeled substrate, the formation of [14C]carbamoyl aspartate was quantitated by high performance liquid chromatography (HPLC) using an anion-exchange column with UV detection at 200-280 nm and an on-line liquid scintillation detector. A gradient method from an initially low concentration of ammonium phosphate, 1 mM (pH 3.0), to a higher concentration, 38 mM (pH 4.5), was used. The apparent Km values of carbamoyl phosphate and aspartate were 58 microM and 1.9 mM, respectively. ACTase inhibition by N-(phosphonacetyl)-l-aspartate (PALA) was consistent with a competitive model with respect to carbamoyl phosphate. The assay conditions were optimized to permit measurement of ACTase activity prior to and following therapy with PALA; ACTase was inhibited in a dose-dependent manner. This HPLC method permits direct quantitation of both the product of the reaction and the initial integrity of the substrate, [14C]carbamoyl phosphate, which is unstable in aqueous solutions.
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Pregnancy is a remarkable ground for studying the biopsychosocial perspective of psychosomatics, because there is a close correlation between biological conditions, that quickly change in time, and emotional implications that are this result of women psychological structure, her psychosexual maturation degree and her social and environment past and present influences.
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Baseline SAI was significantly reduced in AD patients. In the control subjects rPAS induced a significant increase in MEP amplitudes and a decrease of SAI in the APB muscle persistently for up to 1 h. Conversely 5Hz-rPAS did not induce any significant changes in MEP amplitudes and SAI in mild AD patients.
Data collected from 613 children aged 2-14 years who had been hospitalized for acute bronchitis, wheezing, or pneumonia were analysed to evaluate the prescribing practices of pediatricians treating community-acquired lower respiratory tract infection. Antibiotics were prescribed for 92.1% of the children: 85% had acute bronchitis, 72% had wheezing, and 97.9% had pneumonia. A high frequency of antibiotic overuse and inappropriate prescriptions was noted. In order to contain costs and limit the risk of resistant bacteria emerging, it is urgent that pediatricians and parents be educated in the proper use of antibiotics.
Twelve patients with clinical and laboratory findings typical of essential mixed cryoglobulinemia, type II (EMC II) underwent multiple liver and bone marrow biopsies. In 9 of 12 cases (all hepatitis B surface antibody-negative), routine histology revealed patent infiltration of liver portal tracts, lobules and sinusoids by small lymphocytes provided with cytological characteristics closely resembling those of the LP immunocytoma of the Kiel classification. At immunophenotyping on frozen sections, these elements expressed the CD22 antigen (marker of B cells) and bore the same type of immunoglobulin (IgM/k = 8, IgM/lambda = 1) as the monotypic component in the serum. Furthermore, in 7 of 9 patients repeated bone marrow needle biopsies showed multiple foci of infiltration by plasmacytoid cells, often with paratrabecular location. In the remaining 3 cases (all hepatitis B surface and core antigen-positive), liver biopsies were consistent with a diagnosis of cirrhosis (two) or chronic active hepatitis (one). In two of them, however, Jamshidi needle biopsy evidenced bone marrow infiltrates quite similar to those observed in the other group. On the basis of these findings, the authors discuss the hypothesis that most EMC II are substained by a low-grade malignant lymphoma.
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Our results are consistent with the hypothesis that the TNFalpha system could be involved in the regulation of plasma leptin concentrations in obese subjects.
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Potency of the antihistamine effects of olopatadine, cetirizine and fexofenadine in standard-dose application were compared from 11.5 to 24 h after application. The test was designed in a double-blind, randomized, crossover, placebo-controlled study of ten healthy volunteers on histamine-induced flare and wheal response using an iontophoresis technique. The suppressive effect of olopatadine on the wheals induced by a 0.1-mA histamine iontophoresis lasted for 24 h after dosing. Fexofenadine administered using the same regimen was the least effective among three drugs tested. Suppression of the wheal response by cetirizine, taken once-daily, decreased with time. Olopatadine completely suppressed even the wheal response induced by a 0.2-mA histamine iontophoresis, although fexofenadine and cetirizine were less effective on the wheals induced by the same histamine challenge. There were no significant differences in subjective drowsiness and objective cognitive function between drug- and placebo-treated subjects. These results demonstrate that olopatadine is the most potent antihistamine among the three H(1)-blockers when administered in a standard dosage.
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Since most classical (first-generation) antihistamines have undesirable sedative effects on the central nervous system (CNS), newer (second-generation) antihistamines have been developed to relieve the sedative effects and to improve the patient's quality of life. However, the psychomotor profiles of second-generation antihistamines are not fully elucidated. In this randomized, double-blind, crossover study, the acute effects of single doses of second-generation antihistamines, fexofenadine (120 mg) and olopatadine (10 mg), on cognitive and psychomotor performance were investigated in comparison with those of placebo and d-chlorpheniramine (4 mg), a first-generation antihistamine, using objective and subjective assessments, in 11 healthy Japanese volunteers. In a battery of psychomotor tests, d-chlorpheniramine impaired tracking ability in the compensatory tracking task and caused a reduction in behavioural activity as continuously measured by wrist actigraphy. Olopatadine, like d-chlorpheniramine, reduced the behavioural activity, while fexofenadine had no effect in any of the tests. No significant changes in the subjects' self-ratings of drowsiness were found with the three antihistamines. These results suggest that d-chlorpheniramine and olopatadine, but not fexofenadine, produce sedative effects on psychomotor performance, and that the CNS profile of fexofenadine is different from that of olopatadine.
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Spontaneous cervical epidural hematoma is a rare cause of neck pain. We present the case of a 64-year-old woman who presented to the emergency department with neck pain from a partial Brown-Sequard syndrome secondary to spontaneous cervical epidural hematoma. The prompt recognition of this entity resulted in a favorable outcome.
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Combination therapy is more effective than fexofenadine alone or pseudoephedrine alone in relieving the full spectrum of SAR symptoms (ie, both the primarily histamine-related symptoms and nasal congestion).
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Antihistamines are a mainstay treatment for allergic rhinitis; however, many older agents cause adverse events, including sedation and central nervous system (CNS) impairment. Research has shown sedating effects of antihistamines on driving; currently, no known study has examined whether cellular phone usage while driving further compounds impairment in individuals administered antihistamines. The aim of this study was to examine this endpoint. In a randomized, double-blind, placebo-controlled, three-way crossover study, healthy volunteers received fexofenadine HCl 120 mg, hydroxyzine HCl 30 mg and placebo. Brake reaction time (BRT) was used to examine driving performance across four conditions: driving only; driving while completing simple calculations; complex calculations; and conversing on a cellular phone. Subjective sedation assessments were also conducted. Brake reaction time with and without cellular phone usage in fexofenadine-treated subjects did not differ significantly from placebo in any condition. In contrast, hydroxyzine-treated subjects were significantly more sedated and had slower BRTs, suggesting slower hazard recognition and brake application, compared with the fexofenadine and placebo groups in all conditions. Importantly, cellular phone operation was an additive factor, increasing BRTs in hydroxyzine-treated volunteers. Fexofenadine did not impair CNS function in subjects involved in a divided attention task of driving and cellular phone operation.
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Individuals were divided based on the genotype of SLCO2B1 c.1457C> T (n = 14, c.[1457C]+ c.[= ] 5,c.[1457C]+ c.[1457C> T] 5, and c.[1457C> T]+c.[1457C> T] 4). The oral pharmacokinetics of 60 mg fexofenadine and 5mg midazolam were assessed with water or apple juice (1200 ml/day) in a randomized crossover study. OATP2B1-mediated uptake of fexofenadine and midazolam was evaluated with Xenopus laevis oocyte gene-expression system.
Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K(+) current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K(+) current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results- We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is approximately 350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block.
Recently, folate-dependent enzymes in the de novo thymidine and purine biosynthetic pathways have come under scrutiny as potential sites for chemotherapeutic exploitation by antifolates. In this manuscript we report on the progress that has been made in designing inhibitors of these pathways. In addition, a molecular model is proposed for the design of new antifolates directed against thymidylate synthase (TS).
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The three active treatments clearly inhibited the wheal and flare areas throughout the 24-hour period compared with placebo. Maximal inhibition occurred at 4 hours postdose. Between 4 and 24 hours postdose, the time course of inhibition by cetirizine differed significantly (P < 0.001) from that by fexofenadine at either dose, which did not differ from each other. At 24 hours, fexofenadine inhibited <40% of the skin reaction, whereas cetirizine reduced 60% of the wheal. The duration of effect, considered as the time for wheal to be inhibited by at least 70%, also significantly favored cetirizine (19 hours) compared with fexofenadine (9.3 and 8.5 hours for 180 and 120 mg, respectively; P < 0.001). Consistency of activity was evaluated by the frequency of total inhibition of the wheal (> or =95%). Consistency was observed in 26 of 26 participants for cetirizine, 21 of 26 for fexofenadine, 180 mg, and 10 of 26 for fexofenadine, 120 mg (P < 0.001), suggesting better consistency for cetirizine. There was no serious adverse event.
Understanding the molecular and cellular processes underlying melanoma plasticity and heterogeneity is of paramount importance to improve the efficiency of current treatment and to overcome resistance to chemotherapy drugs. The notion of plasticity and heterogeneity implies the existence of melanoma cell populations with different phenotypic and tumorigenic properties. Using melanoma cell lines and melanoma cells freshly isolated from patient biopsies, we investigated the relationship between ABCB5+, CD271+ and low-MITF, expressing populations that were reported to display melanoma initiating cell properties. Here, we showed that ABCB5+ and CD271+ populations poorly overlap. However, we found that the CD271+ population is enriched in low-MITF cells and expresses a higher level of stemness genes, such as OCT4, NANOG and NES. These features could explain the increased tumorigenicity of the CD271+ cells. The rapid conversion of CD271+ to CD271- cells in vitro demonstrates the plasticity ability of melanoma cells. Finally, we observed that the transient slow-growing population contains only CD271+ cells that are highly tumorigenic. However, the fast growing/CD271+ population exhibits a poor tumorigenic ability. Taking together, our data show that CD271 is an imperfect marker for melanoma initiating cells, but may be useful to identify melanoma cells with an increased stemness and tumorigenic potential.
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Here we present a new procedure aimed at improving the sensitivity and/ or specificity of poorly-performing patterns. The procedure can be summarised as follows: 1. residues structurally conserved in different proteins, that are true positives for a pattern, are identified by means of a computational technique and by visual inspection. 2. the sequence positions of the structurally conserved residues falling outside the pattern are used to build extended sequence patterns. 3. the extended patterns are optimised on the SWISS-PROT database for their sensitivity and specificity. The method was applied to eight PROSITE patterns. Whenever structurally conserved residues are found in the surface region close to the pattern (seven out of eight cases), the addition of information inferred from structural analysis is shown to improve pattern selectivity and in some cases selectivity and sensitivity as well. In some of the cases considered the procedure allowed the identification of functionally interesting residues, whose biological role is also discussed.
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The study population consisted of 45 patients with adenocarcinoma arising in the gastrointestinal tract. Thirty-seven patients received therapy containing IFN alpha-2a at a median dose of 5 million U/m2 per day (range, 1.7-7.5 million U/m2 per day) starting on day 1 and continuing through either day 7 or day 14 in conjunction with intravenous high-dose leucovorin (LV) followed by bolus 5-FU on days 2-6. Eight patients received the same schedule of 5-FU and LV daily for 5 days without IFN alpha-2a but with granulocyte-macrophage colony-stimulating factor starting on day 6 and ending at least 3 days prior to the start of the next cycle. Peripheral blood was collected during 70 cycles on days 1, 2, and 4 prior to the daily treatment with IFN alpha-2a + 5-FU+LV and during 19 cycles on days 1 and 4 prior to the daily treatment with 5-FU+LV without IFN alpha-2a. In a given patient cycle, matched samples were drawn at approximately the same time of day. PBMCs were isolated, and the intact cells were exposed to 4 microM [3H]5-FU, and the formation of [3H]dihydrofluorouracil was determined by reverse-phase high-performance liquid chromatography.
Predictive saccadic and vergent eye movements induced many common sites of significant functional cortical activity including: the dorsolateral prefrontal cortex (DLPFC), parietal eye field (PEF), cuneus, precuneus, anterior and posterior cingulate, and the cerebellum. However, differentiation in spatial location was observed within the frontal lobe for the functional activity of the saccadic and vergent network induced while studying prediction. A paired t-test of the beta weights from the individual subjects showed that peak activity induced by predictive versus random vergent eye movements was significantly (t > 2.7, p < 0.03) more anterior within the frontal eye field (FEF) and the supplementary eye field (SEF) when compared to the functional activity from predictive saccadic eye movements.