Enhancement of theophylline clearance by oral albuterol.

The possible effect of albuterol on theophylline clearance was studied in ten adult volunteers. Subjects received intravenous aminophylline loading dose (5.6 mg/kg), with oral albuterol (4 mg every 6 h), or inhaled albuterol (200 micrograms every 6 h), or alone (control). Theophylline levels were determined for 12-h periods. Theophylline clearance and elimination t 1/2 were calculated. Theophylline clearance was significantly higher when given with oral albuterol, in comparison with control (0.83 +/- 0.05 vs 0.73 +/- 0.06 ml/kg/min, p less than 0.02). Theophylline elimination t 1/2 was shorter with the coadministration of oral albuterol, compared with control (7.1 +/- 0.3 vs. 8.1 +/- 0.6 h, p less than 0.02). These alterations in theophylline clearance and elimination were greater in subjects who had lower control theophylline clearance. Theophylline clearance and elimination t 1/2 recorded with inhaled albuterol were not significantly different from control values. Coadministration of oral albuterol and theophylline resulted in enhancement of theophylline clearance, particularly in subjects with initially slow theophylline elimination. Such patients may require theophylline dosage adjustment as a result of this interaction.     

Enhancement of theophylline clearance by intravenous albuterol

Co-administration of intravenous albuterol and theophylline resulted in increased theophylline clearance in a child with severe asthma. This required a threefold increase in theophylline dosage to maintain therapeutic serum theophylline concentrations. The possible effect of intravenous albuterol on theophylline metabolism was further supported by a 50 percent decrease in theophylline clearance upon discontinuation of albuterol and a second increase in its clearance when albuterol was readministered. To the best of our knowledge, this is the first documentation of enhanced theophylline clearance by albuterol.     

Human basophil releasability. VIII. Increased basophil releasability in patients with scleroderma.

We evaluated basophil releasability in 16 female patients with scleroderma (systemic sclerosis) and in 16 normal age- and sex-matched donors. Basophils from patients with scleroderma released significantly more histamine "spontaneously" than did those from normal donors (12.9 +/- 2.1% versus 4.5 +/- 0.7%; P less than 0.0005). Basophil reactivity (maximal percentage histamine release) to anti-IgE was higher in patients with scleroderma than in controls (57.0 +/- 7.5% versus 35.4 +/- 7.8%; P less than 0.05). Basophil sensitivity (the concentration of anti-IgE that causes 40% of maximal percentage histamine release) to anti-IgE in scleroderma patients was similar to that found in controls (4.6 +/- 2.8 x 10(-2) micrograms/ml versus 2.3 +/- 1.0 x 10(-1) micrograms/ml; P not significant). Scleroderma patients also showed enhanced releasability compared with that of the controls when challenged in vitro with interleukin-3 (8.3 +/- 1.7% versus 3.2 +/- 0.6%; P less than 0.01). Releasability induced by the formyl-containing tripeptide, f-met peptide, was significantly higher in the scleroderma patients than in the controls at the 2 lower concentrations used. No differences in basophil reactivity and sensitivity to f-met peptide and calcium ionophore A23187 were found between patients and normal donors. These results show that spontaneous basophil releasability and releasability in response to IgE cross-linking and activation of interleukin-3 receptors are increased in patients with scleroderma.     

Enhancement of stress-induced apoptosis in B-lineage cells by caspase-9 inhibitor

We have established human B-lineage (BLIN) acute lymphoblastic leukemia cell lines that retain a dependency on fibroblast monolayers for survival and proliferation. Eight hours following removal from adherent cell contact BLIN cells undergo a decrease in mitochondrial transmembrane potential and an increase in annexin V binding. Unexpectedly, the caspase-9 inhibitor (C9i) benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethylketone enhanced the appearance of apoptotic cells within 8 hours following removal of BLIN cells from fibroblast monolayers. C9i enhancement of apoptosis was dose dependent and did not occur with irreversible inhibitors of caspases-2, -3, -6, and -8. C9i also enhanced apoptosis in cord blood-derived CD19(+) B-lineage cells (but not myeloid cells) removed from murine stromal cells. Longer exposure (> 18 hours) to C9i culminated in apoptosis in a panel of B-lineage acute lymphoblastic leukemia (ALL) cell lines in the presence or absence of fibroblast monolayers, as well as in 2 proliferating leukemic cell lines (RAMOS and CEM). BLIN-4L cells made deficient in caspase-9 by RNA interference exhibited no resistance to apoptotic signals and actually showed increased apoptotic sensitivity to staurosporine. These collective results suggest that a 4-amino acid caspase inhibitor of caspase-9 can promote apoptosis and that at least some types of apoptotic pathways in B-lineage ALL do not require caspase-9.     

Human basophil releasability. VI. Changes in basophil releasability in patients with allergic rhinitis or bronchial asthma.

We evaluated basophil releasability in two groups of allergic patients with positive skin tests to Dermatophagoides pteronyssinus major allergen (Der p l) (29 adults with bronchial asthma and 17 with allergic rhinitis) and in 31 age-matched normal donors. Both basophil reactivity (maximal percent histamine release) and basophil sensitivity (the concentration that causes 50% of maximal percent histamine release: HC50) to Der p l in patients with asthma were similar to those in patients with allergic rhinitis. On the contrary, basophil reactivity to anti-IgE was significantly higher in patients with asthma (58.0 +/- 3.6%) than in patients with allergic rhinitis (46.3 +/- 5.2%; p less than 0.05). Both groups of patients showed an increased releasability compared to control subjects (27.3 +/- 4.6%; p less than 0.001), whereas there were no significant differences in basophil sensitivity to anti-IgE among the three groups of donors. Differences were also found with respect to basophil reactivity and sensitivity to f-met peptide, whereas no differences appeared when basophils from the three groups of donors were challenged with the Ca2+ ionophore A23187. There was a significant correlation between basophil reactivity and sensitivity to Der p l and to anti-IgE in both asthmatic and allergic rhinitis patients. A significant correlation was found between basophil reactivity and sensitivity to anti-IgE and serum IgE level only in patients with bronchial asthma, whereas no correlations were found in patients with allergic rhinitis. There was no correlation between in vivo mast cell releasability and in vitro basophil releasability in response to Der p l in either group of allergic patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of colonic glycoprotein synthesis by dibutyryl cyclic AMP and theophylline.

The effects of dibutyryl cyclic AMP (B2cAMP) and theophylline on glyoprotein synthesis in rabbit colon were studied in mucosal organ cultures using [3H]glucosamine as a precursor. Addition of B2cAMP (1 mm) to culture medium caused a significant increase in glycoprotein synthesis after 12 and 24 hr compared with biopsies cultured in control medium. The increase in glycoprotein synthesis was observed only if the cyclic nucleotide was present continuously in the incubation medium for at least 12 hr. The stimulatory effect of B2cAMP on [3H]glucosamine incorporation was blocked by cycloheximide. B2cAMP also stimulated mucosal uptake of glucosamine into the intracellular pool and markedly enhanced specific activity of mucosa galactosyltransferase, an enzyme involved in glycoprotein synthesis. Addition of 5mM theophylline caused a greater than 2-fold increase in cAMP levels, which was also accompanied by an increase in glucosamine uptake and incorporation into mucosal glycoproteins. This study demonstrates that elevation of intracellular cAMP concentration in colon epithelium in vitro is associated with an increase in glycoprotein synthesis. These effects may be mediated in part by (1) increased uptake of glycoprotein precursors such as glucosamine, and (2) increased activity of glycoprotein synthetic enzymes.     

Adenosine-induced bronchoconstriction in asthma. Antagonism by inhaled theophylline

Inhaled adenosine causes bronchoconstriction in asthmatic patients. Antagonism of the bronchoconstrictor effect of endogenous adenosine has been proposed as a possible mechanism of action of theophylline in asthma. To directly investigate this, we have compared the airway responses to inhaled adenosine and histamine, with and without the prior administration of inhaled theophylline in 8 allergic asthmatic subjects. Airway response was measured both as forced expiratory volume in one second (FEV1) and as specific airway conductance (SGaw). Inhaled adenosine was less potent than histamine in producing bronchoconstriction, with geometric mean concentrations required to produce a 20% fall of FEV1 (PCf20) and a 40% fall of SGaw (PCs40) being 0.27 and 0.25 mg/ml for adenosine and 0.10 and 0.09 mg/ml for histamine. In a total nebulized dose of 37.5 mg, inhaled theophylline was a weak bronchodilator that caused maximal increases in FEV1 of 2 +/- 2% (mean +/- SE, p less than 0.05) and in SGaw of 8 +/- 4% (p greater than 0.05). However, theophylline significantly inhibited adenosine-induced bronchoconstriction, increasing the PCf20 and PCs40 values for adenosine to 1.66 (p less than 0.001) and 2.34 (p less than 0.005) mg/ml, respectively. Inhibition of histamine-induced bronchoconstriction was less marked, with PCf20 and PCs40 values of 0.19 (p greater than 0.05) and 0.21 (p less than 0.05) mg/ml. Thus, adenosine is a bronchoconstrictor in asthma whose effects are preferentially antagonized by concentrations of theophylline that cause little change in baseline airway caliber.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nonlinear theophylline pharmacokinetics. A preventable cause of iatrogenic theophylline toxic reactions

When theophylline is used for the treatment of patients with obstructive pulmonary diseases, most clinicians attempt to maintain serum levels between 55 and 110 mumol/L because higher levels are associated with an increased risk of serious toxic effects. Nonlinear theophylline kinetics are known to occur in animals, in some pediatric patients, and at very high toxic levels in adults. However, within the usual therapeutic range of serum levels, first-order kinetics are assumed to operate, and, thus, a one-compartment model or a model-independent approach is routinely used for dose adjustments. We have recently encountered two adult patients in whom nonlinear theophylline kinetics existed within the subtherapeutic and therapeutic range of serum levels. In both cases this was not immediately recognized by the clinician, resulting in prolonged use of subtherapeutic doses of theophylline. In addition, in one case our empiric attempts to achieve therapeutic serum levels resulted in serious theophylline toxicity. We present only the data from this latter patient to be used as a case study. Based on this example and a review of the literature, we propose that to avoid such a potentially fatal complication the following steps should be taken when dealing with a patient in whom serum theophylline levels fail to rise as expected with increasing oral doses: (1) supervised administration of oral theophylline to rule out noncompliance; (2) discontinuation of further empirical increases of the oral dose of theophylline; (3) obtention of steady-state serum levels on at least two different oral doses of theophylline; and (4) calculation of the appropriate maintenance dose of theophylline for that individual patient using any of the methods cited in this report.     

Anaphylaxis caused by cloxacillin: diagnosis with seriated analysis by way of basophil activation test.

We report a case of anaphylaxis caused by cloxacillin in a 13-year-old patient. The basophil activation test, performed 25 days after the anaphylactic reaction, was positive to cloxacillin, amoxicillin, and penicillin G and negative to ibuprofen, tolerated by the patient. The analysis was performed 17 days after the reaction was not conclusive because 74% of the basophil population was activated in basal conditions. The abnormally high activation was similar to that found in an analysis before the reaction, exactly 4 days after finishing a well-tolerated treatment with amoxicillin. This first analysis was available because a patient's sample was taken from the emergency laboratory as a blind control for a study to assess the basophil activation test reliability in diagnosis of hypersensitivity to NSAIDs. The high number of activated basophils in basal conditions after treatment with amoxicillin and before the anaphylactic reaction to cloxacillin probably reflects the beginning of the sensitization. Until now, no cases of hypersensitivity to cloxacillin have been diagnosed by means of the basophil activation test.     

Study of IgE-dependent basophil releasability in allergic patients.

For this study, venous blood from 160 patients with a diagnosis of asthma and/or rhinitis was used. Histamine release test (H.R.T.) with anti-IgE at 1/5 and 1/25 dilutions and with causal antigen in the case of atopic patients (144) was carried out on all patients. Basophils from atopic patients released more histamine than those from nonatopic patients (p < 0.001). Basophils of atopic patients released more histamine with 1/5 anti-IgE dilution (p < 0.01), while non-atopic patients did so with the 1/25 dilution (p < 0.05). On grouping atopic patients according to positive or negative results in Ag-specific histamine release, 14% of patients presented negative Ag-specific H.R.T. and 85.7% of the cases did not respond to anti-IgE stimulus; this was 12% of the total number of atopics. On the other hand, 17% of the patients studied did not show positive histamine release against anti-IgE and 70.6% of them had negative Ag-specific release. As for the effect of age on IgE-dependent histamine release, the group of patients who presented greater releasability corresponded to those older than 6 years of age. The discrepancies observed between the clinical history, skin tests, serum IgE and antigen-dependent histamine release in some patients could be related to the individual basophil ability to release histamine. Therefore, this basophil releasability evaluation has an important practical application in discerning false negatives in antigen-specific H.R.T.     

Ocular allergy treatment comparisons: Azelastine and olopatadine

Azelastine hydrochloride 0.05% and olopatadine hydrochloride 0.1% are topical ocular allergy treatments that have demonstrated multiple pharmacologic actions, including antihistamine, mast cell stabilization, and inhibition of proinflammatory mediators. In this article, the mechanisms of action, efficacy, and tolerability of these two agents on ocular signs and symptoms are examined. By studying the various target sites of drug action, an enhanced clinical response algorithm of these topical ocular agents can be implemented to maximize the response for patients suffering from ocular allergy.     

Modulation by theophylline and enprofylline of the excitatory non-cholinergic transmission in guinea-pig bronchi.

The mechanism of action of xanthines in asthma remains controversial. Since sensory innervation may play a role in the pathogenesis of asthma, we investigated whether xanthines were capable of reducing the contractile response of the bronchi to nerve stimulation. In guinea-pig bronchi in vitro, electrical field stimulation (EFS: 40 V, 16 Hz, 0.2 ms during 10 s) induces a rapid cholinergic contraction followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. We measured isometric neuronally-mediated contractions of bronchial smooth muscle and studied the effects of increasing concentrations of two xanthine derivatives, theophylline, an antagonist of adenosine receptors, and enprofylline, which has no effect on adenosine receptors. Both enprofylline (1-50 microM) and theophylline (10-100 microM) inhibited, in a concentration-dependent manner, the peptidergic contraction, an effect which was more marked with enprofylline than theophylline (EC50 = 9.6 +/- 0.7 microM and 62.0 +/- 4.7 microM, respectively). Conversely, the cholinergic response was unaffected. Contractions induced by exogenous substance P (0.03-3 microM) were also unaffected by theophylline and enprofylline at the above mentioned EC50s. Our results suggest that concentrations of theophylline, similar to those used therapeutically, reduce the release of sensory neuropeptides from C-fibre endings. This effect is unrelated to adenosine receptor blockade, since enprofylline had a similar inhibitory effect.     

Improved quality of life among seasonal allergic rhinitis patients treated with olopatadine HCl nasal spray 0.4% and olopatadine HCl nasal spray 0.6% compared with vehicle placebo.

Seasonal allergic rhinitis (SAR) exerts a significant adverse impact on health-related quality of life (QoL) and productivity of those who suffer from it. Unfortunately, some therapies for SAR also have a negative impact. Therefore, it is important to scrutinize the influence of new SAR therapies on patients' QoL and ability to function. The purpose of this study was to evaluate the effect of a new nasal antihistamine, olopatadine, on QoL in SAR patients. In a multicenter, randomized, double-blind SAR study comparing olopatadine 0.6 and 0.4% to placebo nasal spray, patients completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at baseline and after 2 weeks of treatment. The RQLQ is a validated questionnaire that addresses overall QoL and 7 domains of impairment associated with rhinoconjunctivitis (activities, sleep, non--nose/eye allergy symptoms, practical problems, nasal symptoms, eye symptoms, and emotional impairment). The overall RQLQ mean changes from baseline with olopatadine 0.6% (-1.1 +/- 1.4) and 0.4% (-1.1 +/- 1.3) nasal sprays were superior (p < 0.05) to placebo (-0.8 +/- 1.2). Olopatadine spray 0.6% was superior to placebo in six of the seven RQLQ domains and olopatadine 0.4% was superior to placebo in five RQLQ domains (p < 0.05). The correlation between the olopatadine 0.6% mean total symptom scores and mean RQLQ score was r = 0.66 (p < 0.0001), indicating that the enhancement in QoL derived from olopatadine therapy was significantly associated with symptom reduction. Olopatadine nasal spray is an effective antiallergy medication that significantly improves the QoL of patients suffering from SAR.     

Enhancement of colony-stimulating activity production by lithium.

Since lithium causes granulocytosis in some patients, its effect upon granulocyte production was investigated using mouse marrow in the agar culture system. When lithium was added to semisolid cultures of mouse marrow, there was no stimulation of colony formation in the absence of colony-stimulating activity (CSA). In addition, lithium did not potentiate the action of already formed CSA. However, lithium did stimulate the production of CSA by lung tissue. Lithium enhancement of CSA production was blocked by puromycin, indicating that lithium action required active new protein synthesis. It was concluded that lithium promoted enhanced granulocyte production in vitro by stimulating the synthesis of CSA.     

实验性大鼠迟发性脑血管痉挛的细胞增生、凋亡和坏死

目的 探讨SAH后DCVS及其迟发性神经功能缺损的发生机制。方法 HE和TUNEL染色检测脑血管内皮细胞、平滑肌细胞及神经细胞增生、凋亡和坏死改变。结果 TUNEL检测发现SAH后30min海马、皮层、及基底节区可见凋亡细胞开始出现，血管和神经细胞形态结构基本正常．SAH后3d凋亡细胞开始增多，部分神经细胞核固缩、浓染、染色质集聚，血管内皮和平滑肌凋亡细胞开始出现，血管外膜可见炎细胞。SAH后7d凋亡和坏死的神经细胞明显增多，而血管在坏死和凋亡的基础上增生性改变更加明显。结论 SAH迟发性脑血管痉挛及其迟发性神经细胞损伤的病理过程中，既有细胞坏死，也有细胞凋亡的病理生理过程，血管内皮细胞和血管平滑肌细胞还有病理性增生的血管重构改变，是多种病变形式并存的病理过程。     

Reciprocal regulation of human basophil and eosinophil differentiation by separate T-cell-derived factors

Basophil and eosinophil progenitors are present in human hemopoietic tissues, including cord blood. In the present studies, cord blood cultures demonstrating differentiation of basophils or eosinophils have been maintained for prolonged periods in the presence of conditioned medium from a human T-cell leukemia line (Mo-CM). Peak basophil counts and histamine levels were followed almost invariably by a second peak of eosinophils in vitro. Morphologic examination revealed the consistent presence of cells with mixed basophil-eosinophil granulation. Both basophil and eosinophil growth-stimulating activities were found in Mo-CM, were heat stable and nondialyzable, and could be partially separated from each other by a multistep procedure that included ion-exchange chromatography on DEAE-cellulose. Mixing experiments using separated basophil- and eosinophil-stimulating activities revealed that suppression of basophil growth was accompanied by reciprocal enhancement of eosinophil growth, a finding that could be confirmed on analysis of morphology of single colonies from cord blood progenitors in methylcellulose. These studies point to the existence of regulatory growth factors in Mo-CM that stimulate and/or inhibit the growth and differentiation of human basophils and eosinophils from a common, committed progenitor cell.     

Social nocturnal alcohol consumption and pharmacokinetics of theophylline.

Although moderate alcohol consumption is postulated to enhance theophylline metabolism, to our knowledge, the effect of casual nocturnal alcohol consumption has not been assessed. Eight normal volunteers, at the same time, one week apart, were given whiskey, 3 ml/kg of body weight, on one evening and on the alternate evening an equivalent volume of water. Each evening was followed by assessment of the pharmacokinetics of fast-release bibtheophylline, 5 mg/kg, taken the next morning at 9 AM. Alcohol taken the night before caused a statistically significant decrease in plasma clearance together with an increase in elimination half-life of 33 percent with consequent increases in plasma concentrations. These findings have potentially important implications for the accuracy of outpatient monitoring of serum theophylline and might explain intermittent toxic reactions occurring in some patients.