The Rho family GTPase Cdc42 regulates the activation of Ras/MAP kinase by the exchange factor Ras-GRF.

The Ras guanine-nucleotide exchange factor Ras-GRF/Cdc25(Mn) harbors a complex array of structural motifs that include a Dbl-homology (DH) domain, usually found in proteins that interact functionally with the Rho family GTPases, and the role of which is not yet fully understood. Here, we present evidence that Ras-GRF requires its DH domain to translocate to the membrane, to stimulate exchange on Ras, and to activate mitogen-activated protein kinase (MAPK). In an unprecedented fashion, we have found that these processes are regulated by the Rho family GTPase Cdc42. We show that GDP- but not GTP-bound Cdc42 prevents Ras-GRF recruitment to the membrane and activation of Ras/MAPK, although no direct association of Ras-GRF with Cdc42 was detected. We also demonstrate that catalyzing GDP/GTP exchange on Cdc42 facilitates Ras-GRF-induced MAPK activation. Moreover, we show that the potentiating effect of ionomycin on Ras-GRF-mediated MAPK stimulation is also regulated by Cdc42. These results provide the first evidence for the involvement of a Rho family G protein in the control of the activity of a Ras exchange factor.

Myeloid leukemia cell growth and differentiation are independent of mitogen-activated protein kinase ERK1/2 activation.

The mitogen-activated protein kinase ERK1/2 pathway is essential in the control of cell proliferation and differentiation in most cellular systems. As such, it has been considered a potential target for antineoplastic therapy. For this purpose, we have examined the role of ERK activation in myeloid leukemia cell growth and differentiation. Using a representative set of myeloid leukemia cell lines, we show that cell proliferation was not accompanied by increases on ERK1/2 activation, and mitogenic stimulation did not enhance ERK activity. Moreover, abolition of ERK function by the inhibitor PD98059 or by a dominant inhibitory mutant ERK2 had no significant effects on proliferation. With the aid of various differentiation inducers, we found that within the same cell line, differentiation to a given lineage could occur with and without ERK1/2 activation, depending on the stimulus. Also, a differentiator could have the same effect in the presence or absence of ERK stimulation, depending on the cell line. ERK inhibition did not affect the differentiation elicited by stimuli whose effects were accompanied by ERK activation. Finally, constitutive ERK activity was also ineffective on proliferation and differentiation. Thus, our results indicate that ERK1/2 activation is not an essential requirement for leukemic cell growth and differentiation.

Human FRAG1 encodes a novel membrane-spanning protein that localizes to chromosome 11p15.5, a region of frequent loss of heterozygosity in cancer.

We have previously identified a chromosomal rearrangement between fibroblast growth factor receptor 2 (FGFR2) and a novel gene, FRAG1, in a rodent model of osteosarcoma. To assess the potential role of FRAG1 in disease further, we have isolated cDNA and genomic clones of human FRAG1. Sequence analysis of the cDNA revealed the presence of an insertion not contained in the original FRAG1 sequence. This insertion in human FRAG1 encoded a region highly homologous to and immediately following the first 55 amino acids of the protein, indicating the presence of a repetitive domain within FRAG1, designated the FRAG1 homology (FH) domain. Analysis of FRAG1 gene structure revealed that the FH domains were encoded by tandem duplicated exons. Database searches identified several transmembrane proteins displaying homology to the FH domain of FRAG1. In addition, hydropathy analysis predicted FRAG1 to encode an integral membrane protein with multiple membrane-spanning segments. FRAG1 mRNA was ubiquitously expressed in human adult tissues and several tumor cell lines at varying levels of abundance. Human FRAG1 was mapped by fluorescence in situ hybridization and radiation hybrid analysis to chromosome 11 at band p15.5, a region implicated in Beckwith-Wiedemann syndrome and a region of frequent loss of heterozygosity in multiple tumor types. These results suggest that FRAG1 may be a useful candidate gene for genetic disorders associated with alterations at 11p15.5.

The safety and efficacy of ALLERVAX CAT in cat allergic patients.

Conventional immunotherapy for cat allergy is effective in reducing cat allergy symptoms in many patients, but this type of immunotherapy can cause severe reactions, including anaphylaxis, and often requires years of injections for successful desensitization. To improve the efficacy of immunotherapy for cat allergic patients, synthetic cat allergen peptides (ALLERVAX CAT) were generated, based on analysis of the immunodominant T cell epitopes of cat allergen. These peptides lack the tertiary structure of native Fel d1 and possess a significantly reduced capacity to bind to Fel d1-specific IgE. Using these peptides, we performed a multicenter, randomized, double-blind, placebo-controlled study of 133 cat allergic patients chronically exposed to cats or who had failed previous conventional cat immunotherapy. We evaluated the safety of ALLERVAX CAT treatment and determined whether ALLERVAX CAT treatment improved tolerance to cat allergen, as measured by symptom analysis and pulmonary function testing. Three of the ALLERVAX CAT-treated patients required systemic epinephrine for adverse reactions, but the frequency of all adverse reactions in both groups was not statistically different from that of the placebo group. The majority of adverse events were "late" events, most commonly associated with respiratory symptoms, and these events declined with successive injections. ALLERVAX CAT given at a dose of 750 microg/dose improved pulmonary function in patients with reduced baseline FEV1, and global evaluation of the subjects' ability to tolerate cats improved significantly in the actively treated groups relative to placebo. Thus, although therapy with ALLERVAX CAT is associated with some adverse events in patients with severe cat sensitivity, such therapy is an effective approach for the management of cat allergy, since it improves tolerance to cats and improves pulmonary function in cat allergic patients with reduced FEV1.

Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler.

AIMS: The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg, 800 microg or 1600 microg administered twice daily by a dry-powder inhaler (Turbuhaler ) in adult patients with mild asthma. METHODS: A total of 38 patients received budesonide by inhalation, 13 received 400 microg twice daily, 12 received 800 microg twice daily and 13 received 1600 microg twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.9 l min-1 in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry. RESULTS: Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (tmax ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1. 4(2.0) nmol l-1 (single (repeated) doses), 2.6(3.6) nmol l-1 and 5. 4(6.4) nmol l-1 after 400, 800 and 1600 microg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l-1 min. Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0, infinity,SD)(P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. CONCLUSIONS: In this relatively small study, budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients.

Rapid onset of control with budesonide Turbuhaler in patients with mild-to-moderate asthma.

BACKGROUND: Budesonide (Pulmicort) is an inhaled corticosteroid with high topical potency but low systemic activity. Turbuhaler is a novel breath-actuated, multi-dose, dry-powder inhaler. OBJECTIVES: This study was conducted to determine the efficacy and safety of two different dose regimens of budesonide Turbuhaler, compared with placebo, in adult patients with mild-to-moderate asthma not well-controlled with bronchodilator therapy. METHODS: This double-blind, randomized, placebo-controlled, parallel-group, multicenter study compared the efficacy and safety of 200 microg and 400 microg of budesonide, administered twice daily via Turbuhaler, with placebo, in 273 adult patients (aged 19 to 70 years) with mild-to-moderate asthma (FEV1 67% of predicted normal), not well-controlled with bronchodilator therapy. Efficacy was assessed by pulmonary function tests and patient assessments of asthma symptom control. Safety was assessed in terms of adverse events, laboratory evaluations, and physical examinations. RESULTS: Two hundred and 400 microg of budesonide bid were significantly more effective than placebo at improving morning PEF (mean differences from placebo of 43.63 L/min and 40.10 L/min, respectively; P < .001) and FEV1 (mean differences from placebo of 0.44 L, and 0.50 L, respectively; P < .001) over the 12-week treatment period. Onset of action as assessed by morning PEF was within two days. Basal and stimulated plasma cortisol concentrations were not significantly affected by budesonide treatment compared with placebo. CONCLUSIONS: Treatment of adults suffering from mild-to-moderate asthma with budesonide Turbuhaler is well tolerated and results in a rapid onset of asthma control which is maintained over time.

Ipratropium bromide nasal spray 0.03% and beclomethasone nasal spray alone and in combination for the treatment of rhinorrhea in perennial rhinitis.

BACKGROUND: Perennial rhinitis is a common condition that affects up to 10% to 20% of the population. Multiple agents are frequently administered since no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important especially for newly approved agents such as ipratropium bromide nasal spray 0.03%, a topical anticholinergic agent, approved specifically for the treatment of rhinorrhea in allergic and non-allergic perennial rhinitis. OBJECTIVE: To compare the efficacy and safety of the combined use of ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) and beclomethasone dipropionate nasal spray (84 microg per nostril bid) against that of either active agent alone for the treatment of rhinorrhea. DESIGN: Multicenter, 6-week, double-blind, randomized active- and placebo-controlled, parallel trial. SETTING: Allergist and general practitioner clinical practices. PATIENTS: Five hundred thirty-three patients with perennial rhinitis (279 allergic and 274 non-allergic), 8 to 75 years of age, who had at least a mild degree of severity of rhinorrhea for a minimum of 2 hours per day during the 1 week screening period as well as congestion or sneezing also of at least mild severity. INTERVENTION: Either (1) ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) plus beclomethasone dipropionate nasal spray (84 microg per nostril bid), (2) ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) alone, (3) beclomethasone dipropionate nasal spray (84 microg per nostril bid) alone, or (4) vehicle [matching placebo nasal spray for the ipratropium bromide (2 sprays per nostril tid)] or beclomethasone dipropionate (2 sprays per nostril bid). MAIN OUTCOME MEASURE: Severity and duration of rhinorrhea, and patient and physician global assessment of control of rhinorrhea. RESULTS: Ipratropium bromide nasal spray plus beclomethasone nasal spray was more effective than either active agent alone or vehicle in reducing the average severity and duration of rhinorrhea during 4 weeks of treatment. The advantage of ipratropium bromide plus beclomethasone nasal spray was evident by the first day of combined treatment and continued throughout the 2-week treatment period. Ipratropium bromide nasal spray had a faster onset of action during the first week of treatment and reduced the duration of rhinorrhea more than beclomethasone. Beclomethasone nasal spray was more effective in reducing the severity of congestion and sneezing than ipratropium. In patients who had not responded well to a nasal steroid prior to participation in the study based on a questionnaire administered at screening, ipratropium bromide was as effective in the steroid non-responders as steroid responders, whereas beclomethasone was more effective in steroid responders. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide or beclomethasone nasal spray alone. CONCLUSIONS: The combined use of ipratropium bromide nasal spray with beclomethasone dipropionate nasal spray is more effective than either active agent for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions. Ipratropium bromide nasal spray 0.03% alone should be considered in patients for whom rhinorrhea is the primary symptom, and its use in combination with a nasal steroid should be considered in patients where rhinorrhea is one of the predominant symptoms, or in patients with rhinorrhea not fully responsive to other therapy.

Transforming G protein-coupled receptors block insulin and ras-induced adipocytic differentiation in 3T3-L1 cells: evidence for a PKC and MAP kinase independent pathway.

We have used the expression of muscarinic m1 receptors in the preadipocytic 3T3-L1 cell line for dissecting the nature of the G protein-linked pathways governing adipocytic differentiation, a complex process controlled by many stimuli and their downstream targets. 3T3-L1 cells can be differentiated by insulin or by ras oncogenes, and MAP kinase has been implicated in this process. However, m1 stimulation failed to induce differentiation of 3T3-L1 cells. Furthermore, it prevented insulin or v-ras-induced adipocytic differentiation, utilizing a protein kinase C-independent pathway. m1 stimulation did not alter the phosphorylation state of the insulin receptor substrates IRS-1 and SHC, nor the recruitment of Grb-2. Interestingly, whereas m1 receptors potently activated MAP kinase, another differentiation-inhibitor, TNF alpha, did not affect it. These results suggest that the control of adipocytic differentiation can occur utilizing a biochemical route independent of protein kinase C, and acting downstream, or independently from the Ras-MAP kinase pathway.

Effects of budesonide by means of the Turbuhaler on the hypothalmic-pituitary-adrenal axis in asthmatic subjects: a dose-response study.

BACKGROUND: As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects. OBJECTIVES: This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma. METHODS: Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin. RESULTS: After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo). CONCLUSIONS: In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.

Ipratropium bromide nasal spray 0.03% provides additional relief from rhinorrhea when combined with terfenadine in perennial rhinitis patients; a randomized, double-blind, active-controlled trial.

Medical treatment of perennial rhinitis is aimed at providing symptomatic relief of individual symptoms. Multiple agents are administered when no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important, especially for newly available agents such as ipratropium bromide nasal spray, a topical anticholinergic agent approved for the treatment of rhinorrhea in allergic and nonallergic perennial rhinitis. The objective was to determine whether the combined use of ipratropium bromide nasal spray 0.03% (42 mcg per nostril) administered three times daily with a nonsedating antihistamine (terfenadine, 60 mg administered twice daily) is safe and provides greater clinical benefit than use of the placebo nasal spray plus terfenadine. Our method was a multicenter, 6-week, double-blind, randomized, active-controlled, crossover trial of 205 patients with perennial rhinitis (114 allergic and 91 nonallergic), 18 to 75 years of age, who had clinically significant rhinorrhea. After a 1-week run-in period, patients were treated for 2 weeks with one of the two treatment regimens, followed by a 1-week washout period, and then were treated for another 2 weeks with the other treatment regimen. Daily diary symptoms scores of rhinorrhea, congestion, and sneezing were obtained, as well as biweekly patient and physician global assessments of treatment effectiveness of each of the nasal symptoms. Ipratropium bromide nasal spray plus terfenadine was more effective than vehicle plus terfenadine in reducing the average severity (38% versus 28%) and duration (46% versus 30%) of rhinorrhea during the 2 weeks of treatment from baseline (p < 0.05). The advantage of ipratropium bromide nasal spray plus terfenadine was evident by the second day of treatment and continued throughout the 2-week treatment period. Of patients who responded more to one treatment than another, 69% responded to ipratropium bromide nasal spray plus terfenadine, compared to 31% to vehicle plus terfenadine (p < 0.05). Both physicians and patients rated control of rhinorrhea and sneezing by ipratropium bromide nasal spray plus terfenadine as superior to vehicle plus terfenadine (p < 0.05). The symptom of congestion was controlled equally well by both treatments. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide nasal spray alone. The combination of ipratropium bromide nasal spray with terfenadine is more effective than vehicle plus terfenadine for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions.

Dose ranging study of mometasone furoate (Nasonex) in seasonal allergic rhinitis.

BACKGROUND: Topical nasal corticosteroids are rapidly gaining acceptance as first-line therapy for seasonal allergic rhinitis, but there is a desire for effective corticosteroids with an improved safety profile over existing products. OBJECTIVE: A multicenter, double-blind dose ranging study was conducted to compare the activity and tolerance of four doses of mometasone furoate nasal spray (tradename Nasonex) and placebo in adult patients with seasonal allergic rhinitis. METHODS: Four hundred eighty patients with seasonal allergic rhinitis were enrolled and randomized to receive mometasone furoate nasal spray 50 micrograms (n = 96), 100 micrograms (n = 95), 200 micrograms (n = 98) or 800 micrograms (n = 95), or placebo vehicle (n = 95) once daily for 28 days. RESULTS: All of the doses of mometasone furoate nasal spray showed activity in reducing the severity of rhinitis. The 200-microgram dose reduced total nasal symptom scores and total symptom scores throughout the study (P < .05 versus placebo vehicle). The 50-microgram dose and the 100-microgram dose showed less consistent activity at early timepoints (days 3 and 7), while the 800 microgram dose did not provide significant additional benefits over the 200-microgram dose. All dose levels were well tolerated CONCLUSION: The results of this trial indicate that 200 micrograms once daily is the optimum dose of mometasone furoate nasal spray for the treatment of seasonal allergic rhinitis.

Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and mild asthma.

BACKGROUND: Antihistamines have been shown to have a variety of therapeutic effects in asthma. Although nasal obstruction may play an important role in modulating lower airway function, no prior trial has used a decongestant in combination with an antihistamine in patients with allergic rhinitis and concomitant asthma. OBJECTIVE: We sought to determine the efficacy and safety of loratadine (5 mg) plus pseudoephedrine (120 mg) (L/P) twice daily in patients with seasonal allergic rhinitis and mild asthma. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of L/P in 193 subjects during the fall allergy season. Nasal and chest symptoms, albuterol use, and peak expiratory flow rates were recorded daily for 6 weeks. Spirometry was measured at baseline and after 1, 2, 4, and 6 weeks of therapy, and health-related quality of life was rated at the beginning and end of the study. RESULTS: Total rhinitis and asthma symptom severity scores were significantly reduced in patients receiving active therapy compared with those receiving placebo throughout the 6-week study. Peak expiratory flow rates improved significantly in patients treated with L/P during weeks 2 through 6 (peak effect [mean +/- SEM]: L/P, 26.23 +/- 4.64 L/min vs placebo, 8.52 +/- 3.53 L/min, p = 0.002) as did FEV1 (peak effect [mean +/- SEM]: L/P, 170 +/- 53 ml vs placebo, 20 +/- 40 ml, p = 0.01) at all clinic visits. In addition, select measures of asthma-specific quality of life improved significantly relative to placebo. CONCLUSIONS: L/P significantly improved nasal and asthma symptoms, pulmonary function, and quality of life in patients with seasonal allergic rhinitis and concomitant mild asthma.

A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray.

BACKGROUND: Topical nasal corticosteroids have become a mainstay of treatment for the symptoms of seasonal allergic rhinitis (SAR). It is likely that topical corticosteroids, by blocking an initial influx of inflammatory cells in the nasal mucosa induced by aeroallergens, may have a preventive effect on nasal allergy symptoms when administered before the pollen season. OBJECTIVE: This study was designed to assess the efficacy and safety of an 8-week course of mometasone furoate nasal spray (MFNS), 200 micrograms once daily, in the treatment of SAR compared with beclomethasone dipropionate aqueous nasal spray (BDP), 168 micrograms twice daily, and placebo vehicle, when treatment is initiated before the anticipated onset of the ragweed season. METHODS: Three hundred forty-nine patients with SAR to ragweed pollen from nine centers in the Northeast and Midwest of the United States were randomized to one of the three intranasal study medications (MFNS, 200 micrograms once daily, BDP, 168 micrograms twice daily, or placebo vehicle), starting 4 weeks before the estimated start of the ragweed season. RESULTS: The proportion of "minimal symptom" days (total nasal symptom score < or = 2) was statistically significantly higher in both the MFNS and BDP groups when compared with the placebo vehicle group (p < 0.01). The two active treatment groups were not statistically significantly different from each other. MFNS and BDP displayed a similar safety profile that did not differ from placebo. CONCLUSIONS: This suggests that MFNS, 200 micrograms (once daily), is a useful therapy in the prophylactic treatment of SAR.

Rac-1 dependent stimulation of the JNK/SAPK signaling pathway by Vav.

The protein product of the human vav oncogene, Vav exhibits a number of structural motifs suggestive of a role in signal transduction pathways, including a leucine-rich region, a plekstrin homology (PH) domain, a cysteine-rich domain, two SH3 regions, an SH2 domain, and a central Dbl homology (DH) domain. However, the transforming pathway(s) activated by Vav has not yet been elucidated. Interestingly, DH domains are frequently found in guanine nucleotide-exchange factors for small GTP-binding proteins of the Ras and Rho families, and it has been recently shown that, whereas Ras controls the activation of mitogen activated kinases (MAPKs), two members of the Rho family of small GTPases, Rac 1 and Cdc42, regulate activity of stress activated protein kinases (SAPKs), also termed c-jun N-terminal kinases (JNKs). The structural similarity between Vav and other guanine nucleotide exchange factors for small GTP-binding proteins, together with the recent identification of biochemical routes specific for members of the Ras and Rho family of GTPases, prompted us to explore whether MAPK or JNK are downstream components of the Vav signaling pathways. Using the COS-7 cell transient expression system, we have found that neither Vav nor the product of the vav proto-oncogene, proto-Vav, can enhance the enzymatic activity of a coexpressed, epitope tagged MAPK. On the other hand, we have observed that, whereas proto-Vav can slightly elevate JNK/SAPK activity, oncogenic Vav potently activates JNK/SAPK to an extent comparable to that elicited by two guanine-nucleotide exchange factors for Rho family members, Dbl and Ost. We also show that point mutations in conserved residues within the cysteine rich and DH domains of Vav both prevent its ability to activate JNK/SAPK and render Vav oncogenically inactive. In addition, we found that coexpression of the Rac-1 N17 dominant inhibitory mutant dramatically diminishes JNK/SAPK stimulation by Vav, as well as reduces the focus-forming ability of Vav in NIH3T3 murine fibroblasts. Taken together, these findings provide the first evidence that Rac-1 and JNK are integral components of the Vav signaling pathway.

Evaluation of cetirizine in patients with allergic rhinitis and perennial asthma.

BACKGROUND: Cetirizine, a highly specific H1 receptor antagonist with modest sedation and anticholinergic effects at the higher doses required for bronchodilation, may be useful for treating concomitant allergy and symptoms of asthma. OBJECTIVE: This study evaluated the effectiveness of cetirizine compared with placebo in patients with allergic rhinitis and concomitant symptomatic mild to moderate perennial asthma. METHODS: Twenty-eight patients (13 females and 15 males) aged 13 to 59 years having allergic rhinitis and mild to moderate perennial asthma were treated for 26 weeks with 20 mg cetirizine or placebo. Daily diary entries of symptoms, medications taken and peak expiratory flow rate measurements (morning and evening), biweekly pulmonary function tests, and monthly global evaluations by investigators were performed. RESULTS: Cetirizine treatment significantly reduced baseline severity of several symptoms of rhinitis (itchy nose, nasal congestion, and watery eyes), and asthma (chest tightness, wheezing, shortness of breath, and nocturnal asthma). Although not statistically significant, cetirizine also reduced other symptoms of rhinitis (sneezing, itchy eyes, postnasal drip, and runny nose) and asthma (cough and sputum production), reduced albuterol use, and increased mean peak expiratory flow rates compared with placebo. No differences between treatment groups were noted for patient satisfaction, patient and physician global assessments of asthma management, pulmonary function, and methacholine challenge tests. Of two cetirizine patients with adverse events, one event, moderate drowsiness, was considered to be related to study drug. CONCLUSIONS: Cetirizine reduced symptoms of rhinitis as well as symptoms of asthma in patients with allergic rhinitis and concomitant perennial asthma.

Effects of terfenadine on psychomotor performance. An overview.

Sedation and impairment of psychomotor performance are well known adverse effects of the traditional antihistamines. These effects appear to be caused by different mechanisms, but both may have potentially dangerous consequences. while several of the newer antihistamines, such as terfenadine, have overcome the problem of sedation, it is also important to establish their propensity to cause psychomotor impairment. Many single- and multiple-dose studies (mostly in healthy volunteers) have compared the effects of terfenadine on psychomotor performance with those of placebo, as well as traditional and other nonsedating antihistamines. Over half of the studies employed divided-attention tasks that are considered relevant to everyday activities, such as driving. Like several other nonsedating antihistamines, single doses of terfenadine of up to 120 mg did not impair driving performance and generally had no significant effects on other psychomotor tests compared with placebo. In most of the multiple-dose studies, terfenadine 60 mg twice daily was administered for up to 5 days. Again, the effects of terfenadine on psychomotor performance differed little from those of placebo. Thus, the available evidence suggests that the problem of impaired psychomotor performance associated with the older, traditional antihistamines does not apply to terfenadine.

Comparative efficacy of H1 antihistamines.

Second-generation H1 receptor antagonists (cetirizine, terfenadine, astemizole, loratadine, azelastine, and acrivastine) offer several important advantages over the older first-generation antihistamines. They are substantially less sedating and have little or no anticholinergic activity. Many of them are effective for 12 to 24 hours, thereby increasing compliance. In addition to acting as competitive inhibitors of histamine, several seem to have other antiallergic mechanisms as well. They are all absorbed well when taken orally. Many studies demonstrate their effectiveness compared with placebo in the treatment of seasonal and perennial rhinitis and chronic urticaria, and several studies suggest that they have a role in the treatment of bronchial asthma. A number of multicenter, double-blind, placebo-controlled studies comparing the effectiveness of terfenadine, 60 mg bid, with chlorpheniramine, 8 mg bid, in seasonal allergic rhinitis demonstrate that both drugs are approximately equally potent in reducing the symptoms of sneezing, rhinorrhea, and nasal itching and are statistically significantly better than placebo. Ocular symptoms were reduced somewhat less but still significantly. No differences from placebo were recorded in their effect on nasal congestion. The effectiveness of cetirizine, 10 mg once daily, compared with astemizole, 10 mg once daily, was measured in double-blind, placebo-controlled studies of patients with seasonal allergic rhinitis. These studies also demonstrate statistically significant benefit from the study drugs compared with placebo in relieving all nasal symptoms except congestion. Both drugs also relieved ocular pruritus. Fewer studies have assessed azelastine, acrivastine, and loratadine, but all have been shown to provide significant relief of seasonal allergic rhinitis compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)