Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis.

With enhanced concerns of terrorist attacks, dual exposure to radiation and thermal combined injury (RCI) has become a real threat with devastating immunosuppression. NLRP12, a member of the NOD-like receptor family, is expressed in myeloid and bone marrow cells and was implicated as a checkpoint regulator of inflammatory cytokines, as well as an inflammasome activator. We show that NLRP12 has a profound impact on hematopoietic recovery during RCI by serving as a checkpoint of TNF signaling and preventing hematopoietic apoptosis. Using a mouse model of RCI, increased NLRP12 expression was detected in target tissues. Nlrp12-/- mice exhibited significantly greater mortality, an inability to fight bacterial infection, heightened levels of proinflammatory cytokines, overt granulocyte/monocyte progenitor cell apoptosis, and failure to reconstitute peripheral myeloid populations. Anti-TNF Ab administration improved peripheral immune recovery. These data suggest that NLRP12 is essential for survival after RCI by regulating myelopoiesis and immune reconstitution.

5-chloro-2'-deoxyuridine cytotoxicity results from base excision repair of uracil subsequent to thymidylate synthase inhibition.

The lack of a phenotypic alteration of 5-hydroxymethyluracil (hmUra) DNA glycosylase (hmUDG) deficient Chinese hamster V79mut1 cells exposed to DNA-damaging agents known to produce hmUra has raised the question whether there might be DNA substrates other than hmUra for hmUDG. Based on the structural similarity between 5-chlorouracil (ClUra) and hmUra and the observations that 5-chloro-2'-deoxyuridine (CldUrd) induces base excision repair (BER) events, we asked whether hmUDG or some other DNA BER enzyme is responsible for the removal of ClUra from DNA. An in vivo flow cytometry assay with FITC-anti-BrdUrd (which cross-reacts with CldUrd) showed that exogenous CldUrd is incorporated into DNA. However, both in vivo and in vitro experiments indicated that ClUra is not excised from DNA by hmUDG or other DNA glycosylase activities. The absence of removal of ClUra by hmUDG raised the question whether DNA strand breaks occurred subsequent to thymidylate synthase inhibition, leading to deoxyuridine incorporation, followed by cleavage of uracil from DNA by uracil DNA glycosylase (UDG). An in vivo thymidylate synthase activity assay in V79 cells demonstrated that CldUrd treatment inhibits thymidylate synthase as effectively as 5-fluoro-2'-deoxyuridine (FdUrd) treatment. Uracil, a known UDG inhibitor, partially reverses the cytotoxic effects of CldUrd on V79 cells, thus confirming that CldUrd induced cytotoxicity is a result of UDG activity. Our results demonstrated that while CldUrd is not directly repaired from DNA, its cytotoxicity is directly due to the UDG removing uracil subsequent to inhibition of thymidylate synthase by CldUMP.

A combination of amoxicillin and clavulanate every 12 hours vs every 8 hours for treatment of acute bacterial maxillary sinusitis.

OBJECTIVE: To compare the safety and efficacy of a combination of amoxicillin and clavulanate potassium given orally every 12 hours (amoxicillin, 875 mg; clavulanate, 125 mg) with that given every 8 hours (amoxicillin, 500 mg; clavulanate, 125 mg) for the treatment of patients with acute bacterial maxillary sinusitis. DESIGN: Multicenter double-blind randomized double-dummy controlled trial. SETTING: Physicians' offices and ambulatory care clinics. PATIENTS: One hundred seventy patients at least 18 years of age with acute bacterial maxillary sinusitis who could be treated with an oral antimicrobial agent were randomized, and data from 134 were suitable for evaluation. Four patients were withdrawn from this study because of adverse effects. INTERVENTIONS: Patients received a combination of amoxicillin and clavulanate orally every 12 hours (amoxicillin, 875 mg; clavulanate, 125 mg) or every 8 hours (amoxicillin, 500 mg; clavulanate, 125 mg) for 14 days. MAIN OUTCOME MEASURE: Clinical success at the end of therapy. RESULTS: Clinical success at the end of therapy was similar for the 2 treatment groups, 93% and 88% of patients in the every 12-hour and every 8-hour groups, respectively (P = .76; 95% confidence interval, -4.0% to 15.6%). Clinical success rates at follow-up 2 to 4 weeks after the end of therapy were also similar in the 2 groups. Adverse events related to treatment were reported with similar frequency in the 2 groups. CONCLUSION: Amoxicillin and clavulanate given every 12 hours is as effective and as safe as administration every 8 hours for the treatment of acute bacterial maxillary sinusitis.

Brompheniramine, loratadine, and placebo in allergic rhinitis: a placebo-controlled comparative clinical trial.

A double-blind, randomized, placebo-controlled, parallel-group, multicenter study was conducted to compare the effectiveness of an extended-release formulation of a classical antihistamine, brompheniramine, and a second-generation compound, loratadine, in the treatment of allergic rhinitis. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg twice daily (n = 112), loratadine 10 mg once daily (n = 112), or placebo twice daily (n = 114) for 7 days. Study medications were blinded using a double-dummy technique. Subjects completed an overall evaluation of symptom relief on a daily basis and returned on treatment days 3 and 7, at which times the investigator assessed symptom severity. The investigator and subject each completed a global efficacy evaluation, and subjects were interviewed regarding adverse experiences. The primary efficacy variable was the physicians' global efficacy evaluation on day 3. Symptoms also were analyzed as summed severity scores for all symptoms and for the nasal symptom cluster of rhinorrhea, sneezing, and nasal blockage. At all post-baseline evaluations (days 3, 7, and averaged over the two days), brompheniramine was significantly better than loratadine and placebo for both sets of summed symptom scores and all three global assessments. Loratadine was significantly better than placebo for physician ratings of total symptom severity averaged over the two days and for the physician and subject ratings of the nasal cluster on day 3. Central nervous system-related symptoms were the most frequently reported adverse experiences; somnolence was reported most frequently by patients taking brompheniramine, and its occurrence was less frequent as treatment continued. A nonprescription, extended-release formulation of brompheniramine 12 mg twice daily provided significantly better relief of symptomatic allergic rhinitis than loratadine 10 mg once daily.

Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study.

Community-acquired pneumonia remains an important infectious disease problem, with more than 4 million cases occurring in the United States annually. Although Streptococcus pneumoniae remains the most commonly identified organism, a variety of bacterial and nonbacterial pathogens may be involved. Hospitalization is unnecessary in most cases, and oral antibiotic therapy is common. In the majority of cases, the etiology of pneumonia is unknown at the time of presentation, necessitating the use of empiric therapy. Quinolones have not been utilized in this setting in the past because of their inconsistent coverage of S pneumoniae. Sparfloxacin (RP 64206) is a broad-spectrum fluoroquinolone with excellent activity in vitro against the majority of bacteria involved in community-acquired pneumonia, including pneumococcus. We therefore studied the efficacy and safety of sparfloxacin compared with the second-generation cephalosporin cefaclor as empiric therapy for patients with community-acquired pneumonia in a double-masked, double-dummy, multicenter trial. Three hundred thirty patients aged 18 years or older with community-acquired pneumonia suspected of being bacterial in etiology were enrolled at 74 centers in the United States from June 1, 1992, to March 4, 1995. Patients meeting the inclusion criteria were randomized to receive 10 days of either sparfloxacin 400 mg orally once followed by sparfloxacin 200 mg orally daily (n = 168), or cefaclor 500 mg orally every 8 hours (n = 162). There were no significant differences between groups with regard to baseline characteristics. Patients were followed up serially at 4 +/- 1 days, 20 +/- 3 days, and 38 +/- 7 days after the beginning of therapy. Patients were evaluated for clinical response, clinical recurrence of infection, and eradication of baseline pathogens. The primary efficacy variable was the clinical response (cured or improved) in the subgroup of patients meeting the definition of clinically assessable. Responses were also evaluated in the intent-to-treat population. In the intent-to-treat population, 35.7% of patients receiving sparfloxacin were clinically cured, compared with 32.1% of patients receiving cefaclor. Clinical successes (patients clinically cured plus improved) were also comparable (72.6% of patients in the sparfloxacin group and 71.0% of patients in the cefaclor group). Similar clinical success rates were noted using only the clinically assessable population (primary efficacy variable). Forty-four percent of patients receiving sparfloxacin and 39.1% of patients receiving cefaclor were clinically cured. In the sparfloxacin group, 86.6% of patients were clinical successes, compared with 84.4% of patients in the cefaclor group. Microbiologic cures were comparable in both groups. There was no difference in the incidence of recurrence of infection or superinfection. Adverse events thought to be due to study drug occurred equally in both groups (14.3% in the sparfloxacin group vs 14.8% in the cefaclor group). Results show that sparfloxacin is a safe and effective empiric therapy for patients with community-acquired pneumonia and is comparable to cefaclor.

Double-blind comparison of cetirizine and placebo in the treatment of seasonal rhinitis.

The efficacy and safety of cetirizine were evaluated in 419 patients with seasonal allergic rhinitis. Using a 4-way, double-blind randomization schedule, patients were given a 1-week course of once daily cetirizine (5, 10, or 20 mg) or placebo. Patient and physician efficacy ratings corresponded, indicating superiority of cetirizine to placebo (P less than .05) in reducing symptom severity scores for sneezing, rhinorrhea, ocular pruritus, nasal pruritus, watering of the eyes, and redness of the eyes. All cetirizine doses achieved higher efficacy ratings (72.7%, 79.2%, and 75.7%, respectively) than placebo (52.9%; P less than .05) by the physician's global assessment. Cetirizine was well tolerated, with sedation being the most common adverse experience, increasing in frequency at higher doses. A dose-response relationship was evident for selected symptoms, and the once daily 5-mg dose was found to be an effective minimum dose.

Comparison of safety and efficacy of inhaled pirbuterol with metaproterenol.

This multicenter study was performed to compare the safety and efficacy of a new beta-2 selective beta agonist, pirbuterol, with metaproterenol. The study followed a double-blind parallel design evaluating 133 asthmatic patients for 12 weeks. There were essentially no clinical differences between groups and no differences in onset of action, peak effect, side effects, or development of tolerance between these two agents. Our conclusion is that pirbuterol is at least as effective and safe under conditions of chronic administration to asthmatics as metaproterenol and therefore can be considered a suitable alternative for therapy.

Procaterol metered-dose inhaler: a multiclinic study evaluating the efficacy and safety in patients with asthma.

Procaterol hydrochloride aerosol, a potent beta 2-adrenergic bronchodilator, was evaluated in a double-blind, placebo-controlled study for efficacy and safety in 210 patients with documented mild to moderate reversible airway obstruction. Patients were randomized to receive procaterol in two inhalations (high dose) or one inhalation (low dose), 0.01 mg/inhalation, three times daily, or placebo. Pulmonary function tests were recorded at five and 30 minutes and hourly for eight hours after the first dose and following 1 and 2 weeks of treatment. Both doses of procaterol produced significantly greater improvement in PFTs at one hour and for up to seven hours after dosing compared with placebo (p less than 0.05). Mean percent increases in FEV1 were 35% in the high-dose group and 29% in the low-dose group at week 2. The high-dose group showed no loss of duration of bronchodilation with continued dosing. Improvement in PFTs and peak flow rates was significantly greater in the high-dose than in the low-dose group (p less than 0.05). Tremor was the most frequent side effect. Procaterol had no effect on electrocardiograms, heart rate, blood pressure, or clinical laboratory tests. The high dose of procaterol aerosol was shown to be an effective and well-tolerated bronchodilator with a rapid onset and long duration of action.

Arbaprostil [15(R)-15-methyl prostaglandin E2] in a single nighttime dose of either 50 or 100 micrograms in acute duodenal ulcer.

To determine the efficacy of single nighttime doses of arbaprostil [15(R)-15-methyl prostaglandin E2], 50 or 100 micrograms for 4 wk, a double-blind randomized placebo-controlled multiclinic trial was undertaken. Success was defined as complete healing of the ulcer documented by endoscopy. Fifty-one of 64 patients enrolled were considered evaluable. Ulcer healing was documented in 64.3%, 85.7%, and 31.2% of the 100-micrograms arbaprostil, 50-micrograms arbaprostil, and placebo treatment groups (p value vs. placebo = 0.003 and 0.002, respectively). No difference in side effects or changes in laboratory parameters were found between the treatment groups except that diarrhea, usually mild, was found more often in the 100-micrograms arbaprostil group (60.0%) than in the 50-micrograms arbaprostil (31.8%) or placebo groups (23.5%) (p value 100 micrograms arbaprostil vs. placebo = 0.02). A single nighttime administration of arbaprostil seems to be a safe and efficacious agent for the treatment of acute duodenal ulcer.

A comparison of oral procaterol and albuterol in reversible airflow obstruction.

The efficacy and safety of orally administered procaterol hydrochloride, a potent beta 2-adrenergic bronchodilator, was compared with that of albuterol in an eight-center, double-blind study conducted in 223 patients with mild to moderate, reversible bronchial airway obstruction. After a 1-wk placebo washout period, patients were administered either procaterol 0.05 mg twice daily for 2 wk followed by 0.10 mg twice daily for 10 wk or albuterol 2 mg three times a day for 2 wk followed by 4 mg three times a day for 10 wk. Spirometry determinations 1.5 h postdose showed consistently greater percent improvements from predose in FVC, FEV1, and FEF25-75 with procaterol than with albuterol at Weeks 1, 2, 4, 8, and 12. Treatment differences were statistically significant (alpha = 0.05) after 2 wk, 2 months, and 3 months of treatment. Bronchodilatation was evident 0.5 h after dosing and peaked at 1.5 to 3 h postdose for both treatments. The duration of action (i.e., time until spirometry determinations were lower than those at 0.5 h postdose) was at least 5 h after procaterol but only 3 h after albuterol. There was no evidence of tolerance with continued procaterol treatment, whereas a diminished duration of response to albuterol was observed with long-term treatment. Tremor was reported statistically more frequently in patients receiving procaterol than in those receiving albuterol (alpha = 0.05); the frequencies of other adverse events were similar for the two groups. No statistically significant treatment differences were noted for asthma symptoms, global evaluations, ECG results, vital signs, or clinical laboratory measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

A placebo-controlled trial of procaterol: a new long-acting oral beta 2-agonist in bronchial asthma.

Procaterol hydrochloride, a potent beta 2-adrenergic bronchodilator developed in Japan, was evaluated in a double-blind, placebo-controlled study for efficacy and safety in 45 patients (ages 18 to 55 yr) with chronic documented reversible airway disease. After a 1-week placebo washout period, patients were administered either 0.05 mg or 0.10 mg of procaterol or placebo twice daily for 2 wk. Spirometric determinations, vital signs, and ECGs were obtained at 1/2, 1, 2, 4, 6, and 8 hr after the first dose and at the same time intervals after 1 and 2 wk of treatment. Patients recorded on a daily basis peak flow rates, asthma symptoms, need for supplemental aerosol, concurrent medications, and side effects. Spirometry results indicated significant improvement in pulmonary function with both doses of procaterol compared with placebo (P less than 0.05). The larger dose was generally more effective. Bronchodilatation was evident 1/2 hr after dosing and peaked at 2 hr. At 8 hr after 0.10 mg of procaterol, FEV1 was still above predose values. Daily peak flow rates were significantly higher with 0.10 mg than with 0.05 mg (P less than 0.05) and placebo (P less than 0.001). Tremor and nervousness were the most frequent side effects. They occurred in a dose-related frequency, were mild and transient, and occurred early in treatment. No significant drug-related changes were noted in ECGs, heart rate, blood pressure, or clinical laboratory data. Procaterol was found to be an effective, well-tolerated oral bronchodilator with a long duration of action, especially at 0.10 mg twice daily.

Factorial rating system for comparative efficacy of antiasthmatic medication: a multicentric study report.

Faced with 1-year daily medication diaries from over 300 patients, each documenting the use of from one to five medications a day, we found it was necessary to devise a system which would reduce this data into a form which would allow a meaningful interpretation of changes of medications in a single patient or group of patients. Since the medications were principally steroids, beta agonists, or xanthines, representative agents were chosen as the standard for each class and the other medications were rated against them. A conversion factor was then determined to allow comparison between classes. Each medication taken by a patient could now be expressed as a single number and the sum of all the medications would be the individual's Asthma Medication Index. The AMI allowed (i) evaluation of a single patient over time, (ii) comparison of different patients at any single point or over a period of time, and (iii) evaluation of entire groups of patients over time as was the case in our evaluation of Zaditen. Application of the system allowed the differentiation of two therapeutic agents versus placebo during a 1-year study, revealing excellent correlation with the physician's global assessment of the patient's improvement. With proper modification of the basic drug groups and intergroup factor relationship, the Index can be adapted to any disease state where a change in concomitant medication is an indicator of therapeutic effect.

Short-term topical corticosteroid therapy (halcinonide ointment) in the management of atopic dermatitis.

The efficacy of short-term treatment of acute exacerbations of atopic dermatitis with a corticosteroid ointment (halcinonide, 0.1 percent) was demonstrated by comparing such a formulation with its ointment base (placebo). A double-blind, paired comparison study was conducted in 214 patients. Within two weeks the therapeutic response was judged excellent in 137 (64 percent) of the patients receiving the corticosteroid treatment. The number of responses judged good to excellent was 182 (85 percent). With the placebo, there was an excellent response in 50 (23 percent) of the patients and the number judged good to excellent was 95 (44 percent). Although these placebo responses attested to the appropriateness of a highly occlusive ointment vehicle in this condition, the corticosteroid containing formulation was superior (p less than 0.001). In only 10 (5 percent) of the patients was there a poor response to corticosteroid treatment. direct comparison of the response of similar bilateral lesions showed the corticosteroid to be superior to the placebo in 147 (69 percent) patients and the placebo to be superior in just 31 (15 percent) (p less than 0.001). No adverse reactions occurred with either preparation. We conclude that in the management of atopic dermatitis, full advantage should be taken of short-term corticosteroid therapy (preferably in ointment form), which is virtually free of those potential unwanted effects of chronic therapy with this class of drugs.

Multicentric study of beclomethasone dipropionate nasal aerosol in adults with seasonal allergic rhinitis.

A double-blind, parallel-design multicentric study, in two phases, was conducted to examine the safety and efficacy of 2-wk treatment with various doses of beclomethasone dipropionate nasal aerosol (BDNA) and placebo in adults with seasonal allergic rhinitis. In phase I, 162 patients received BDNA, 33.5 micrograms/burst (o.d.,b.i.d., t.i.d., q.i.d.), or placebo; in phase II, 189 patients received BNDA 42, micrograms/burst (b.i.d. q.i.d.), or placebo. In both phases, statistically significant (p less than 0.05) differences favoring BDNA over placebo were found for all efficacy measures (global evaluation and total and individual symptom scores). In phase I, response to treatment increased as BDNA dosage increased, with a leveling off at t.i.d. dosage. In both phases, marked improvements were seen by week 1, with maximum improvement during week 2. Eighty-seven patients had adverse reactions-sneezing and nasal burning were most common. No suppression in morning cortisol levels was seen, nor were Candida infections promoted. A 2-wk treatment with BDNA was safe and effective in the treatment of seasonal allergic rhinitis in adults.

Clinical studies of terfenadine in seasonal allergic rhinitis.

alpha-[4-(1,1-Dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) was evaluated in groups of at least 30 patients per drug for relief of symptoms of active allergic pollinosis on a double-blind basis during the pollen season for 3 successive years. Terfenadine 20 mg 3 times a day was as effective as chlorpheniramine maleate 4 mg 3 times a day. In each study chlorpheniramine consistently showed a higher incidence of sedation than placebo. None of the terfenadine dosage schedules up to 200 mg 3 times a day caused sedation significantly different from that of placebo or efficacy greater than that seen with 20 mg 3 times a day. The incidence of central nervous system stimulation in the terfenadine group was also not different from that of placebo.

Pirbuterol vs. hydroxyzine vs. theophylline vs. placebo in the treatment of bronchial asthma.

Pirbuterol (10mg and 15mg capsules) was found to be an effective bronchodilator on large and small airways in bronchial asthm. Benefit occurred within one hour and it lasted five or more hours. It had no significant effect on ECG, blood pressure or heart rate. Mild nervousness and/or muscle tremor occurred occasionally. Hydroxyzine usually prevented these side effects.

Clinical investigation of terfenadine, a non-sedating antihistamine.

Terfenadine was evaluated for the relief of symptoms in patients with allergic pollinosis on a double-blind basis. Terfenadine 20 mg tid was as effective as Chlorpheniramine maleate 4 mg tid. Chlorpheniramine consistently showed a higher incidence of sedation than placebo. None of the terfenadein dosage schedules up to 200 mg tid caused sedation significantly different from that of placebo. Terfenadine appears to be the first antihistamine to lack significant central nervous system effects.