Jacob L. Pinnas

A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma

BACKGROUND There is a paucity of data comparing the long-term safety and efficacy of long-acting inhaled beta2-agonists versus low-dose inhaled corticosteroids in the treatment of asthma. OBJECTIVE To compare the safety and efficacy of salmeterol xinafoate, beclomethasone dipropionate (BDP), and placebo over a 6-month treatment period in patients with persistent asthma. METHODS Salmeterol (42 microg twice daily), BDP (84 microg four times daily), or placebo was administered via metered-dose inhaler to 386 adolescent and adult inhaled corticosteroid-naive patients in a randomized, double-blind, double-dummy, parallel-group study. Eligible patients demonstrated a forced expiratory volume in 1 second (FEV1) from 65% to 90% of predicted values. Pulmonary function, symptom control, frequency of asthma exacerbations, bronchial hyperresponsiveness (BHR) to methacholine challenge, and adverse events were assessed. RESULTS There were few statistically significant differences between the two active treatments over 6 months of therapy. Asthma symptoms and lung function were significantly improved with both salmeterol and BDP compared with placebo (changes from baseline in FEV1 of 0.28 L (SE = 0.04) and 0.23 L (SE = 0.04), respectively, compared with 0.08 L (SE = 0.04); P < or = .014). There were no significant differences among the treatment groups with respect to the distribution of asthma exacerbations over time. Both salmeterol and BDP significantly reduced BHR compared with placebo (P < or = .033; changes from baseline of 1.29 (SE = 0.26) and 1.42 (SE = 0.24) doubling doses at 6 months, respectively, compared with 0.24 (SE = 0.29) doubling dose for placebo). No rebound effect in BHR was seen upon cessation of any of the three treatment regimens. There were no clinically important differences in the safety profiles among the three treatments. CONCLUSIONS Both salmeterol and BDP are effective and well-tolerated when administered for 6 months to inhaled corticosteroid-naive patients with persistent asthma.

SCH 434: A new antihistamine/decongestant for seasonal allergic rhinitis☆

In a double-blind, multicenter study, we compared the effects of SCH 434 (Claritin-D; Schering Corp., Kenilworth, N.J.), a new sustained-release, combination antihistamine/decongestant medication, with the effects of its individual components and placebo in 435 patients with seasonal allergic rhinitis. SCH 434 contains 5 mg of loratadine, a nonsedating antihistamine, and 120 mg of pseudoephedrine as the decongestant component. Administered twice daily in this study, SCH 434 effected a 50% decrease in total symptom scores at day 4 and was significantly (p less than or equal to 0.03) more effective than the components alone or the placebo. Loratadine or pseudoephedrine alone, with 43% and 33% decline in symptom scores, respectively, also was more effective than placebo (p less than 0.05). As expected, pseudoephedrine alone was more effective than loratadine (p less than 0.01) in relieving nasal stuffiness; SCH 434 was more effective (p less than or equal to 0.01) than placebo and loratadine in relieving nasal stuffiness. All treatments were safe and well tolerated, although insomnia and dry mouth were noted in a significant number of patients who received either SCH 434 or pseudoephedrine. No serious side effects were noted. The incidence of sedation did not differ significantly among the four treatment groups. We conclude that SCH 434 is a safe and effective treatment for symptoms of seasonal allergic rhinitis. The combination drug (SCH 434) was better than its components for some, but not all, symptoms.

Harvester ant sensitivity: in vitro and in vivo studies using whole body extracts and venom.

Harvester ant stings by Pogonomyrmex maricopa (Pm) or Pogonomyrmex rugosus (Pr) resulted in serious reactions in 8 patients, 4 with generalized reactions and 1 with large local reactions. Exposure to one species in the genus Pogonomyrmex (P) appeared to cross-sensitize ant-sensitive patients to other species in the same genus as evidenced by skin testing and leukocyte histamine release, but these patients were less sensitive to extracts from other stinging Hymenoptera, including bee, wasp, yellow jacket, hornet, and Formica ant. Pr ant venom was obtained by electrical stimulation of live ants for leukocyte histamine release studies. The venom preparation was considerably more effective in inducing histamine release than a body extract derived from gasters, the posterior abdominal segments. Rabbits immunized with an extract from one species produced precipitating antibodies against the injected extract withich cross-reacted with extracts from other species of harvester ant, but not with other stinging Hymenoptera. Humans and rabbits appear to react to certain genus-specific antigens present in Pogonomyrmex whole body extracts. Proper identification of the offending ant is crucial for proper testing and treatment of ant-sensitive patients.

Immunochemical properties of malondialdehyde-protein adducts

Malondialdehyde (MDA), a product of lipid peroxidation, can bind to and modify proteins by adduct formation. To determine whether MDA adducts were immunogenic, MDA was added to rabbit serum albumin (RSA) in order to characterize MDA-proteins and to immunize rabbits. Bound MDA was proportional to the concentration of MDA added in the range of 2.5-20 mM as measured by thiobarbituric acid reactivity. MDA adducts of RSA migrated further toward the anode than native serum protein in zone and immunoelectrophoresis indicating increased negative charge. Rabbits immunized with MDA-RSA produced high titers of IgG antibodies to MDA-RSA as measured by enzyme-linked immunosorbent assay (ELISA). Hapten specificity of the antibody was demonstrated by antisera reactivity with MDA-RSA but not with unaltered RSA. Our findings support the possibility that MDA may serve as a hapten to form neoantigens which may represent a pathway by which lipid peroxidation could produce tissue damage via an immunologic mechanism.

Pneumococcus‐specific immunoglobulin E in cigarette smokers

A relationship between elevated scrum immunoglobulin E levels and smoking has been demonstrated in epidemiological studies. Allergy skin test data suggest that the excess immunoglobulin E of smokers is not specific for aeroallergens. It is possible that the excess immunoglobulin E is specific for microorganisms that often infect the lower respiratory tract of smokers. To investigate this possibility we utilized a radio‐allergosorbent test assay for detecting serum immunoglobulin E specific for Streptococcus pneumoniae, an organism commonly isolated from the respiratory tract of smokers with chronic bronchitis. We assayed sera of thirty smokers and thirty nonsmokers for immunoglobulin E specific for Streptococcus pneumoniae. Individual sera were considered positive for pneumococcus‐specific immunoglobulin E if the binding was at least twice the non‐specific binding at the total immunoglobulin E concentration of the particular serum. Eleven of the thirty sera of smokers and two of the thirty nonsmokers were positive for pneumococcus‐specific immunoglobulin E. By chi‐square analysis of these data, the prevalence of pneumococcus‐specific immunoglobulin E was significantly greater in the smoking group compared with the non‐smoking group (P<0·02). These results suggest that the excess immunoglobulin E of smokers is, at least in part, specific for microorganisms that infect the airways.

Malondialdehyde modified proteins and their antibodies in the plasma of control and streptozotocin induced diabetic rats

One of the possible mechanisms of diabetes-related tissue damage is modification of various proteins via lipid peroxidation byproducts such as malondialdehyde (MDA). To determine the extent of MDA derivatization of plasma proteins, Western blots were carried out using anti-MDA antisera to study plasma proteins in control and streptozotocin (STZ)-induced diabetic rats. Since MDA can modify proteins and may alter or enhance their antigenicity, we screened plasma samples for anti-MDA antibodies using enzyme-linked immunosorbent assay (ELISA), and confirmed antibody specificity by inhibition ELISA. Circulating immune complexes containing MDA were also assayed. This study is the first demonstration of the existence in plasma of MDA-modified proteins with a molecular weight of approximately 100 Kd. Both control and diabetic rats have similar concentrations of plasma anti-MDA antibodies and circulating immune complexes. These results do not support the notion that diabetes alters the immune response to MDA modified proteins. Whether MDA modification of proteins participate in immunological processes that lead to tissue injury remains to be demonstrated.

Effect of select antioxidants on malondialdehyde modification of proteins.

To determine whether commonly used antioxidants alter malondialdehyde (MDA) modification of proteins, a known mechanism of free radical-related tissue injury, we studied the effect of adding 1 mg/mL of pycnogenol, 5 mM of alpha-tocopherol, 5 mM of ascorbate, and 0.2 mg/mL of an ethanol equivalent of red and white wine on MDA-protein content of endothelial cells in culture. The addition of pycnogenol but not of the other antioxidants was associated with significant reduction in MDA-protein content compared with controls (0.521 +/- 0.041 in arbritrary units versus 1.011 +/- 0.021, P < 0. 001). To determine whether the observed effect occurs distal to MDA generation, the effect of these antioxidants on the modification of bovine serum albumin with MDA generated in a cell-free system was studied. In this cell-free assay, pycnogenol but not the other antioxidants reduced MDA-BSA generation by approximately 50%. It is concluded that pycnogenol may reduce MDA modification of proteins at a step distal to MDA generation. This may be an additional mechanism of protective effects of pycnogenol against oxidative stress.

Studies of kissing bug-sensitive patients: Evidence for the lack of cross-reactivity between Triatoma protracta and Triatoma rubida salivary gland extracts*

In the southern and western sections of the United States, bites from the reduviid bug, commonly known as the kissing bug, genus Triatoma, may induce serious life-threatening allergic reactions. This study was undertaken to identify the allergens responsible for patient sensitization and to determine the extent of cross-reactivity of these allergens. The Triatoma spp. most commonly encountered in California and Arizona, T. protracta and T. rubida, were obtained, maintained in the laboratory, and dissected to prepare extracts for testing. Extracts were prepared from T. protracta and T. rubida for study by RAST, lymphocyte transformation, leukocyte histamine release, and RAST inhibition. Sera and cells were collected from patients who had generalized reactions to Triatoma bites. Our results indicate that T. protracta and T. rubida antigens to which patients are sensitized are present in extracts that contain saliva and that human responses are specific for T. protracta or T. rubida, i.e., allergic cross-reactivity could not be demonstrated.

Adverse reactions to ants other than imported fire ants

OBJECTIVE To identify ants other than Solenopsis invicta and Solenopsis richteri reported to cause adverse reactions in humans. DATA SOURCES We conducted a literature review to identify reports of medical reactions to ants other than S. invicta and S. richteri. Our review of medical and entomological literature on stinging ants was generated from MEDLINE and FORMIS, respectively, using the key words stinging ants and ant stings. The search was limited to articles in English published from 1966 to 2004 on MEDLINE and all years on FORMIS. We also present 3 new case reports of severe reactions to stings by 2 different species of ants, Pseudomyrmex ejectus and Hypoponera punctatissima. STUDY SELECTION Articles that concerned anaphylactic (IgE-mediated) or anaphylactic-like (resembling anaphylaxis but mechanism unknown) immediate reactions to ant stings or bites were included in this review. RESULTS Taken together, our data demonstrate that S. invicta and S. richteri are not alone in their capability to cause serious allergic or adverse reactions. A diverse array of ant species belonging to 6 different subfamilies (Formicinae, Myrmeciinae, Ponerinae, Ectatomminae, Myrmicinae, and Pseudomyrmecinae) and 10 genera (Solenopsis, Formica, Myrmecia, Tetramorium, Pogonomyrmex, Pachycondyla, Odontomachus, Rhytidoponera, Pseudomyrmex, and Hypoponera) have now been shown to have this capability. CONCLUSION Awareness that species other than imported fire ants may cause severe reactions should lead to more rapid evaluation and treatment and further investigation of the medical entomology of these ants.

GLYCOSYLATION ENHANCES MALONDIALDEHYDE BINDING TO PROTEINS

To determine whether glycosylation of proteins increases their susceptibility to modification with malondialdehyde (MDA), bovine serum albumin, which was pretreated with 500 mg/dl dextrose at 37 degrees C for 0, 1, 2, and 4 weeks, were incubated with 100 mM MDA at 37 degrees C for 24 h. The MDA content of the protein samples were determined after dialysis using thiobarbituric acid (TBA) assay. In addition, a specific anti-MDA protein antiserum was used to demonstrate MDA proteins with immunoblotting technique. The MDA content of BSA preincubated with dextrose for 4 weeks and reincubated with MDA (0.0649 +/- 0.0019 microgram MDA/mg protein) was significantly higher (p < .001) than the MDA content of BSA preincubated with dextrose for only one (0.0227 +/- 0.0031 microgram/mg) or two (0.0347 +/- 0.0034 microgram/mg) weeks or the MDA content of nonglysolated BSA incubated with MDA at the same experimental conditions (0.0201 +/- 0.0029 microgram/mg). These differences could also be found in the immunoblots. However, the correlation of TBA assay with the estimates on immunoblots was poor. It is likely that the immunoblotting assay is more of an estimate of the number of BSA molecules modified with MDA, rather than MDA content of each BSA molecule. It is concluded that in vitro glycosylation of proteins increases their susceptibility to MDA-modification. This may well be an additional pathway of diabetes-related modification of proteins.