David Ikle

Studies of allergen extract stability: The effects of dilution and mixing

BACKGROUND However potent the allergy extracts provided by manufacturers, they are subject to deterioration with storage, especially after dilution or mixture with other extracts. OBJECTIVE This study was performed to assess separately the deterioration during storage in allergen extract potency caused by dilution or by mixture with allergen extracts that have been reported to contain proteases. METHODS To assess the effect of dilution, three serial 10-fold dilutions of cat, short ragweed, Bermuda grass, and Dermatophagoides farinae extracts were prepared alone or combined with other extracts. They were stored at 4 degrees C for 3 and 12 months. To assess the effect of mixing with other extracts that have been reported to contain proteases, extracts of timothy grass, Bermuda grass, short ragweed, Russian thistle, white oak, box elder, D. farinae, and cat were stored alone or combined with one or more extracts of American cockroach, Alternaria spp., Cladosporium spp., Penicillium spp., and a house dust mite mix for 3 months at 4 degrees C. RESULTS Bermuda grass, cat, and house dust mite extracts incurred significant loss of potency at all dilutions with storage. Short ragweed was stable at all dilutions. Potency of extracts of timothy grass, Bermuda grass, Russian thistle, white oak, box elder, and cat were all reduced by combination with one or more extracts potentially containing proteases. Only short ragweed and D. farinae, which was in a final concentration of 25% glycerin, were resistant. Alternaria extract was most frequently responsible for loss of potency, followed by cockroach and Cladosporium extracts. Combination with extracts of Penicillium and a house dust mite mix did not reduce the potency of any extract. CONCLUSIONS Both dilution alone and mixture with extracts reported to contain proteases caused loss of potency of most extracts tested. Ragweed was uniquely resistant under both conditions of storage.

Comparative performance of five commercial prick skin test devices

Five commercially available devices for performing prick skin testing were compared for reproducibility, patient acceptance, occurrence of false-negative skin test results, and size distribution of reactions at the negative control sites. Reproducibility of skin testing with 10 mg/ml histamine base, as expressed by coefficient of variation, was similar. However, a clear range of trauma to the skin was produced by the devices. This trauma was least with the Hollister-Stier and ALK Laboratories lancets, intermediate for the bifurcated needle by either prick or puncture, and greatest for the Multi-Test and DermaPIK devices. The more traumatic devices produced larger mean wheals and more frequent and large reactions at saline control sites, and were less acceptable to subjects. However, except for the Multi-Test device, they less often yielded false-negative responses. It is proposed that for each device a different size of wheal must be produced at the allergen site to have confidence that it exceeds the control site. The wheal size necessary for 99% specificity were as follows: Hollister-Stier lancet, 2 mm; ALK lancet, 3.0 mm; bifurcated needle prick, 4.0 mm; bifurcated needle puncture, 4.5 mm; Multi-Test device, 5.0 mm; and DermaPIK device, 5.5 mm. An additional observation was the presence of a significant gradient of reaction size on the back to both histamine and allergen (p < 0.0001), with the smallest reactions in the upper third and the largest in the lower third of the back.

Prediction of early-onset asthma in genetically at-risk children.

The W.T. Grant Foundation Asthma Risk Study was designed to prospectively examine children who were considered at a genetically increased risk for the development of asthma. The respective contributions of 11 potential risk factors, both environmental and biological, were assessed in order to determine their relative roles in affecting the early onset of asthma. This is a report of an inception cohort of children born to asthmatic mothers and followed for a 3‐year period. All 150 families were recruited from the general community and living within 2 h of the National Jewish Center for Immunology and Respiratory Medicine (Denver, CO). Mothers in the index risk sample had been previously diagnosed with asthma and were recruited during their pregnancy through physician referrals and media solicitation. The index sample of 150 families was 92% Caucasian and predominantly middle class.

Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma

BACKGROUND Troleandomycin (TAO), a macrolide antibiotic, was studied as an alternative treatment in 18 children with severe, steroid-requiring asthma. METHODS In this investigation three treatment arms were used in randomized, double-blind, parallel fashion: combination TAO and methylprednisolone (MPn), combination TAO and prednisone, and MPn alone. RESULTS All groups tolerated a considerable reduction in glucocorticoid dose over the 12 weeks of the study: 80% +/- 6% for TAO-MPn, 55% +/- 8% for TAO-prednisone, and 44% +/- 14% for MPn alone. These reductions are all statistically significant (p < 0.05) within groups, and the differences between groups were statistically significant between the TAO-MPn and MPn alone groups. The concentration of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second and pulmonary function were not significantly improved in any treatment group. Safety parameters including blood chemistry and hematology, adrenal function assessment; bone densitometry, and muscle strength testing, were not altered significantly. Two patients who received TAO had elevated liver enzyme levels; one required discontinuation of TAO and one experienced spontaneous resolution without intervention. Lack of statistically significant changes in the efficacy parameters were likely a result of small sample size and effects of the glucocorticoid dose taper. CONCLUSIONS TAO is safe and may be a reasonable treatment alternative in a limited trial for patients who are unable to tolerate tapering of their glucocorticoid dosage. Therapy should be guided by the goal of treatment, that is, glucocorticoid dose reduction or improvement of pulmonary function with appropriate monitoring of pulmonary function and adverse effects.

Pilot Trial Evaluating an 123I-Labeled 80-Kilodalton Engineered Anticarcinoembryonic Antigen Antibody Fragment (cT84.66 Minibody) in Patients with Colorectal Cancer

Purpose: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (VL-linker-VH-CH3; 80 kDa) that demonstrates bivalent and high affinity (4 × 1010 m−1) binding to carcinoembryonic antigen (CEA). The variable regions (VL and VH) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the CH3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab′)2 fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether 123I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer. Experimental Design: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5–10 mCi (1 mg) of 123I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48–72 h. Surgery was performed immediately after the last nuclear scan. Results: Tumor imaging was observed with 123I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. 123I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9–65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed. Conclusion: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as 111In.

Prognostic Impact of Acute Myeloid Leukemia Classification

To evaluate the prognostic impact of acute myeloid leukemia (AML) classifications, specimens from 300 patients with 20% or more bone marrow myeloblast cells were studied. Specimens were classified according to the French-American-British Cooperative Group (FAB), the World Health Organization (WHO), the Realistic Pathologic Classification, and a cytogenetic risk group scheme. Cases with fewer than 30% blast cells did not have a 5-year survival significantly different from cases with 30% or more blast cells, and survival was similar for the low blast cell count group and cases with multilineage dysplasia and 30% or more blasts. Categories of AML with recurrent cytogenetic abnormalities of t(15;17), t(8;21), inv(16)/t(16;16), and 11q23 showed significant differences in 5-year survival. No significant difference was identified between AMLs arising from myelodysplasia and de novo AMLs with multilineage dysplasia, but all cases with multilineage dysplasia had a worse survival than all other AMLs and other AMLs without favorable cytogenetics. FAB types M0, M3, and M4Eo showed differences in survival compared with all other FAB types, with M0 showing a significant association with high-risk cytogenetics and 11q23 abnormalities. Other FAB groups and WHO AML, not otherwise categorized subgroups did not show survival differences. These findings suggest that the detection of recurring cytogenetic abnormalities and multilineage dysplasia are the most significant features of current AML classification.

Outcomes with the ARISE approach to engaging reluctant drug- and alcohol-dependent individuals in treatment.

Our goal was to explore, through a Stage I NIH clinical study, the effectiveness of a manual‐driven, timely response method for helping the “concerned other” get resistant substance abusers into treatment/self‐help with minimum professional time/effort. A manual‐driven protocol, “A Relational Sequence for Engagement (ARISE),” was applied with 110 consecutive, initial calls/contacts from concerned others; no cases excluded for research, refusal, or other reasons. The research was conducted at two upstate New York outpatient drug/alcohol clinics. Participants were concerned others who called regarding a cocaine, alcohol, or “other drug” abuser (N = 110); participating family/friends: 11 ARISE clinicians; and 110 substance abusers. ARISE is a graduated continuum starting with the least demanding option/stage, increasing effort as needed to engage substance abusers in treatment/self‐help. Stage I: Coaching the concerned other to arrange a meeting of significant others, inviting the substance abuser; Stage II: 1 to 5 additional meetings (median = 2); Stage III: A modified Johnson “Intervention.” Primary outcome variables were substance abuser engagement (or not) in treatment/self‐help; days between first call and engagement; clinician time/effort. Predictors were concerned other, substance abuser, and clinician demographics; number of participants per case; and Collateral Addiction Severity Index. ARISE resulted in an 83% success rate (55% at Stage I). Median days to engagement was 7 (IQR = 2 to 14). Average total time (telephone, sessions) per case was 1.5 hours. Treatment/self‐help chosen was 95% treatment and 5% self‐help. Number of family/friends involved correlated 0.69 with a success/efficiency index. Conclusions. A call from a family member or concerned other for help in getting a loved one into treatment is a rich opportunity for treatment professionals and agencies to engage substance abusers in treatment. These initial calls are similar to referral calls from EAPs or probation officers looking to get an individual started in treatment. ARISE provides an effective, swift, and cost‐efficient option for engaging substance abusers in treatment or self‐help. The more significant others involved, the greater the success of treatment engagement.

Retention of asthmatic patients in a longitudinal clinical trial

BACKGROUND Prevention of study patient attrition and assessment of its impact on outcome data are problems that receive little attention despite their obvious importance in asthma research. OBJECTIVE The medical, demographic, and psychologic characteristics of asthmatic children and adults who dropped out of a yearlong medication trial were assessed to determine whether this group differed from those who completed the study, potentially introducing bias into the data set and interfering with completion of the studys objectives. METHODS Profiles of 362 adult and pediatric asthmatic patient dropouts from the multicenter trial were contrasted with profiles of those who completed the study. Despite a 1-month prerandomization screening, 24% of patients failed to complete the trial for varied reasons, which largely included noncompliance and treatment dissatisfaction. RESULTS Although attrition rates were equal among adults and children, dropout-completer differentiation was not. Adult completers did not differ from dropouts in any variables. However, pediatric dropouts were more likely than completers to be female (67% and 36%, p = 0.008) and to have more reactive airways (PD20, 2.29 +/- 1.32 and 5.2 +/- 1.23, p = 0.05), to have reduced scores on tests of intelligence (Full Scale IQ, 102.2 +/- 2.6 and 112.5 +/- 1.6, p = 0.002) and problem solving (Wisconsin Card Sorting Test Error Scores, 39.8 +/- 4.1 and 29.1 +/- 2.0, p = 0.01), and to have increased behavioral problems (Child Behavior Checklist Total Problem Score, 60.7 +/- 2.5 and 53.6 +/- 1.1, p = 0.003). CONCLUSION These findings demonstrate the potential of patient attrition to bias outcome in clinical trials and underscore the necessity of: (1) preventing its occurrence, (2) correctly assessing its causes, and (3) determining its ultimate impact on study results. Strategies for each of these three tasks should be implemented at the studys initial planning stages.

Reliability of the model MC-311 MDI Chronolog

BACKGROUND The Model MC-311 MDI Chronolog (Medtrac Technologies, Lakewood, Colo) is an electronic device for monitoring adherence to metered-dose inhalers (MDIs). It is a thermistor-actuated, microprocessor-equipped device that dispenses inhaled medication while recording the date and time of each canister activation. OBJECTIVE We evaluated the reliability of the MC-311 MDI Chronolog to determine whether the model could accurately record and report the date, time, and number of MDI actuations. METHODS Twenty-four of the MC-311 Chronologs were discharged at 8 hourly intervals across 8 days. Battery voltage was assessed before and after the experiment. The mouthpieces of 12 Chronologs were washed daily. RESULTS By using generous criteria for acceptable reliability, only 10 of 24 (42%) were rated as acceptable. None of these 10 Chronologs recorded 320 or greater actuations (mean +/- SD, 293.9 +/- 13.3; range, 266 to 308); all reliable Chronologs underestimated MDI activation. An additional 6 devices had an initial signature of erroneous recordings dating from device initialization. After removing this signature, the remaining data showed acceptable reliability. All the remaining Chronologs judged to be unacceptable showed time series patterns of seizures (ie, bursts of clustered, erroneous records). Seizures were distributed across trial days, were associated with washing, and preceded all 4 cases of battery failure. Damage to the thermistor is the likely cause of seizure-pattern failures. CONCLUSIONS In summary, because of a combination of a clear underreporting bias with frequent initialization and seizure-pattern failures, the Model MC-311 MDI Chronolog is not recommended for use in clinical care or research

Neuropsychological and behavioral changes in asthmatic children treated with beclomethasone dipropionate versus theophylline

Objective. Results from previous investigations that examined the psychological side effects of theophylline have been inconsistent, and none have reported about inhaled corticosteroids. The objective of this study was to assess the relative psychological side effects of theophylline and beclomethasone in asthmatic children. Methods. This was a multicenter, randomized, double-blind, parallel-groups study in which 102 asthmatic patients were assigned to one of two treatments: beclomethasone three times daily or theophylline twice daily. At baseline, 1 month, and 1 year, parents completed standardized behavioral questionnaires while the children received psychometric testing of attention and concentration, memory and learning, and problem-solving. Results. Although power was sufficient to detect meaningful mean score changes, no consistent differential treatment effects were observed. Two significant treatment-by-period interactions were discordant, with one suggesting slightly better attention in the theophylline group, whereas the other indicated a small advantage in attention scores in the beclomethasone group. Numerous significant period effects revealed that behavior and cognitive test performance improved over the 1-year period, regardless of treatment, and confirmed a well established practice effect resulting from repeated administrations of such tests. Conclusions. Neither theophylline nor beclomethasone should be avoided out of concern for significant psychological side effects. The possibility remains that a subset of asthmatic children may be susceptible to such medication-induced changes; investigators have suggested that preschool children may be at particular risk, although no controlled studies with this age group have been conducted. Parental perceptions of medication side effects can be influenced by temporary effects present at initiation of treatment or by erroneous attribution of the psychological effects of the chronic illness. Reports of psychological changes in response to asthma medications must be addressed respectfully but objectively, with due consideration of available evidence and an awareness of other potential explanations.