Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.

Anaphylaxis is an acute and potentially lethal multi-system allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The Committee strongly believes that epinephrine is currently underutilized and often dosed suboptimally to treat anaphylaxis, is under-prescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate i.m. doses.

Pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient children.

Long-term GH replacement therapy is indicated for children with growth failure due to GH deficiency (GHD). We evaluated the feasibility of administering a long-acting GH preparation [Nutropin Depot (somatropin, rDNA origin) for injectable suspension] to prepubertal children with GHD by examining pharmacokinetic and pharmacodynamic response parameters after single or multiple doses. Data were collected from three studies involving 138 children treated with Nutropin Depot 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. Twenty-two patients underwent intensive sampling to estimate mean peak serum GH concentrations (C(max)) and time to achieve C(max) for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. C(max) and area under the curve were approximately proportional to the dose administered. Fractional area under the curve data indicate that at least 50% of GH exposure occurs during the first 2 d after administration. Serum GH levels remained above 1 microg/liter for 11-14 d. IGF-I levels remained above baseline for 16-20 d, but increases were not proportional to dose. After multiple doses over a 6-month period, peak and trough concentrations showed no progressive accumulation of GH, IGF-I, or IGF binding protein-3. Nutropin Depot administration once or twice per month provides serum levels of GH and IGF-I expected to promote growth, without accumulation of GH, IGF-I, or IGF binding protein-3, in children with GHD.

A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency.

Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.

Expanding habitat of the imported fire ant (Solenopsis invicta): a public health concern.

Residents in the southeastern United States would hardly describe life with the aggressive imported fire ant as peaceful coexistence. The continued spread of these insects has produced agricultural problems, changes in the ecosystem, and increasing numbers of subjects with sting sequelae, including hypersensitivity reactions, secondary infections, and rare neurologic sequelae. Evolutionary changes have facilitated their expansion northward into Virginia and westward into California, and increasing urbanization will likely permit further expansion. Recent reports of building invasion with sting attacks inside occupied dwellings, including health care facilities, heighten public health concerns. This article reviews the medically important entomology, clinical aspects of stings, and the current approaches to chemical control of fire ants. We also propose directions for future research and treatment.

Effect of newborn screening for congenital adrenal hyperplasia.

OBJECTIVE: To compare the incidence of diagnosis and morbidity in newborns who were screened with newborns who were not screened for congenital adrenal hyperplasia (CAH). DESIGN: A retrospective cohort study. SETTING: Arkansas, Oklahoma, and Texas. PATIENTS: An unscreened population in Arkansas and Oklahoma (n = 400118) was compared with a screened population in Texas (n = 1613378) during a 5-year period. Simultaneous data were collected on the incidence of diagnosis and associated morbidity in patients with CAH. MAIN OUTCOME MEASURES: Diagnosis of CAH, age (in days) at diagnosis, and frequency and length of initial hospitalization. RESULTS: The incidence of diagnosis of classic CAH per 100000 newborns in the unscreened cohort (5.75) and in the screened cohort (6.26) was similar (relative risk, 0.92; 95% confidence interval, 0.58-1.44). The unscreened group had 0.73 fewer male newborns with salt-wasting CAH diagnosed per 100000 newborns (relative risk, 0.73; 95% confidence interval, 0.35-1.56). The median age at diagnosis was 26 days for male newborns with salt-wasting CAH in the unscreened cohort vs 12 days in the screened cohort (z = 2.49; P = .01). Male newborns with simple-virilizing CAH and newborns with nonclassic CAH were detected only in the screened cohort. CONCLUSIONS: There was not a statistically significant (P = .73) increase in the diagnosis of salt-wasting CAH in the screened cohort. Male newborns benefited as a result of significantly (P = .01) earlier diagnosis, reduced morbidity, and shorter lengths of hospitalization. Large collaborative studies or meta-analyses are needed to determine the life-saving benefits of screening.

Analysis of bone age data from national cooperative growth study substudy VII.

National Cooperative Growth Study substudy VII was conducted 1) to compare standardized hand-wrist and knee bone age determinations in pubertal children treated with growth hormone (GH); 2) to compare local determinations of bone ages with centrally determined bone ages; 3) to relate the response to GH therapy to the bone age determinations; and 4) to ascertain the predictive value of each type of bone age determination. Eligible subjects were those in the National Cooperative Growth Study who were at Tanner pubertal stage 2 or greater for breasts (girls) or genitals (boys). Radiographs of the hand-wrist were taken annually, and radiographs of the knee were taken at the beginning and the end of the study. Separate bone age determinations were made from these radiographs. A combined hand-wrist and knee bone age determination also was derived. There were 990 patients in the study; in 925 (677 boys), there were both hand-wrist and knee bone age determinations from the baseline pubertal radiographs. There was only one radiographic assessment in 496 patients, two in 205 patients, and three to eight in the remaining patients. The strongest correlation was between the hand-wrist bone age and the hand-wrist plus knee bone age (r =.995). Also strongly correlated were knee with hand-wrist (r =.872) and knee with hand-wrist plus knee (r =.914). For none of these bone age methods was any statistically significant difference found between the methods. The locally determined bone ages correlated strongly with the centrally determined bone ages for knee (r =.850), hand-wrist (r =.928), and hand-wrist plus knee (r =.930); however, the locally determined knee and hand-wrist values were less (by approximately 0.3 year) than the centrally determined values. These differences, however, do not appear to be clinically significant.

Effects of recombinant human growth hormone on height and skeletal maturation in growth hormone-deficient children with and without severe pretreatment bone age delay.

UNLABELLED: The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. METHODS: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score

Effect of long-term recombinant growth hormone therapy in children--the National Cooperative Growth Study, USA, 1985-1994.

Over a 9-year period (1985-1994) approximately 20,000 children received recombinant human growth hormone (rhGH) while enrolled in the National Cooperative Growth Study (NCGS), an observational, longitudinal study designed to monitor the long term efficacy and safety of rhGH administered to children in North America. Forty-four percent of the patients had idiopathic growth hormone deficiency (IGHD), 13.8% organic GHD (OGHD), 25% idiopathic short stature (ISS), 9.9% Turner's syndrome (TS), and 7.3% miscellaneous disorders. Eighty-five percent of the patients enrolled were Caucasian, and approximately two-thirds of the non-Turner patients were male. For the subset of patients treated for at least 4 years and who were prepubertal throughout this period (IGHD N=308, OGHD N=93, ISS N=169, TS N=82), mean growth rates increased in all patient categories and remained at or above pretreatment growth rates through 4 consecutive years of therapy with rhGH. Growth rates during administration of rhGH were greater in children in whom the pretreatment maximum stimulated GH concentration was < or =3 microg/l. Patients treated with 6 or 7 doses of rhGH each week grew more rapidly than did those receiving thrice weekly dosages, although the ratios of the increment in bone age to the increment in height age after two years of therapy were similar in the two treatment regimens. For patients treated with rhGH for 7 consecutive years, the mean height standard deviation scores increased by 2.5 in IGHD (N=169), 2.0 in OGHD (N=50), 1.9 in ISS (N=69), and 1.3 in TS (N=19), but remained below target heights in all categories. It is concluded that administration of rhGH increases growth rates in patients with IGHD, OGHD, ISS, and TS, and that this stimulatory effect can persist for at least 4 years.

Allergic reactions to drugs and biologic agents.

Drug allergies are adverse reactions resulting from immunologic responses to drugs or their metabolites. These reactions result in predictable patterns of organ-specific or systemic hypersensitivity that usually recur on subsequent exposure to the same drug. Although diagnostic testing for drug allergy is available for only a few drugs, protocols have been developed to assist in management of allergic reactions to many drugs and biologic agents. Other protocols assist in the management of patients who develop drug reactions while undergoing multiple drug therapy or those with a history of adverse drug reactions who again require treatment for the same condition.

Renal structural-functional relationships in early diabetes mellitus.

To define the earliest renal morphological changes in patients with type I diabetes, we studied renal function and morphometric analysis of renal biopsies in 59 patients with diabetes for 5-12 years and normal blood pressure, normal creatinine clearance (CCr), and negative dipstick urinary protein. Arteriolar hyalinization and intimal fibrous thickening were noted in 43%. Glomerular basement membrane thickness and fractional mesangial volume were increased in 51% and 56%, respectively. The pre-pubertal and post-pubertal years of diabetes were associated with similar degrees of renal structural changes, but during the pre-pubertal years normal urinary albumin excretion (UAE) was seen. Principal factor analysis of morphometric structural parameters yielded four clusters of variables: "glomerular size" correlated with patient age, CCr, and UAE; "peripheral capillary decrease" correlated with glycosylated hemoglobin, diastolic blood pressure, glomerular filtration rate, and UAE; "mesangial increase" correlated with UAE; and "interstitial scarring" correlated with diastolic blood pressure. This study provides unique documentation of renal structural abnormalities which precede clinically evident renal functional abnormalities and documents that these early structural abnormalities are present in the pre-pubertal years of diabetes as well as postpuberty, and are associated with each other in constellations that correspond to postulated mechanisms in diabetic nephropathy.

Skin test and crossreactivity studies with Euroglyphus maynei and Dermatophagoides pteronyssinus.

BACKGROUND: The prevalence of sensitization to Euroglyphus maynei (E. maynei) in the United States has not been reported previously. OBJECTIVES: To determine: (1) the prevalence of skin-test reactivity in allergic subjects to E. maynei compared to D. pteronyssinus, D. farinae, and B. tropicalis and (2) the allergenic crossreactivity between D. pteronyssinus and E. maynei. METHODS: Skin testing with extracts of B. tropicalis and E. maynei (1:50 w/v) and standardized D. pteronyssinus and D. farinae extracts (1:50 w/v; 10,000 AU/mL) provided data on 250 subjects (87 males and 163 females) aged 9-77 years (mean age, 39.8 years) with possible allergic respiratory diseases. RAST inhibition assays were used to study crossreactivity between D. pteronyssinus and E. maynei. RESULTS: One hundred (40%) of 250 subjects had insignificant or no allergic diseases. Of the 150 allergic subjects (53 males, 97 females), 101 (67.3%) had a positive test (a percutaneous test with a weal diameter > or = 3 mm larger than the saline control) to at least one mite species; 60.7%, 60.0%, 28.7%, and 52.0% reacted to D. farinae, D. pteronyssinus, B. tropicalis, and E. maynei, respectively; 40 (26.7%) reacted to the four mite species. Positive tests to D. farinae, D. pteronyssinus, B. tropicalis, or E. maynei alone occurred in six (4.0%), four (2.7%), two (1.3%), and 0%, respectively. D. pteronyssinus and E. maynei showed moderately high crossreactivity in RAST inhibition assays. CONCLUSION: There is a high rate of skin-test reactivity to E. maynei in Florida. Moderately high crossreactivity exists between E. maynei and D. pteronyssinus.

Effective use of magnetic resonance imaging in the assessment of children with possible growth hormone deficiency.

OBJECTIVE: To present our experience with diagnosis of growth hormone (GH) deficiency in children and to determine which patients are most likely to benefit from magnetic resonance imaging (MRI). METHODS: We retrospectively reviewed medical records of pediatric patients who underwent assessment for possible GH deficiency during a 6-year period and correlated clinical variables, stimulated GH responses, and MRI findings. RESULTS: Of 100 children who failed outpatient GH screening tests, 14 were classified as at risk for hypothalamic pituitary defects, and 86 were considered not at risk, having short stature only. Patients were further stratified by age, sex, growth variables, maximal GH response to provocative testing, and MRI findings. A significant relationship existed between the presence of risk factors, maximal GH of <5 mg/L, and sellar defects. With no risk factors, MRI scans showed normal findings in 15 of 17 patients with maximal GH of <5 mg/L, in 33 of 34 patients with GH between 5 and 10 mg/L, and in all 35 patients with GH of >10 mg/L. Abnormal MRI findings included posterior pituitary ectopy, decreased pituitary size, absent midline central nervous system structures, enlarged infundibulum, and hamartoma. In one child with a 4-year history of growth failure and a maximal GH of 3.5 mg/L, craniopharyngioma was diagnosed. CONCLUSION: MRI scans should be obtained in any child with multiple pituitary hormone deficiencies, hypoglycemia, ophthalmologic anomalies, low-stimulated GH, or acquired growth failure. Otherwise asymptomatic children with growth delay and maximal GH of >10 mg/L do not need routine MRI screening. Such a strategy could result in substantial cost savings.

Anaphylaxis. A review of 266 cases.

BACKGROUND: A presentation of findings from a large population of anaphylaxis cases. METHODS: Retrospective chart review and follow-up questionnaire provided data on 266 subjects (113 males and 153 females) aged 12 to 75 years (mean age, 38 years) who were referred to a university-affiliated private allergy-immunology practice in Memphis, Tenn, for evaluation and management of anaphylaxis from January 1978 through March 1992. RESULTS: Of 266 subjects, 162 (61%) had three or more anaphylactic episodes, 41 (15%) had two episodes, and 63 (24%) had one episode. Atopy was present in 98 individuals (37%). Physicians thought foods, spices, and food additives caused anaphylaxis in 89 individuals (34%); crustaceans and peanut accounted for about half of these cases. Medications were thought to have caused the anaphylactic episodes in 52 individuals (20%); nonsteroidal anti-inflammatory drugs in about half of these cases. Other probable causes included exercise (n = 19), latex (n = 2), hormonal changes (n = 2), and insect bites (n = 4). A suspected cause could not be determined in 98 individuals (37%). These subjects were diagnosed as having idiopathic anaphylaxis. Of the 266 subjects, 102 responded to a follow-up survey; 68 (67%) of the 102 were thought to have identifiable causes of anaphylaxis (32 of whom [47%] failed to carry epinephrine syringes for self-administration despite instructions to do so). In contrast, of 34 subjects with idiopathic anaphylaxis who responded to the survey, only three (9%) did not carry epinephrine. CONCLUSIONS: (1) Atopy is common in subjects who experience anaphylaxis, regardless of its origin; (2) crustaceans and nonsteroidal anti-inflammatory drugs are the most common food and medication groups, respectively, thought to cause anaphylaxis; (3) causative agents can be identified for two thirds of the subjects, and recurrent attacks are the rule; and (4) subjects with idiopathic anaphylaxis are more likely to carry epinephrine for self-administration than those with identifiable causes.

Glyburide protein binding and the effect of albumin glycation in children, young adults, and older adults with diabetes.

Because glyburide is a weak acid that is more than 98% bound to albumin, the authors evaluated the binding in vitro and the influence of albumin glycation in children, young adults, and older adults with diabetes mellitus. Glyburide binding to non-glycated albumin was greater than 98%, and remained constant over a total concentration range of 50 to 1000 ng/mL. Increasing the albumin concentration from 0.5 to 5.0 g/dL was logarithmically related to the free fraction of glyburide. After the in vitro glycation of albumin (range, 5.7-15.6%), mean (+/- SD) glyburide binding was 99.05 +/- 0.082%, a value in agreement with that obtained from control serum. Serum samples from 57 subjects with type I and 16 patients with type II diabetes were incubated with 300 ng/mL of unlabeled glyburide and 200 ng/mL of 14C-glyburide. The extent of albumin glycation varied from 5 to 22% for the type I subjects and 5 to 14% for the type II subjects. The free fraction from these groups ranged from 1.07 to 1.75% and 0.66 to 0.88% for the type I and type II subjects, respectively. Although these values did not differ significantly from those of the control samples, the glyburide free fraction in patients with type I diabetes (1.39 +/- 0.85%) was significantly greater than that found for the 16 elderly patients with type II diabetes (0.78 +/- 0.05%). A significant linear relationship was not found between glyburide free fraction and the degree of albumin glycation for either group. Glyburide protein binding did not appear to be influenced by the extent of albumin glycation.

Clinical and biochemical correlates of growth associated with short-term administration of methionyl growth hormone.

Twenty newly diagnosed growth hormone-deficient children (19 males) were randomized to receive methionyl growth hormone (0.3 mg/kg/week) in subcutaneous doses divided daily (n = 12) or 3 times per week (TIW). With the initial dose and at 4-6 weeks after beginning therapy, procollagen type III propeptide (PIIIP) concentrations were determined. Growth velocities were calculated before and at 1, 3, and 6 months after beginning the therapy. Pretreatment growth velocities were 3.66 +/- (SD) 1.45 and 3.79 +/- 0.55 cm/year for the daily and TIW groups, respectively. At 1, 3, and 6 months mean growth velocities increased to 17.2, 10.2, and 9.5 cm/year for the daily group and 9.8, 6.8, and 7.6 cm/year for the TIW group, with differences between groups significant (p < 0.05) at 1 and 3 months. PIIIP concentrations increased significantly (p < 0.05) over 1 month in both groups, from 11.3 to 18.8 ng/ml and from 10.0 to 12.0 ng/ml in the daily and TIW groups, respectively. In addition PIIIP concentrations were significantly higher (p < 0.05) in the daily group at 1 month. A significant correlation was found between PIIIP concentrations at 1 month and the growth velocity at 1 (r = 0.47), 3 (r = 0.60), and 6 (r = 0.67) months. Pretreatment growth velocity was weakly correlated with posttreatment growth velocity at both 1 (r = -0.45) and 3 (r = -0.42) months. We conclude that (1) growth hormone is more effective when administered daily, (2) pretreatment growth velocity and PIIIP plasma concentration at 1 month correlate with 1 month growth velocity, and (3) PIIIP at 1 month provides a good evaluation of 6 months' response to methionyl growth hormone therapy.