Slope Of Dose-response Curve Research Articles

Relative potency of pregabalin, gabapentin, and morphine in a mouse model of visceral pain

Pregabalin is probably more effective than prototype gabapentin in different kinds of pain treatments. This study was performed to compare the potency of gabapentin, pregabalin, and morphine in a well-established model of visceral pain. The number of abdominal contractions was counted for 30 min in adult male mice that received different doses of pregabalin, gabapentin, morphine, or placebo intraperitoneally 30 min before receiving 0.6% acetic acid 10 mL·kg(-1).The antinociceptive effect of each drug dose was determined as a percentage of the reduction in the number of acetic acid-induced writhes. The effective doses, for 20%, 50%, and 80% response (ED(20), ED(50), and ED(80), respectively), of each drug were calculated using least squares linear regression analysis, and then dose-response curves were compared. Pregabalin, gabapentin, and morphine produced a linear dose-dependent antinociceptive effect (coefficient of determination [r(2)] > 0.9). No difference was observed between slopes of dose-response curves. The ED(50) estimates (95% confidence interval) for pregabalin, gabapentin, and morphine were 17.1 (12.9 to 22.1) mg·kg(-1), 87.1 (45.8 to 129.8) mg·kg(-1), and 0.2 (0.1 to 0.3) mg·kg(-1), respectively. In this animal model of visceral pain, all three drugs exhibited parallel dose-response curves. Pregabalin had five times the potency of gabapentin and 1/85(th) the potency of morphine. Similar potency ratios may apply in clinical practice. Despite some limitations of animal studies, this model could be useful for comparing new analgesics in visceral pain treatment.

A Quantitative Measurement of Antiviral Activity of Anti-Human Immunodeficiency Virus Type 1 Drugs against Simian Immunodeficiency Virus Infection: Dose-Response Curve Slope Strongly Influences Class-Specific Inhibitory Potential

Simian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.

Mutagenicity assessment of contaminated soil in the vicinity of industrial area

In the industrial area of Chinhat, Lucknow (India) wastewater coming from pesticide manufacturing and other industries is used to irrigate the agricultural crops. This practice has been polluting the soil and pollutants might reach the food chain. Gas chromatographic analysis revealed the presence of certain organochlorine pesticides in soil samples. Samples were extracted using different solvents, i.e., hexane, acetonitrile, methanol, chloroform, and acetone (all were HPLC-grade, SRL, India). Soil extracts were assayed for mutagenicity using Ames Salmonella/mammalian microsome test. Mutagenicity was observed in the test samples and TA98 was the most responsive strain for all the soil extracts (irrigated with wastewater) in terms of mutagenic index in the presence (+S9) and absence (-S9) of metabolic activation. In terms of slope (m) of linear dose-response curve for the most responsive strain TA98 exhibited highest sensitivity against the soil extracts in the presence and absence of S9 fraction. Hexane-extracted soil sample (wastewater) exhibited maximum mutagenicity in terms of net revertants per gram of soil in the presence and absence of S9 mix as compared to the other soil extracts. Groundwater-irrigated soil extracts displayed low level of mutagenicity as compared to wastewater-irrigated soil. The soil is accumulating a large number of pollutants due to wastewater irrigation and this practice of accumulation has an adverse impact on soil health.

Pulmonary function, bronchial reactivity, and epithelial permeability are response phenotypes to ozone and develop differentially in healthy humans

Effect of laboratory exposure to O₃ (220 ppb) and filtered air (FA) on respiratory physiology were evaluated at two time points (acute and 1 day postexposure) in healthy cohort (n = 138, 18-35 yr, 40% women) comprised mainly of Caucasian (60%) and African American (33.3%) subjects. Randomized exposures had a crossover design and durations of 2.25 h that included rest and treadmill walking. Airway responsiveness (AHR) to methacholine (Mch) and permeability of respiratory epithelium (EI) to hydrophilic radiomarker ((99m)Tc-DTPA, MW = 492), were measured at 1-day postexposure. O₃ significantly affected FEV₁ and FVC indices acutely with mean decrements from pre-exposure values on the order of 7.7 to 8.8% and 1.8 to 2.3% at 1-day post. Acute FEV₁ and FVC decreases were most robust in African American male subjects. At 1-day post, O₃ induced significant changes in AHR (slope of Mch dose response curve) and EI (Tc(99m)-DTPA clearance half-time). Based on conventional thresholds of response and dichotomous classification of subjects as responders and nonresponders, sensitivity to O₃ was shown to be nonuniform. Acute decrements ≥ 15% in FEV₁, a doubling of Mch slope, or ≥ 15% increase in EI developed in 20.3%, 23.1%, and 25.9%, respectively, of subjects evaluated. Results demonstrate a diffuse sensitivity to O₃ and physiological responses, either acutely (decreases in FEV₁) or 1 day post (development of AHR or change in EI) occur differentially in healthy young adults. Random overlap among subjects classified as responsive for respective FEV₁, AHR, and EI endpoints suggests these are separate and independent phenotypes of O₃ exposure.

Susceptibility of Field Populations of Blattella germanica (Blattaria: Blattellidae) to Spinosad

The German cockroach is an important household insect pest worldwide and acts as a mechanical vector and reservoir for pathogenic agents. The aim of this study was to examine the basic laboratory toxicity of Blattella germanica to spinosad. The M, T, A22, AZAR4, BOOSTAN7 and ABAN21 strains were collected from field populations of six infested kitchen student dormitories and the SAMAN strain was collected from a residential area after insecticide spraying control failure in Tehran, Iran. Technical grade spinosad was delivered in 0.5 microL acetone to the first abdominal sternum of briefly CO2-anesthetize adult male cockroaches by topical application bioassay. Treated males monitored for mortality. Mortality data from the replicates was assessed by probit analysis. The average LD50 of susceptible strain was 494.3, 148.8 and 55.1 ng per insect after 24, 48 and 72 h, respectively. The LD50 of spinosad decreased with time in the field population strains. All German cockroach strains showed a similar susceptibility or lower tolerance (1.6-folds) for spinosad compared with the susceptible laboratory strain and the steep slopes of dose-response curves indicated that the field population of these German cockroach strains was homogenous in response to spinosad. These results indicated that the spinosad was relatively slow-acting in topical application bioassay, with LD50 values decreasing until 72 h and becoming stable thereafter. The effectiveness of spinosad against susceptible and the field population German cockroach strains in laboratory condition showed that spinosad probably could be useful for the control of the German cockroach.

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC(50) caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC(50), however, and inhibition at clinical concentrations can only be predicted from IC(50) if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC(50). For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC(50) is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC(50), and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC(50), does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.

Anti-nicotinic properties of anticholinergic antiparkinson drugs.

The nature of the antagonism by anticholinergic compounds of nicotine-induced convulsion in mice has not been defined clearly. Although, because they do not compete effectively for agonist binding to brain tissue in-vitro, these compounds are thought to be non-competitive antagonists in the brain, pharmacological evidence is lacking. This study describes the anti-nicotinic properties of the clinically used anticholinergic antiparkinson drugs, benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl. Nicotine-induced convulsion and arecoline-induced tremor in mice were effectively prevented by these drugs. The concentrations of benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl affording 50% prevention of nicotine-induced convulsion (ED50 values) were 7.4, 4.6, 7.8, 4.9, 3.1 and 3.3 mg kg(-1), respectively. The classical muscarinic receptor antagonist atropine had potent anti-muscarinic effects but very weak anti-nicotinic activity. The classical nicotinic receptor antagonist mecamylamine had potent anti-nicotinic activity but no anti-muscarinic effects. The pattern of shift of the dose-response curve for nicotine-induced convulsion in mice was determined in the presence of increasing concentrations of the anticholinergic antiparkinson drugs. These drugs were found to increase the ED50 (0.49 mg kg(-1)) of nicotine-induced convulsion in a dose-related manner. The maximum effect of nicotine and the slope of nicotine dose-response curve were not significantly influenced by either low or high doses of benztropine, procyclidine or trihexylphenidyl, which suggests competitive action. Biperiden, caramiphen and ethopropazine, at low doses which significantly increased the ED50 of nicotine, did not affect the maximum effect of nicotine or the slope of the nicotine dose-response curve; at higher doses, however, they reduced the maximum effect and the slope, which suggests that these drugs have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice. The experiments demonstrate that the anticholinergic antiparkinson drugs and mecamylamine effectively antagonize nicotine-induced convulsion, but atropine does not; some of these drugs have competitive properties whereas others seem to have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice.

Effect of β-adrenoceptor antagonists on the decline of the chronotropic response to isoprenaline

Abstract The effect of three β-adrenoceptor antagonists (propranolol, practolol and H 35/25*) have been investigated on the decline of the tachycardia produced by intravenous doses of isoprenaline. Propranolol (0.5 mg/kg laevo-isomer) caused a significant increase in the rate of decline from 17.2 to 36.5 beats/min. Practolol (2 mg/kg), H 35/25 (2 mg/kg) and the combination of the two did not influence the rate of decline. Only propranolol caused a change in the slope of the isoprenaline heart rate dose-response curve; the observed increase of this slope is the probable cause of the change in rate of decline of the heart rate response.

Baseline Susceptibility of Primary HIV-2 to Entry Inhibitors

The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown. The susceptibility of 19 HIV-2 isolates obtained from asymptomatic and AIDS patients and seven HIV-1 clinical isolates to the fusion inhibitors enfuvirtide (ENF) and T-1249, and to the coreceptor antagonists AMD3100, TAK-779 and MVC, was measured using a TZM-bl cell-based assay. The 50% inhibitory concentration (IC(50)), 90% inhibitory concentration (IC(90)) and dose-response curve slopes were determined for each drug. ENF and T-1249 were significantly less active on HIV-2 than on HIV-1 (211- and 2-fold, respectively). AMD3100 and TAK-779 inhibited HIV-2 and HIV-1 CXCR4 tropic (X4) and CCR5 tropic (R5) variants with similar IC(50) and IC(90) values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC(90) values (42.7 versus 9.7 nM; P<0.0001) and lower slope values (0.7 versus 1.3; P<0.0001) than HIV-1. HIV-2 R5 variants derived from AIDS patients were significantly less sensitive to MVC than variants from asymptomatic patients, this being inversely correlated with the absolute number of CD4(+) T-cells. T-1249 is a potent inhibitor of HIV-2 replication indicating that new fusion inhibitors might be useful to treat HIV-2 infection. Coreceptor antagonists TAK-779 and AMD3100 are also potent inhibitors of HIV-2 replication. The reduced sensitivity of R5 variants to MVC, especially in severely immunodeficient patients, indicates that the treatment of HIV-2-infected patients with MVC might require higher dosages than those used in HIV-1 patients, and should be adjusted to the disease stage.

ATM is the Predominant Kinase Involved in the Phosphorylation of Histone H2AX after Heating

Heating induces histone H2AX phosphorylation at serine 139 (gammaH2AX). Phosphorylated H2AX subsequently forms foci in numerous mammalian cell lines. The aim of this study was to clarify details in the mechanisms involved in the phosphorylation of H2AX after heating. The cell lines used were DNA-PKcs knockout cells, ATM knockout cells, and their parental cell lines. To elucidate mechanisms of induction of phosphorylation of H2AX after heating, ATM/ATR inhibitor (CGK733) and DNA-PK inhibitor (NU7026) were used. The intensity of gammaH2AX signals was assayed with flow cytometry. The thermal dose-response curve for the fluorescence intensity of gammaH2AX appearance in DNA-PKcs-/- cells during the heating period was similar to that observed in DNA-PKcs+/+ cells. On the other hand, the slope of thermal dose-response curve for them in ATM-/- cells was lower than that in ATM+/+ cells. Phosphorylation of H2AX after heating was suppressed by a combination of CGK733 and NU7026 in the culture medium in DNA-PKcs-/- cells, ATM-/- cells and in their parental cells. Although the phosphorylation of H2AX after heating was not suppressed by NU7026 in their parental cells, such phosphorylation was suppressed by CGK733 in their parental cells. These results indicate that ATM is the predominant protein which is active in the phosphorylation of histone H2AX after heating.

Improved MAGIC gel for higher sensitivity and elemental tissue equivalent 3D dosimetry

Polymer-based gel dosimeter (MAGIC type) is a preferable phantom material for PET range verification of proton beam therapy. However, improvement in elemental tissue equivalency (specifically O/C ratio) is very desirable to ensure realistic time-activity measurements. Glucose and urea was added to the original MAGIC formulation to adjust the O/C ratio. The dose responses of the new formulations were tested with MRI transverse relaxation rate (R2) measurements. The new ingredients improved not only the elemental composition but also the sensitivity of the MAGIC gel. The O/C ratios of our new gels agree with that of soft tissue within 1%. The slopes of dose response curves were 1.6-2.7 times larger with glucose. The melting point also increased by 5 degrees C. Further addition of urea resulted in a similar slope but with an increased intercept and a decreased melting point. Our improved MAGIC gel formulations have higher sensitivity and better elemental tissue equivalency for 3D dosimetry applications involving nuclear reactions.

New approaches for quantitating the inhibition of HIV-1 replication by antiviral drugs in vitro and in vivo

With highly active antiretroviral therapy, HIV-1 infection has become a manageable lifelong disease. Developing optimal treatment regimens requires understanding how to best measure anti-HIV activity in vitro and how drug dose-response curves generated in vitro correlate with in-vivo efficacy. Several recent studies have indicated that conventional multiround infectivity assays are inferior to single cycle assays at both low and high levels of inhibition. Multiround infectivity assays can fail to detect subtle but clinically significant anti-HIV activity. The discoveries of the anti-HIV activity of the hepatitis B drug entecavir and the herpes simplex drug acyclovir were facilitated by single-round infectivity assays. Recent studies using a single-round infectivity assay have shown that a previously neglected parameter, the dose-response curve slope, is an extremely important determinant of antiviral activity. Some antiretroviral drugs have steep slopes that result in extraordinary levels of antiviral activity. The instantaneous inhibitory potential, the log reduction in infectivity in a single-round assay at clinical drug concentrations, has been proposed as a novel index for comparing antiviral activity. Among in-vitro measures of antiviral activity, single-round infection assays have the advantage of measuring instantaneous inhibition by a drug. Re-evaluating the antiviral activity of approved HIV-1 drugs has shown that the slope parameter is an important factor in drug activity. Determining the instantaneous inhibitory potential by using a single-round infectivity assay may provide important insights that can predict the in-vivo efficacy of anti-HIV-1 drugs.

A novel method for determining the inhibitory potential of anti-HIV drugs

In the absence of cure, most HIV-1-infected individuals will require lifelong treatment. It is therefore essential to optimize highly active antiretroviral therapy. Recent research has shown that the slope parameter or Hill coefficient, which describes the steepness of a dose-response curve, is a critical missing dimension in the evaluation of the activity of antiviral drugs. Based on this finding, instantaneous inhibitory potential (IIP) has been derived as a new measure of antiviral drug activity. IIP incorporates the slope parameter and thus is a more accurate pharmacodynamic measure of antiviral activity than current measures such as IC(50) and inhibitory quotient. Determining how to use IIP to predict the in vivo efficacy of anti-HIV-1 drugs is nevertheless important. This article discusses recent advances in in vitro measures of antiviral activity and the therapeutic implications of the dose-response curve slope and IIP.

Quantification of the neutralization of cytokine biological activity by antibody: the ten-fold reduction bioassay of interleukin-6 as growth factor.

The measurement of neutralizing antibodies (NAbs) to biological therapeutic agents is important clinically as well as for the preclinical evaluation of product immunogenicity. To determine whether the theoretical concepts and experimental data from studies of the nature of antibody neutralization of interferons (IFNs) can apply to unrelated protein effector molecules, neutralization experiments were undertaken with interleukin-6 (IL-6), a proinflammatory, highly pleiotropic cytokine. By following IL-6 induction of hybridoma cell growth, we demonstrated that anti-IL-6 monoclonal and polyclonal NAbs can be measured with a bioassay design structured to reduce 10 Laboratory Units (LU)/mL to 1 LU/mL. Results are reported in Ten-fold Reduction Units (TRU)/mL, as recommended for the standardization of IFN NAb unitage. The bioassay was shown to be sensitive, reproducible, and robust in measuring IL-6 potency and NAb titer, as well as for evaluating dose-response curve slope differences. This bioassay design should be applicable to any cytokine, growth factor, protein hormone, or similar effector molecules for which an adequately sensitive cellular response can be quantified.

Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs

Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.

Soluble Flt‐1 induces hypertension and vascular dysfunction in pregnant rats

The balance between pro‐ and anti‐angiogenic factors such as vascular endothelial growth factor (VEGF) and soluble Flt‐1 (sFlt‐1) is altered in preeclampsia (PE) and may be a contributing factor in the development and progression of the syndrome. We hypothesized chronic infusion of sFlt‐1 into pregnant rats to mimic the increase observed in PE would reduce plasma VEGF concentrations, restrict feto‐placental growth, increase arterial pressure (AP) and cause vascular dysfunction in the pregnant rat. Concentration of plasma sFlt‐1 was increased (299±33 vs. 100±16 pg/ml; P&lt;0.01) and free VEGF (570 ± 77 vs. 780 ± 48 pg/ml; P&lt;0.01) decreased in sFlt‐1 compared to vehicle infused dams. AP was increased (117±6 vs. 98±4 mm Hg; P&lt;0.01) while fetal (1.4±0.03 vs. 1.6±0.04, P&lt;0.01) and placental (0.50±0.01 vs. 0.45±0.01, P&lt;0.01) weight were decreased in the sFlt‐1 group compared to the vehicle group. Vasorelaxation to acetylcholine (ACh) and sodium nitroprusside were decreased (P&lt;0.05) and the Hill slope of the ACh dose response curve was altered (P&lt;0.05) in the sFlt‐1 group compared to the vehicle group. These findings support our hypothesis that chronic VEGF antagonism via sFlt‐1 results in vascular dysfunction and increased AP. These data indicate that elevated maternal concentrations of sFlt‐1 during pregnancy have deleterious effect on vascular function and may contribute to the hypertension observed in preeclampsia.

Biological effectiveness of 12C and 20Ne ions with very high LET

Purpose: To determine the relationship between the relative biological effectiveness (RBE) for cell inactivation and linear energy transfer (LET) in the Bragg peak region of 12C and 20Ne ions.Materials and methods: Chinese hamster ovary (CHO-K1) cells were exposed to high LET 12C (33.2 MeV, 20.3 MeV, 9.1 MeV at cell entrance) and 20Ne ions (56.2 MeV, 34.7 MeV, 15 MeV at cell entrance) and to low LET x-rays. Technical details of the irradiation facility are presented which is based on the Monte Carlo simulation of the lateral spread of heavy ions as a result of the multiscattering small-angle process in physical conditions of the experimental set-up.Results: RBE has been measured for LET values close to the Bragg peak maximum, i.e., 440–830 keV/μm for 12C and for 1020–1600 keV/μm for 20Ne ions. RBE values at several levels of survival were estimated and were found to decrease with increasing LET. The inactivation cross sections were calculated from the final slope of dose-response curves and were found to increase with increasing LET.Conclusions: The RBE decreases with increasing LET in the range between 440 and 1600 keV/μm for the two types of radiations forming a single line when plotted together, pointing towards LET as the single determinant of RBE. The inactivation cross section describing the killing efficiency of a single particle at the end of particle range comes close to the size of the cell nucleus.

Comparative Susceptibility of Cypermethrin in Ornithodoros lahorensis Neuman and Argas persicus Oken (Acari: Argasidae) Field Populations

The toxicity of cypermethrin was determined in five different soft tick strains of Argas persicus Oken and Ornithodoros lahorensis Neuman by topical application method. The O. lahorensis Bij, O. lahorensis west O1, O. lahorensis Mesh, A. persicus Lor, A. persicus West Ap strains were collected from Bijar, Kurdistan province, Takab, Western Azerbaijan province, Meshkinshar, Ardebil province, Khoramabad, Lorestan province, Takab, Western Azerbaijan province of different areas of Islamic Republic of Iran, respectively during 2004 and 2005. In the topical application bioassay, the average LD50 of O. lahorensis Bij, West O1, Mesh and A. reflexus Lor and West AP strains were 0.03, 0.04, 1.7, 0.7 and 1.7 microg tick(-1), respectively and the steep slopes of dose-response curves indicated that the field population of these soft tick strains were homogenous in response to cypermethrin. Comparison of the resistance ratio of collected strains with susceptible strain showed a resistance ratio of 56.7 and 2.4-folds for cypermethrin in O. lahorensis Mesh and A. reflexus West Ap strains, whereas the O. lahorensis West O1 completely susceptible to cypermethrin.

Dose Response for UV-induced Immune Suppression in People of Color: Differences Based on Erythemal Reactivity Rather than Skin Pigmentation¶†

Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation and UVR sensitivity were evaluated using Fitzpatrick classifications, minimal erythemal dose (MED), slope of the erythemal dose response curve (sED), baseline pigmentation and tanning response. To assess immune responses dinitrochlorobenzene (DNCB) was applied to irradiated buttock skin 72 h after irradiation. Two weeks later DNCB was applied to the inside upper arm. Skin thickness was measured before and after challenge. Dose response was modeled (to obtain a regression line) for the entire group of 185 subjects. With the exception of sED none of the above-mentioned pigmentation indicators contributed significantly to variability around the regression line. Thus, differences in sensitivity for multiple skin types based on Fitzpatrick classification or MED were not observed. However, differences in immune sensitivity to UVR were detected between subjects with steep erythemal dose response curves and those with moderate or flat responses. For subjects with steep erythemal responses the dose calculated to suppress the immune response by 50% was 114 mJ/cm2. This group included individuals with Fitzpatrick skin types I–V, MED for these subjects ranged from 30 to 80 mJ/cm2. The 50% suppression dose for subjects with weak or no erythemal response could not be computed (the dose response was flat). This resistant group included subjects with skin types IV–VI and MED for these subjects ranged from 41 to >105 mJ/cm2. This study provides a human dose response for UVR suppression of contact sensitivity that will be useful in risk assessment. It is the first study to provide this information using the FS sun lamp and is the first study to include people of color. The sED appears to be a new variable for identifying sensitive subjects at risk of UVR-induced immune suppression.

Effect of Age on Bronchial Reactivity in Children with Asthma

In contrast to an abundance of data concerning age-related changes of bronchial sensitivity, the relationship between age and rapidity of bronchoconstriction (bronchial reactivity) remains unclear. We studied age and bronchial reactivity in children with asthma. Enrolled in this study were 511 asthmatic subjects and 115 age-matched control subjects 1 to 16 years of age. Bronchial reactivity was represented by the slope of the methacholine transcutaneous oxygen pressure dose-response curve (SPO2) in younger children and the slope of the respiratory resistance dose-response curve (SRrs) in older children. Overall, SPO2 and SRrs were higher in asthmatic than control subjects. SPO2 increased significantly from 1 to 6 years in asthmatic subjects, reaching a plateau after age 7. This age-related change in SPO2 also was seen in controls. SRrs in asthmatic subjects decreased after age 13, while SRrs in controls showed no significant change between age 7 and 16. Age-related change in bronchial reactivity occurs during childhood, possibly reflecting early changes in airway smooth muscle maturity and later changes in airway wall rigidity.