Asthma medication - persistence with adrenergics, steroids and combination products over a 5-year period.

BACKGROUND: Many patients with asthma underuse steroids for inhalation. This has been identified as a main cause of therapy failure and of excess health care utilization. OBJECTIVE: To elucidate the medication persistence of patients using asthma drugs, how patients combine the drugs over time and whether medication persistence was influenced by patients switching to combination products. METHODS: Individual patients' drug acquisition data were obtained from a pharmacy record database for the period 2000-2004. A patient was considered to have satisfactory medication possession ratio (MPR) if the medication supplies covered >or=80% of the prescribed treatment. Drug use profiles were constructed as graphs for each patient, showing the date of each refill and the time period covered by the dispensed drugs. From the graphs the combination of drugs, the continuity of the therapy over time and the MPR for each patient could be determined. RESULTS: Of 1812 patients with asthma drugs in the database, 815 fulfilled the inclusion criteria. The percentage of patients with satisfactory MPR was low (11-27%), but significantly higher among patients using combination products than among those using steroids. For patients who switched from adrenergics plus steroids in two inhalers to combination products in one inhaler, the number of patients with satisfactory MPR was significantly increased. CONCLUSION: Satisfactory MPR was low for all types of asthma drugs. More patients had satisfactory MPR with combination products in one inhaler than with adrenergics and steroids in two separate inhalers. Asthma drug-delivery is important and combination products of the two ingredients could therefore improve asthma therapy.

Refill adherence by the elderly for asthma/chronic obstructive pulmonary disease drugs dispensed over a 10-year period.

OBJECTIVE: The objective was to survey prescription refill adherence for preventive asthma/chronic obstructive pulmonary disease (COPD) medication dispensed to patients 60 years and older over a 10-year period. METHODS: A retrospective analysis was conducted based on a Swedish pharmacy record database in the county of Jämtland for the years 1994-2003. Satisfactory refill adherence was set as dispensed refills covering 80-120% of the prescribed treatment time for inhaled corticosteroids, combination products of adrenergics and steroids and anticholinergics. RESULTS AND DISCUSSION: Only 28% (n=160) of the repeat prescriptions for inhaled corticosteroids had been dispensed with a satisfactory refill adherence, 59% showed an undersupply and 12% showed an oversupply. There was no difference in refill adherence in relation to age and gender. However, during the 10-year study period repeat prescriptions being dispensed for 2-4 years showed higher satisfactory refill adherence than those being dispensed for <2 years. CONCLUSIONS: Our study shows that over half of the repeat prescriptions for inhaled corticosteroids dispensed to patients over 60 years showed an undersupply. Therefore, it is likely that elderly patients on long-term therapy have a non-optimal drug use of their preventive asthma/COPD medication.

Refill adherence to repeat prescriptions of cancer drugs to ambulatory patients.

The objective was to study the refill adherence among ambulatory patients with prescribed cancer drugs. The study was based on copies of repeat prescriptions, which were collected at three large Swedish pharmacies during the last 3 months of 2004. Copies of 141 repeat prescriptions were analysed. There was no statistical significant difference between the number of patients with undersupply of cancer drugs (i.e. <80% of prescribed cancer drugs) and that of patients with undersupply of all other drugs, or between the number of patients with oversupply of cancer drugs (>120% of prescribed cancer drugs) and that of patients with oversupply of all other drugs. Undersupply of drugs was found among 14% of the patients. The median treatment gap for these patients was 39 (range 29-49 days) per 98-100 days of prescribed treatment time, meaning that the undersupply leads to treatment gaps that may jeopardize their therapeutic outcome. It is reasonable to expect that more seriously ill patients would be adherent to prescribed medication, and consequently that cancer patients would have high adherence. However, our data show that cancer patients on oral long-term treatment have a non-adherence similar to that of patients in general.

Free radicals in antigen formation: reduction of contact allergic response to hydroperoxides by epidermal treatment with antioxidants.

BACKGROUND: For patients with allergic contact dermatitis, the main therapy is anti-inflammatory steroids, a non-specific and symptomatic treatment. In contact allergy, the antigen formation is considered to be the binding of a chemical (hapten) to a biological macromolecule, e.g. a protein. Limonene-2-hydroperoxide (Lim-OOH) is a hapten with a known allergenic effect. It is likely to bind to proteins in the skin via a radical mechanism. It might be possible to inhibit the allergic reaction by epidermal application of substances that can trap free radicals, e.g. antioxidants such as ascorbic acid or alpha-tocopherol, prior to the application of the hapten. OBJECTIVES: To study the influence of antioxidants on the allergenic effect of Lim-OOH in sensitization experiments on guinea pigs. METHODS: Pretreatment with the antioxidants was performed before induction to study the effect on sensitization as well as before challenge testing to study the effect on elicitation. RESULTS: A reduction in the response rate was found both at sensitization and at elicitation. The antioxidants had no effect on cobalt allergy or on the allergenic effect of haptens that form antigens via nucleophilic-electrophilic reactions. No reduction of the effect was seen for irritants. CONCLUSIONS: The protective effect of antioxidants in elicitation could be of practical therapeutic value, as it indicates a possibility for the treatment of patients who have become sensitized to haptens that form full antigens via a radical mechanism.

Mechanism of the antigen formation of carvone and related alpha, beta-unsaturated ketones.

In the present study, the mechanism for the antigen formation of alpha, beta-unsaturated ketones was investigated. A series of analogues of carvone ((5R)-5-isopropenyl-2-methyl-2-cyclohexenone) with altered chemical reactivity and with retained overall structure or with retained reactivity and altered three-dimensional structure were synthesized. These analogues were tested for cross-reactivity in carvone-sensitized animals. Cross-reactivity was observed for analogue 3 ((5R)-5-isopropyl-2-methyl-2-cyclohexen-1-one). No cross-reactions were observed for analogues 1 ((2R,5R)-5-isopropenyl-2-methyl cyclohexanone) and 4 ((5R)-2,3-dimethyl-5-isopropenyl-2-cyclohexene-1-one). Both those compounds also failed to induce sensitization. These findings demonstrate that alpha, beta-unsaturated ketones form antigens after a nucleophilic attack at the beta-carbon with soft nucleophiles such as thiol in cysteine and not with the formation of a Schiff's base after a nucleophilic attack at the carbonyl carbon with nitrogen nucleophiles. Furthermore, no cross-reactivity was observed between R- and S-carvone indicating the importance of the 3-dimensional structure of haptens (and antigens) in T-cell recognition. The analogues were also tested for cross-reactivity on patients allergic to carvone. The results from the animal study were confirmed.

Identification and allergenic activity of hydroxyaldehydes - a new type of oxidation product from an ethoxylated non-ionic surfactant.

Ethoxylated alcohols, which are widely used as surfactants, are susceptible to oxidation on air exposure. A complex mixture of oxidation products is formed, among which alkylated aldehydes, alkylated formates, formaldehyde and peroxides have previously been identified by our group. In the present study, we have identified a new class of oxidation product from the nonionic ethoxylated surfactant C12E5. These oxidation products are highly water-soluble hydroxyaldehydes with the general formula HO(CH2CH2O)nCH2CHO, n=1-4. To facilitate the identification of the hydroxyaldehydes in oxidized C12E5, reference compounds were synthesized. The sensitizing potential of 1 of the identified hydroxyaldehydes, HO(CH2CH2O)3CH2CHO, was studied in guinea pigs and was found to be weak. A significant cross-reactivity between this aldehyde and the next shorter homologue, HO(CH2CH2O)2CH2CHO, was observed. Irritant components, present in the oxidation mixture, facilitate the skin penetration of allergens, which further accentuates the importance of controlling the conditions of storage and handling of ethoxylated surfactants, to reduce the formation of allergenic and irritant oxidation products.

Structural analogues inhibit the sensitizing capacity of carvone.

The aim of the study was to investigate the effect of non-allergenic structural analogues on the sensitizing potential of carvone, a fragrance allergen. The possibility that one molecule might inhibit the allergenic activity of another molecule has been debated for 25 years. The Research Institute for Fragrance Materials states that the sensitizing activity from certain fragrance aldehydes is "quenched" by the addition of other specific chemicals. However, other studies do not confirm the results, although several attempts have been made. We used a guinea pig method designed to study the sensitizing capacity of fragrance allergens. Induction was performed with either carvone alone or with a mixture of carvone and one of two analogues. A significant difference in the response rates (p < 0.001) was observed between the animals induced with carvone alone and those induced with any of the mixtures. Our investigation shows that by using selected molecules it is possible to significantly reduce the sensitizing effect of a fragrance allergen.

Skin irritation from air-oxidized ethoxylated surfactants.

Surfactants are known to be skin irritants, but change in their irritant potential due to change in composition during handling and storage has not previously been investigated. The aim of this study was to investigate the influence of oxidation products on the irritant potential of a non-ionic ethoxylated alcohol, C12E5. Pure and oxidized C12E5 were tested, using 2 different patch test procedures; 1 with a single 24 h exposure and 1 with repeated exposures. 18 healthy volunteers participated in each of these studies. Evaluations were made by visual scoring and by measurement of transepidermal water loss and skin blood flow. In the single exposure study, no significant difference in skin irritation was observed between pure C12E5 and a sample of oxidized C12E5 at the concentrations tested (1, 3, 9 and 27%). After repeated exposures, however, the oxidized C12E5 was significantly more irritant than pure C12E5 at the concentrations 9% and 27% (p<0.05). Non-ionic ethoxylated surfactants are known for their weak skin irritant effect and are, due to this, often included in products with prolonged contact with the skin, i.e., skin care products. An increased irritant potential after oxidation might be of importance due to the conditions of use.

Direct Ni2+ antigen formation on cultured human dendritic cells.

The possible direct antigen formation of Ni2+ on antigen-presenting cells (APCs) was studied with cultured human dendritic cells (DCs) obtained from 10 subjects contact allergic to Ni2+ and six non-allergic control individuals. All contact allergic subjects showed a significantly increased peripheral blood mononuclear cell (PBMC) response in vitro to Ni2+. DCs were expanded from the plastic-adherent cell fraction of PBMCs by culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 7 days to obtain immature DCs, and with the addition of monocyte-conditioned medium for another 4 days, for DC maturation. The DCs were pulsed for 20 min with Ni2+ (50 micrometers) in protein-free Hank's balanced salt solution (HBSS) and added to freshly prepared autologous responder PBMCs. With five allergic subjects, immature DCs pulsed with Ni2+ demonstrated a significant capacity to activate Ni2+-reactive lymphocytes. With the remaining five patients and the six controls no difference in lymphocyte proliferation was observed between Ni2+-pulsed and non-pulsed immature DCs. In contrast, with mature Ni2+-pulsed DCs from both 'positive responder' (n=4) and 'non-responder' (n=4) patients, there was a significantly stimulated PBMC proliferation, whereas with the controls (n=4) still no activation was observed. Our results indicate that direct formation of the antigenic determinant of Ni2+ on APCs is possible and that Ni2+ uptake and processing mechanisms may not play a major role. Differences in the ease of activation of Ni2+-reactive lymphocytes are discussed in terms of a possible heterogeneity in the availability of Ni2+-reactive groups presented on endogenous peptides bound in the antigen binding groove of human leucocyte antigen (HLA) class-II molecules.

Atmospheric oxidation of poly(oxyethylene) alcohols. Identification of ethoxylated formates as oxidation products and study of their contact allergenic activity.

Ethoxylated alcohols are widely used as surfactants. In the present study we have continued our investigations on the degradation with time upon air exposure of the ethoxylated alcohols at normal storage and handling. As a result, a new group of ethoxylated formates with the general formula C12H25(OCH2CH2)nOCHO (n = 0-4) was identified in C12H25(OCH2CH2)5OH stored and handled at room temperature. To facilitate the identification work, reference compounds were synthesized. The formates showed no allergenic activity in the sensitization studies performed. In previous investigations on the same ethoxylated alcohol, we have identified formaldehyde and ethoxylated aldehydes among the oxidation products formed. Formaldehyde is a common contact allergen, and the ethoxylated aldehydes were shown to have a sensitizing capacity of the same magnitude as formaldehyde. The instability of the ethoxylated alcohols and formation of oxidation products may give an allergenic contribution to hand eczema caused by work with water and surfactants. To investigate the clinical significance in man an appropriate diagnostic patch testing in exposed humans is required.

Free radicals as potential mediators of metal-allergy: Ni2+- and Co2+-mediated free radical generation.

The generation of free radicals by Ni(2+) and Co(2+) was studied at physiological pH in H(2)O(2)-containing solutions in the absence and presence of various radical-mediating ligands and in human peripheral blood mononuclear cell (PBMC) cultures. With ESR spectroscopy, free radical species were identified and quantitated by spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Co(2+) generated hydroxyl radicals from H(2)O(2) in PBS solutions containing glutathione (GSH) or histidine (His). Omission of GSH or His from the reaction mixture significantly reduced the ESR-signal, indicating the importance of metal-chelation in free radical generation. Carnosine did not significantly enhance the reactivity of Co(2+) toward H(2)O(2), whereas cysteine (Cys) and N-acetylcysteine (NAC) suppressed free radical generation. Under identical reaction conditions, Ni(2+) was markedly less reactive toward H(2)O(2) in comparison with Co(2+). GSH, His, Cys and NAC did not enhance free radical generation of Ni(2+) from H(2)O(2). However, in the presence of carnosine weak but significantly enhanced ESR intensities were found. Incubation of PBMC cultures from healthy subjects with Co(2+) (10-50 microM) yielded the DMPO-.OH adduct, suggesting Co(2+)-mediated hydroxyl radical generation. In contrast, incubation of PBMC cultures with Ni(2+) (10-50 microM) did not produce a detectable ESR-signal. Ascorbic acid efficiently inhibited Co(2+)-mediated free radical generation in PBS solutions and PBMC cultures. The observed difference in free radical generating capacity between Ni(2+) and Co(2+) is of interest with respect to the absence of cross-reactivity between the two metal-ions in experimental allergic contact dermatitis.

Formation of formaldehyde and peroxides by air oxidation of high purity polyoxyethylene surfactants.

Ethoxylated alcohols are non-ionic surfactants. The majority are used in household cleaners, laundry products, toiletries and in industrial and institutional cleaners. In previous studies, an ethoxylated non-ionic surfactant of technical quality showed allergenic activity in guinea pig experiments. Chemical analysis revealed a content of formaldehyde, a well-known contact allergen, and peroxides in the surfactant. Most cases of occupational contact dermatitis are considered to be of irritant origin, caused by contact with water and surfactants, but if allergenic autoxidation products can be formed, allergic contact dermatitis cannot be excluded. The sensitizing potential of a chemically defined high purity ethoxylated alcohol was investigated and oxidation under various storage and handling conditions was studied for this and a homologous product. The pure surfactant showed no significant allergenic activity on predictive testing in guinea pigs. When ethoxylated alcohols were stored in the refrigerator, their deterioration was limited. At room temperature, their content of peroxides and formaldehyde increased with time. Levels of formaldehyde above those capable of causing positive patch test reactions were found. Since such surfactants have wide applications, resulting exposure to formaldehyde could be more frequent than is generally realized, contributing to persistence of dermatitis in individuals allergic to formaldehyde.

Lack of antagonism to Ni2+ and Co2+ contact allergy from other essential divalent metal ions.

The potential antagonistic effects of Ca2+, Cu2+, Fe2+, Mg2+, Mn2+ and Zn2+ on contact allergy to Co2+ and Ni2+ were studied. The immune response was characterized by the Co2+ or Ni2+ mediated cellular [methyl-3H]thymidine uptake in peripheral blood mononuclear cell (PBMC) cultures from 6 subjects contact-allergic to Co2+ and Ni2+ and 6 non-allergic control individuals. Results from the in vitro experiments were further evaluated with Co2+-sensitized guinea pigs according to the modified Freund's complete adjuvant test. Ni2+ and Co2+ (10-50 microM) significantly increased the lymphocyte proliferation in PBMC cultures from contact-allergic subjects in comparison with those from control individuals. Pretreatment of the PBMCs with Ca2+, Fe2+, Mg2+ (10-100 microM) or Mn2+ (1-10 microM) did not influence, while Zn2+ (100 microM) enhanced, and Cu2+ (5 and 10 microM) markedly reduced the Ni2+ and Co2+ mediated cellular [methyl-3H]thymidine uptake. The inhibition of the Ni2+- and Co2+-induced cell proliferation by Cu2+ in vitro was probably related to toxicity, since the viability of the cells was significantly reduced by applied combinations of Ni2+ or Co2+ with Cu2+. Topical pretreatment of Co2+-sensitized guinea pigs with maximum non-irritating doses of CuCl2 x 2H2O (0.8%) did not affect the challenge testing to CoCl2 x 6H2O (0.1 and 0.3%). In conclusion, our combined in vitro and in vivo results indicate that Ca2+, Cu2+, Fe2+, Mg2+, Mn2+ and Zn2+ are not able to antagonise the formation of Ni2+ and Co2+ antigens.

Contact allergens from surfactants. Atmospheric oxidation of polyoxyethylene alcohols, formation of ethoxylated aldehydes, and their allergenic activity.

Ethoxylated surfactants are susceptible to oxidation upon air exposure. We have previously studied the rate of peroxidation and formaldehyde formation in the chemically well-defined ethoxylated alcohol C12H25(OCH2CH2)5OH. Formaldehyde is a common cause of contact allergy. The aim of the present study was to identify other oxidation products that could be formed upon air exposure of the ethoxylated alcohol and to determine their allergenic activity. It was shown that air oxidation of C12H25(OCH2CH2)5OH gave all the theoretically possible aldehydes of the general formula C12H25(OCH2CH2)nOCH2CHO (n = 0-4) and that the major oxidation product was C12H25(OCH2CH2)4OCH2CHO, dodecyltetraoxyethyleneoxyacetaldehyde. The structure elucidation and synthesis of these aldehydes are here presented for the first time. The major aldehyde was shown to be a contact allergen with the same sensitizing capacity as that of formaldehyde. A dose-response relationship was observed in the sensitization studies. The allergens were formed from the surfactant itself and the skin reactions cannot be explained due to any impurities that may be present in a technical quality of the surfactant. Cases of allergic contact dermatits to ethoxylated surfactants have been reported. To avoid the formation of allergenic oxidation products it is important to control the conditions for storage, handling, and transportation of ethoxylated surfactants.

Free radicals as potential mediators of metal allergy: effect of ascorbic acid on lymphocyte proliferation and IFN-gamma production in contact allergy to Ni2+ and Co2+.

A possible free radical mechanism in metal allergy was investigated in peripheral blood mononuclear cell (PBMC) cultures from 6 subjects, contact allergic to Ni2+ and Co2+, and 6 control individuals. Ni2+ and Co(2+)-mediated free radical generation was studied with electron spin resonance spectroscopy. The immune response was characterized by cellular [methyl-3H]thymidine uptake and interferon-gamma (IFN-gamma) production Ni2+ and Co2+ (10-50 microM) significantly increased lymphocyte proliferation and IFN-gamma production in PBMC cultures from contact allergic subjects in comparison with cultures from controls. Inhibition of Co(2+)-mediated free radical generation by ascorbic acid did not influence cellular [methyl-3H]thymidine uptake and IFN production. Detectable amounts of free radicals were not obtained with Ni2+. We therefore conclude that it is unlikely that free radicals are involved in contact allergy to Ni2+ and Co2+.