Detection of Asthma Inhaler Use via Terahertz Spectroscopy.

Inhaled medications are commonplace for administering bronchodilators, anticholinergics, and corticosteroids. While they have a defined legitimate use, they are also used in sporting events as performance-enhancing drugs. These performance enhancers can be acquired via both legal (i.e., at a pharmacy through over-the-counter medications or through a prescription) and illicit (i.e., black market and foreign pharmacies) means, thus making monitoring procurement impossible. While urine tests can detect these pharmacological agents hours after they have been inhaled, there is a significant lag time before they are observed in urine. Direct detection of these inhaled agents is complicated and requires a multiplexed approach due to the sheer number of inhaled pharmacological agents. Therefore, detection of propellants, which carry the drug into the lungs, provides a simpler path forward toward detection of broad pharmacological agents. In this paper, we demonstrate the first use of terahertz spectroscopy (THz) to detect inhaled medications in human subjects. Notably, we were able to detect and quantitate the propellant, HFA-134a, in breath up to 30 min after using an asthma inhaler, enabling the use of a point-of-care device to monitor exhaled breath for the presence of propellants. We also demonstrate via simulations that the same approach can be leveraged to detect and identify next-generation propellants, specifically HFA-152a. As a result, we provide evidence that a single point-of-care THz sensor can detect when individuals have used pressure-mediated dose inhalers (pMDIs) without further modification of the hardware.

Use of Ozone-Depleting Substances. Direct final rule.

The Food and Drug Administration (FDA, the Agency, or we) is amending its regulation on uses of ozone-depleting substances (ODSs), including chlorofluorocarbons (CFCs), to remove the designation for certain products as "essential uses" under the Clean Air Act. Essential-use products are exempt from the ban by FDA on the use of CFCs and other ODS propellants in FDA-regulated products and from the ban by the Environmental Protection Agency (EPA) on the use of ODSs in pressurized dispensers. The products that will no longer constitute an essential use are: Sterile aerosol talc administered intrapleurally by thoracoscopy for human use and metered-dose atropine sulfate aerosol human drugs administered by oral inhalation. FDA is taking this action because alternative products that do not use ODSs are now available and because these products are no longer being marketed in versions that contain ODSs.

Beclomethasone dipropionate hydrofluoroalkane for the treatment of allergic rhinitis.

Allergic rhinitis (AR) is a common respiratory disease, and its prevalence is increasing all over the world, both in adults and in children. Patients experience symptoms that may negatively impact on physical, social and psychological well-being. Hence, if left untreated, allergic rhinitis may significantly affect quality of life. Under current guidelines, intranasal corticosteroids are considered the most effective drugs and they are recommended as first-line therapy. Among the several corticosteroid intranasal sprays available, beclomethasone dipropionate is one of the most prescribed. Recently, new intranasal hydrofluoroalkane-propelled formulations with little or no impact on the ozone layer have been developed for the treatment of AR. The use of these devices might improve patients' adherence to treatment, avoiding some of the most common side effects associated with aqueous formulations. This review provides the most recent evidence for the efficacy and safety of beclomethasone dipropionate hydrofluoroalkane nasal aerosol in the treatment of allergic rhinitis.

A systematic review of vapocoolants for reducing pain from venipuncture and venous cannulation in children and adults.

BACKGROUND: Studies of vapocoolants for pain reduction from venipuncture have demonstrated conflicting results. OBJECTIVE: Our aim was to systematically review the literature regarding the analgesic effectiveness of vapocoolants in children and adults. METHODS: We searched MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Cochrane Central Register of Trials using key words: vapocoolant, pain, venipuncture, and cannulation. We included randomized or quasi-randomized studies comparing vapocoolants to placebo or no treatment. Two authors reviewed titles and abstracts and extracted data. Quality was assessed by consensus using the Cochrane risk of bias tool. The primary outcome was self-reported pain using a 100-mm visual analog scale, a 0- to 10-point numerical scale, or observational scale for preverbal children. Data were pooled using a random effects model. RESULTS: Twelve studies including 1266 patients (509 children, 757 adults) were identified. No significant pain reduction was found in children receiving vapocoolants vs. placebo or no treatment (mean difference -10 mm; 95% confidence interval [CI] -26 to 6). In adults, less pain was reported when vapocoolants were compared with no treatment: -10 mm on a 100-mm scale (95% CI -17 to -4); but not when compared to placebo (-12 mm; 95% CI -26 to 2). Pain from application of vapocoolants was greater than placebo (8 mm; 95% CI 4 to 2). CONCLUSIONS: Vapocoolants were ineffective in children and adults when compared to placebo, and effective in adults only when compared to no treatment. The magnitude of effect was low and was offset by increased pain from application. They cannot be recommended for routine use in children or adults.

Efficacy of beclomethasone dipropionate HFA 200 microg once daily in chronic obstructive pulmonary disease and bronchial asthma.

The efficacy and safety of once-daily beclomethasone dipropionate (BDP; 200 microg), in combination with the propellant hydrofluoroalkane-134a (HFA) was compared with that of budesonide turbuhaler (BUD-TH) 400 microg twice daily and fluticasone propionate inhaler (FP-IH) 250 microg twice daily in 40 patients with bronchial asthma or chronic obstructive pulmonary disease. All patients had used inhaled corticosteroids for at least 1 month. On randomization, 20 patients were switched to HFA-BDP and 20 patients remained on their existing BUD-TH or FP-IH treatment. After 8 weeks, HFA-BDP demonstrated a greater improvement in spirometric values, respiratory symptoms and beta2-agonist use. No significant local adverse effects were observed. Blood cortisol levels remained in the normal range in both groups. We conclude that HFA-BDP (200 microg once-daily) offered more benefit in terms of clinical and spirometry indices than BUD-TH (400 microg twice daily) or FP-IH (250 microg twice daily) in patients with moderate asthma and chronic obstructive pulmonary disease.

Efficacy and safety of fluticasone propionate hydrofluoroalkane inhalation aerosol in pre-school-age children with asthma: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of fluticasone propionate (FP) hydrofluoroalkane (HFA) in children age 1 to < 4 years with asthma. STUDY DESIGN: Children were assigned (2:1) to receive FP HFA 88 mug (n = 239) or placebo HFA (n = 120) twice daily through a metered-dose inhaler with a valved holding chamber and attached facemask for 12 weeks. The primary efficacy measure was mean percent change from baseline to endpoint in 24-hour daily (composite of daytime and nighttime) asthma symptom scores. RESULTS: The FP-treated children had significantly greater (P < or = .05) reductions in 24-hour daily asthma symptom scores (-53.9% vs -44.1%) and nighttime symptom scores over the entire treatment period compared with the placebo group. Daytime asthma symptom scores and albuterol use were slightly more decreased with FP than with placebo; however, the differences were not statistically significant. Increases in the percentage of symptom-free days were comparable. The percentage of patients who experienced at least 1 adverse event was similar in the 2 groups. Baseline median urinary cortisol excretion values were comparable between the groups, and there was little change from baseline at endpoint. FP plasma concentrations demonstrated that systemic exposure was low. CONCLUSIONS: FP HFA 88 mug twice daily was effective and well tolerated in pre-school-age children with asthma.

Effects of hydrofluoroalkane and dry powder-formulated corticosteroids on sputum inflammatory markers in asthmatic patients.

BACKGROUND: Inhaled corticosteroids are powerful drugs that can suppress airway inflammation in asthmatic patients. Deposition of most of the inhaled corticosteroid occurs mainly in the central airways. However, a new hydrofluoroalkane formulation of beclomethasone dipropionate (HFA-BDP) is preferentially deposited in the distal airways. Inflammatory characteristics of induced sputum have been shown to differ in samples collected early after sputum induction compared with later. OBJECTIVE: To compare the effects of HFA-BDP and budesonide in a dry powder inhaler (DPI-BUD) on inflammatory cells and inflammatory cytokine expression in early and late induced sputa compared with placebo. METHODS: Seventeen patients with mild, intermittent bronchial asthma were randomly assigned to two treatment groups: eight patients received HFA-BDP and nine patients received DPI-BUD. Each patient was treated with one of the active treatments and placebo (for four weeks), with a two-week washout interval in between. Inflammatory cells and expression of interleukin (IL)-4 and IL-5 were measured in early and late induced sputa before and after active treatment, as well as before and after placebo treatment using immunocytochemistry and in situ hybridization. RESULTS: Compared with placebo, eosinophils were significantly reduced in both early and late induced sputa after HFA-BDP treatment (P<0.05), whereas DPI-BUD had a significant effect only on early induced sputum. Both HFA-BDP and DPI-BUD decreased IL-4 expression in early and late induced sputa, but the effect was more prominent with HFA-BDP. IL-5 expression was reduced in both early and late induced sputa after HFA-BDP treatment. DPI-BUD significantly decreased IL-5 expression in early but not in late induced sputum. The number of lymphocytes was not altered by either treatment. CONCLUSIONS: HFA-BDP reduced eosinophilic inflammation and T helper 2-type cytokine expression in both early and late induced sputa, whereas the effect of DPI-BUD on inflammation was predominantly demonstrated in early induced sputum.

[Clinical study and pathological examination on the treatment of deep partial thickness burn wound with negative charge aerosol].

OBJECTIVE: To investigate the effect of negative charge aerosol (NCA) on the treatment of burn wound. METHODS: Patients with superficial or deep partial thickness burn only were enrolled in the study, and they were randomly divided into trial group (T, including 180 cases of superficial thickness burn and 100 cases of deep partial thickness burn), control group (C, including 30 cases with superficial thickness burn and 30 with deep partial thickness burn), and self control group (SC, including 10 cases with superficial thickness burn and 10 with deep partial thickness burn). The patients in T and SC groups were treated with NCA for 1.5 hours, 1-2 times a day, from 6 postburn hour (PBH) to 2 postburn day (PBD), while those in C group received conventional treatment. For those in SC group, some of the wounds were covered with sterile schissel, while other wounds without schissel covering. The general changes in the wounds during NCA treatment were observed, and bacterial culture before and after NCA treatment was performed. The healing time was recorded and the blood biochemical parameters were determined. Rat model with deep partial thickness scald was established, and the rats were also divided into T and C groups, and received treatment as in human. Tissue samples were harvested from the wounds of rats in the 2 groups before and 1, 2, 3 weeks after treatment for pathological examination. RESULTS: There was no infection and little exudation in the patients in T group. No bacteria were found in the wound before and after NCA treatment. The healing time of the wounds of patients with superficial and deep partial thickness burn in T group was 6.3 +/- 1.6 d and 15.1 +/- 3.1 d, respectively, which was obviously shorter than those in C group (11.3 +/- 1.4 d and 21.2 +/- 1.4 d, P < 0.01). In SC group, the healing time of those with sterile schissel coverage was also significantly shorter than those without covering (P < 0.01). There was no obvious change in the liver and kidney functions and blood biochemical parameters among the patients. Pathological examination showed that the skin structure was almost recovered in the rats in T group 3 weeks after treatment, while those in C group was not. CONCLUSION: Negative charge aerosol is safe and effective in promoting wound healing of the patients with partial thickness burns.

Treatment of exercise-induced asthma with beclomethasone dipropionate in children with asthma.

A new hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) aerosol markedly increases drug delivery to the airways. Therefore, even low doses of HFA-BDP should be effective, and the present study assesses this. A randomised, double-blind, crossover study was used to compare the effect of placebo, HFA-BDP 50 microg or 100 microg given q.d. (QVAR(TM) Autohaler(TM); 3M Pharmaceuticals, St. Paul, MN, USA) on exercise-induced bronchoconstriction and exhaled nitric oxide (eNO). After a 14-day run-in, 25 children (5-14 yrs old) entered three 4-week treatment periods, separated by a 1-week washout. After each period, the fall in forced expiratory volume in one second (FEV1), after an exercise test, and eNO were measured. Significant treatment effects with no carry-over or period effects were seen for both eNO and maximum fall in FEV1 after exercise. Differences were seen between placebo (fall in FEV1=27.9%; eNO=14.4 parts per billion (ppb)) and either dose of HFA-BDP, but not between the two active doses (50 microg: fall in FEV1=20.8%, eNO=9.3 ppb; 100 microg: fall in FEV1=20.9%, eNO=8.9 ppb). In conclusion, low q.d. doses of hydrofluoroalkane-beclomethasone dipropionate reduced exhaled nitric oxide and exercise-induced bronchoconstriction. Further studies are needed to assess whether q.d. administration of beclomethasone dipropionate is as effective as b.i.d. administration.

Cryoanalgesia with dichlorotetrafluoroethane lessens the pain of botulinum toxin injections for the treatment of palmar hyperhidrosis.

BACKGROUND: Hyperhidrosis is a troublesome problem that can be embarrassing in both social and professional situations. Botulinum toxin injections have proven efficacious in the treatment of hyperhidrosis. However, when treating palmar hyperhidrosis, pain at the injection site limits this therapy. We describe a method of cryoanalgesia using dichlorotetrafluoroethane to lessen the pain of botulinum toxin injections during the treatment of palmar hyperhidrosis. OBJECTIVE: To show the successful use of dichlorotetrafluoroethane or Frigiderm in the treatment of palmar hyperhidrosis. METHODS: This is a case report of a patient with a 20-year history of palmar hyperhidrosis who had previously tried several unsuccessful techniques to control pain during botulinum toxin injections to his palms. The left hand of the patient was pretreated with a spray of Frigiderm for 5 seconds before each of the botulinum injections. Two to 3 seconds of dichlorotetrafluoroethane at a distance of 2 to 4 inches were sprayed before each palmar injection. There was 1 to 2 seconds of frosting on the skin before the botulinum toxin was administered. After the botulinum toxin injection was administered, the patient was subjectively asked about pain during injection. RESULTS: The patient subjectively reported a 75% decrease in the intensity of pain with the Frigiderm application, which he said made the injections much more tolerable. No epidermal changes were noted at the time of treatment or at the telephone follow-up visit. The patient presented for follow-up 3 months later. He stated that the sweating had minimally returned but that he had not yet returned to baseline. CONCLUSION: The use of botulinum toxin for the treatment of palmar hyperhidrosis is often limited because of the pain of multiple injections. In this case report, we describe the successful use of cryoanalgesia with dichlorotetrafluoroethane or Frigiderm to lessen the pain of botulinum toxin injections during the treatment of palmar hyperhidrosis.

Small airway asthma therapy, challenges, and the future.

The clinical significance of small airway pathology makes these passages an important therapeutic target in asthma. Conventional chlorofluorocarbon-based formulations of inhaled corticosteroids for asthmatic inflammation produce aerosols with a relatively large particle size, and as such, offer poor access to the small airways. New corticosteroid formulations use hydrofluoroalkane propellants with a smaller average particle size, allowing better access to the distal lung. By extending the delivery of this medication to the peripheral lung and by increasing the efficiency of lung targeting, these new corticosteroid formulations provide more effective treatment at reduced drug doses.

Effective control of asthma with hydrofluoroalkane flunisolide delivered as an extrafine aerosol in asthma patients.

BACKGROUND: Inhaled corticosteroids are established as maintenance therapy for persistent asthma. A new aerosol formulation of flunisolide delivers a small particle size by using a hydrofluoroalkane (HFA) propellant with a built-in spacer. OBJECTIVE: To compare efficacy and safety of two different flunisolide formulations, HFA and chlorofluorocarbon (CFC), with placebo treatment over a range of doses. METHODS: The multicenter, randomized, double-blind, placebo-controlled trial consisted of a 2-week, active run-in phase with CFC flunisolide 500 microg, twice daily, followed by 12 weeks of double-blind treatment with placebo, HFA flunisolide (85, 170, or 340 microg, twice daily), or CFC flunisolide (250, 500, or 1,000 microg, twice daily). Patients (N = 669) were nonsmokers, at least 12 years of age, with mild to moderate asthma who were being treated with inhaled corticosteroids. Outcome measures were change from baseline in forced expiratory volume in 1 second (FEV1), peak expiratory flow rate, as needed albuterol use, nocturnal awakenings, and asthma symptoms. RESULTS: After 12 weeks of treatment, patients receiving 170 microg, twice daily, and 340 microg, twice daily, of HFA flunisolide showed a significant (P < 0.01) improvement in percentage increase in FEV1 (12.22% at 170 microg, twice daily, and 14.69% at 340 microg, twice daily) compared with the placebo group (5.35%). At one-third the dose of CFC flunisolide, HFA flunisolide provided similar improvement in pulmonary function versus placebo. Both formulations demonstrated comparable linear dose dependency for the change from baseline in FEV1 without any evidence of cortisol suppression. Outcome values for all seven secondary efficacy measures were numerically superior in patients receiving HFA flunisolide compared with the CFC formulation. Both formulations seemed to be safe and well tolerated. CONCLUSIONS: HFA flunisolide provides comparable efficacy and safety at one-third the dose of CFC flunisolide.

Comparable bronchodilation with hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in children with asthma.

This was an open-label, parallel group, randomized, age-stratified, multicenter study designed to compare the safety and efficacy of regular use of albuterol formulated in hydrofluoroalkane-134a (HFA albuterol) and albuterol formulated in chlorofluorocarbons-11/12 (CFC albuterol) in children with asthma. Children age 4-11 years using a short-acting inhaled beta2-agonist for 6 months to manage stable asthma, and with a prestudy forced expiratory volume in 1 sec (FEV1) of >50% predicted after withholding short-acting inhaled beta2-agonists for at least 6 hr, an increase in FEV1 > or = 12% within 30 min after two puffs of CFC albuterol, and the capability to comply with medication withholding requirements were eligible for study entry. After screening evaluation, patients entered a minimum 7-day run-in period. On study day 1 spirometry and a baseline 12-lead electrocardiogram (ECG) were performed, pulse and blood pressure were measured, and patients self-administered two puffs of their randomized study drug, either HFA albuterol or CFC albuterol. Serial spirometry was performed over 6 hr after study drug dosing. Pulse and blood pressure were measured just prior to each spirometry and a 12-lead ECG was performed at 60 min postdose. Patients took two puffs of their study drug four times a day for 4 weeks. At study week 4, study day 1 procedures were repeated. Patients maintained a daily diary of morning (A.M.) and evening (P.M.) peak expiratory flow (PEF), daytime asthma symptom scores, nighttime asthma sleep disturbance scores, and study drug use. Demographics and baseline characteristics of the 63 patients randomized to HFA albuterol (33) and CFC albuterol (30) were similar. No significant differences were found between the HFA albuterol and CFC albuterol treatment groups for any of the primary or secondary FEV1 efficacy variables either at study day 1 or study week 4. No significant differences were noted between treatment groups for A.M. and P.M. PEF, individual asthma symptom scores, nighttime asthma sleep disturbance scores, and rescue study drug use over the 4-week study. No significant differences were found between the two treatment groups for change from predose in heart rate, systolic and diastolic blood pressure, and 12-lead ECG intervals at either study day 1 or study week 4. Adverse event reporting was similar for the two treatment groups. In this study, with regular use of HFA albuterol in children with asthma, there was a similar safety profile and comparable bronchodilator efficacy as with CFC albuterol.

Health-related quality of life in moderate asthma: 400 microg hydrofluoroalkane beclomethasone dipropionate vs 800 microg chlorofluorocarbon beclomethasone dipropionate. The Study Group.

OBJECTIVE: To compare the effect of hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP; 400 microg/d) with that of chlorofluorocarbon (CFC) BDP (800 microg/d) on asthma health-related quality of life in a 12-week, parallel-group, multicenter study. BACKGROUND: HFA-BDP is a new CFC-free preparation of BDP, which was developed as a result of CFCs being phased out from metered dose inhalers. METHODS: Following 7 to 12 days of prednisone, 30 mg/d, 347 adults with moderate asthma were randomized to receive either 400 microg/d HFA-BDP, 800 microg/d CFC-BDP, or HFA placebo for 12 weeks (all other oral and inhaled steroids were withdrawn). Patients completed the Asthma Quality of Life Questionnaire (AQLQ), and clinical asthma status was measured at the end of a run-in period, at randomization (after oral steroid treatment), and at the end of the study treatment. RESULTS: Sixty-one patients withdrew, 43 due to worsening asthma (33 placebo; 5 HFA-BDP; 5 CFC-BDP). There was a deterioration in the AQLQ score (- 0.81) in the placebo group, and the difference between this and the stability observed in both the HFA-BDP group (+ 0.13) and the CFC-BDP group (- 0.03) was statistically significant (p

Equivalence of asthma control with new CFC-free formulation HFA-134a beclomethasone dipropionate and CFC-beclomethasone dipropionate.

The study was designed to test for equivalence of asthma control between a new aerosol formulation of beclomethasone dipropionate (BDP) incorporating a chlorofluorocarbon-(CFC) free, hydrofluoroalkane propellant (HFA-134a) and the conventional beclomethasone aerosol formulated in CFC propellants. Sixty-eight asthmatic patients entered an eight-week, randomised, double-blind crossover study. All patients, previously stabilised on BDP, were randomised to receive the same dose of BDP from each of the study treatments. Statistically significant equivalence was demonstrated between HFA-BDP and CFC-BDP for asthma control parameters: FEV1, morning and evening PEF, sleep disturbance, wheeze and cough, morning breathlessness and bronchodilator use. Such equivalence was also demonstrated for safety parameters. To conclude, it has been demonstrated that HFA-BDP achieves a level of asthma control that is clinically and statistically equivalent to CFC-BDP in terms of efficacy and safety, at total daily doses ranging from 200 micrograms to 600 micrograms in asthma patients previously stabilised on inhaled CFC-BDP.