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PubMed1996

The physico-chemical basis of radiolabelling metered dose inhalers with 99mTc.

Over the past decade, a number of different approaches have been proposed for the radiolabelling of metered dose inhalers (MDIs) in order to permit gamma scintigraphic imaging of emitted aerosols following inhaled administration. More recently, methods have been described for the indirect 99mTc-labelling of drugs incorporated into commercial MDI products. This paper attempts to rationalise such methods from a surface chemical perspective in order to: I) elucidate the mechanism of association of the radiolabel and drug; 2) predict the appropriateness of the techniques to all MDI products and; 3) propose in vitro testing methods to validate the labelling efficiency prior to in vivo evaluation.

Administration, Inhalation↗
PubMed1997

The safety of inhaled corticosteroid therapy in children.

Although discussed for many years, systemic adverse effects from inhaled corticosteroid therapy remains a complicated and controversial topic. It is by now well-known that inhaled corticosteroids may affect growth, bone, and adrenal function, yet the clinical relevance and the risks for such adverse effects are poorly defined. Earlier intervention, use of higher doses, differing potency claims, and new inhalers also affect the potential for systemic effects following inhaled administration. Until further research better characterizes these risks and identifies appropriate monitoring, caution in the use of this highly effective therapy is advised.

Administration, Inhalation↗
PubMedDate not supplied

Pharmacoscintigraphic comparison of HMR 1031, a VLA-4 antagonist, in healthy volunteers following delivery via a nebulizer and a dry powder inhaler.

A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.

Administration, Inhalation↗
PubMedDate not supplied

Chronic effects of the novel glucocorticosteroid RPR 106541 administered to beagle dogs by inhalation.

The preclinical safety of RPR 106541, a novel 17-thiosteroid, was evaluated in young adult and mature dogs by inhalation exposure for 26 weeks and 52 weeks, respectively. A dry powder formulation of RPR 106541 in lactose was administered to young adult dogs (approximately 6 months of age at initiation) at doses of 0 (air and placebo controls), 10, 100, or 1,000 microg/kg/d for 26 weeks. A solution-based aerosol formulation was administered to mature dogs (approximately 10 months at initiation) from a pressurized metered dose inhaler at 0 (air and placebo controls), 10, 50, and 150 microg/kg/d for 52 weeks. Clinical evidence of glucocorticosteroid-induced immunosuppression was observed by weeks 20-26 following relatively high dose exposures (100 microg/kg/d and 1,000 microg/kg/d) in young dogs receiving the dry powder formulation for 26 weeks. Classic glucocorticosteroid effects were observed, including adrenocortical atrophy, reduced bone mass with retention of epiphyseal growth plates in long bones, prominence of stromal adipose tissue in bone marrow, and atrophy of lymphoid tissues. Inhalation administration of RPR 106541 to sexually mature dogs facilitated more definitive characterization of endocrine affects of RPR 106541 as compared with administration in younger, sexually immature animals. Significant effects in female reproductive organs included absence of corpora lutea in association with atresia of vesicular follicles within the ovaries, endometrial hyperplasia, and lobular development of mammary tissue. Discordant development of mammary tissue, accumulation of secretory material within hyperplastic endometrial glands, and hypertrophy of uterine lining epithelium in absence of ovulation were consistent with a secondary progestin effect by a potent glucocorticosteroid.

Administration, Inhalation↗
PubMed1998

Preclinical development of low toxicity drugs: focus on zanamivir, an anti-influenza drug.

Developing novel compounds with low toxicity may present more difficulties for pharmaceutical companies than developing compounds with known class-related effects. The absence of clearly identified toxicity may be a consequence either of an inadequate or poorly designed toxicity programme or of the very low toxicity of the novel compound. To enable an informed risk assessment to be undertaken prior to registration, regulatory authorities must satisfy themselves that all efforts to fully evaluate the toxicity profile of a novel compound have been made. Zanamivir is a novel antiviral agent developed for the treatment and prevention of influenza when administered by the oral inhaled route. The toxicology programme for zanamivir was designed to support both a short term treatment indication for patients clinically diagnosed with influenza and a longer term treatment indication for the prevention of influenza. The toxicology studies demonstrated that zanamivir has very low toxicity and no drug-specific toxicities were observed in animal toxicity studies. Systemic plasma concentrations 1336-fold those achieved in clinical use were not associated with significant adverse effects. In the absence of dose-limiting toxicity in animal studies and in an attempt to identify target-organ toxicity, the high dosage level in all repeat dose studies was selected to be the maximum practicable. In the rat, nonspecific effects were seen in the respiratory tract following long term inhaled administration and in the kidneys following continuous infusion. However, these nonspecific effects were consequences of the excessive dosages administered and are not related specifically to zanamivir; thus, they are without relevance to the clinical use of this agent.

Administration, Inhalation↗
PubMedDate not supplied

[The efficacy of inhalations of choline chloride in the treatment of patients with chronic dust-induced bronchitis].

To correct the state of the lung surfactant system there has been employed an inhalation administration of choline chloride, 3 to 5 ml 20% solution once daily for 7 to 10 days. Those dust bronchitis patients who received conventional treatment served as control. The obstructive syndrome has been shown to be alleviated by the above-named drug. There was also an improvement in general well-being and in blood filling of lung tissue, which facts suggest our approach toward treating of patients with dust diseases of the respiratory organs by correction of disorders in pulmonary surfactant to be of promise.

Administration, Inhalation↗
PubMed1992

Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma.

Zardaverine is a newly developed selective phosphodiesterase III and IV inhibitor. This study investigates the bronchodilatory properties of zardaverine, administered by inhalation. Twelve patients with reversible bronchial obstruction (increase in forced expiratory volume in one second (change FEV1 % predicted) at least 15% after 200 micrograms salbutamol, median age 31 yrs, range 21-54 years) entered the double-blind, crossover study. Four puffs of either zardaverine (total dose 6 mg) or placebo were inhaled at 15 min intervals. Pulmonary function (specific airway conductance (sGaw) and FEV1 was measured by body plethysmography at regular intervals (5 and 12 min after each puff and, in addition, 30, 60, 120, 180 and 240 min after the last puff). Compared to placebo, sGaw and FEV1 increased significantly during the first hour of repeated inhalations, but not during the entire observation period of almost 5 h. The maximum mean difference between zardaverine and placebo for FEV1 was 0.3 l or 12% and occurred approximately 1 h after inhalation of the first puff. In seven patients FEV1 increased by > 15%. The duration of action varied considerably between patients. Three patients complained of side-effects (headache, drowsiness, vertigo, nausea), and one of these dropped out of the study due to vomiting. We conclude that inhalational administration of zardaverine has a modest and short-lasting bronchodilating activity.

Administration, Inhalation↗
PubMed1987

Intravenous versus nebulized terbutaline in patients with acute severe asthma; a double-blind randomized study.

Twenty-three patients with acute severe asthma were treated in a randomized double-blind way by either intravenous terbutaline two times at an hour interval 6 micrograms/kg or inhaled terbutaline two times 0.1 mg/kg. Peak expiratory flow rate in percent of expected value rose from 89 L/min to 128 L/min (P less than .01) in the intravenous group and from 97 L/min to 122 L/min (P less than .02) in the inhalation group; this was comparable for both groups. PaO2 initially was 7.55 kPa in the intravenous group and rose by 1.4 after 60 minutes (P less than .02) and by 1.33 after 120 minutes (P less than .01). The mean PaO2 did not change in the inhalation group. The pulse rate and blood pressure did not vary significantly in either of the two groups. We conclude that both the intravenous and inhalational administration of terbutaline are effective in acute severe asthma, but that the intravenous route is possibly better for increasing PaO2.

Acute Disease↗
PubMed1994

[Effects of inhaled SDZ ISQ 844, a cyclic nucleotide phosphodiesterase isoenzyme type III/IV inhibitor, on airway responsiveness in beagles].

To evaluate the effects of inhaled SDZ ISQ 844, a selective cyclic nucleotide phosphodiesterase (PDE) isoenzyme type III/IV inhibitor and inhaled salbutamol on airway responsiveness, we studied the changes in airway responsiveness following inhalation of SDZ ISQ 844 and salbutamol in 7 beagles. Respiratory resistance and airway responsiveness to inhaled methacholine were determined by modified Astograph (7 Hz oscillation method), SDZ ISQ 844 solution (5 x 10(-4) M) and salbutamol solution (5 x 10(-5) M) were delivered as aerosols generated from a Bird nebulizer for ten minutes. After inhalation of salbutamol respiratory resistance showed a slight but significant decrease (p < 0.05). Inhaled SDZ ISQ 844 did not affect respiratory resistance. Airway responsiveness decreased significantly following inhalation of SDZ ISQ 844 and salbutamol (p < 0.02). There was no significant difference between the changes in airway responsiveness following the inhalation of SDZ ISQ 844 and salbutamol. These results indicate that inhalational administration of a selective PDE isoenzyme type III/IV inhibitor, SDZ ISQ 844 decreases airway responsiveness at dosage which does not affect the base-line respiratory resistance.

Administration, Inhalation↗
PubMed1994

The role of soda lime during administration of inhaled nitric oxide.

We have studied the ability of three commercially available preparations of soda lime to act as nitrogen dioxide scavengers during administration of inhaled nitric oxide. Soda lime, with a green to brown colour change (indicator = potassium permanganate), markedly reduced concentrations of nitrogen dioxide, but also markedly reduced inhaled concentrations of nitric oxide. The other varieties of soda lime, with colour changes from pink to white (indicator = kenazol yellow) or white to violet (indicator = ethyl violet), produced little effect on concentrations of nitrogen dioxide. None of the above soda limes can be recommended for use as a nitrogen dioxide scavenger during administration of inhaled nitric oxide.

Calcium Compounds↗
PubMed1997

Delayed administration of inhaled nitric oxide preserves alveolar-capillary membrane integrity in porcine gram-negative sepsis.

OBJECTIVE: To determine the effect of delayed administration of inhaled nitric oxide (NO) on acute lung injury after the onset of gram-negative sepsis. DESIGN: Nonrandomized controlled study. SETTING: University medical center laboratory. SUBJECTS: Yorkshire swine. INTERVENTIONS: Five groups of swine were anesthetized, mechanically ventilated, and studied for 5 hours. After surgical preparation, control (n = 10) and NO-treated control (n = 6) animals received a 1-hour infusion of sterile saline solution. Sepsis was induced with a 1-hour intravenous infusion of live Pseudomonas aeruginosa. Untreated animals with sepsis (n = 10) received no treatment. Inhaled NO at 20 ppm was administered to NO30-treated animals with sepsis (n = 7) and NO60-treated animals with sepsis (n = 8) beginning at 30 and 60 minutes after bacterial infusion was begun, respectively. MAIN OUTCOME MEASURES: Systemic and pulmonary hemodynamics, arterial blood gas determination, bronchoalveolar lavage protein and neutrophil content, neutrophil oxidant burst, lung myeloperoxidase content, and scanning electron micrographic studies. RESULTS: A progressive, significant (P < .05) decline in PaO2 developed in untreated animals with sepsis, which was prevented in NO30- and NO60-treated animals with sepsis. A significant (P < .05) increase in bronchoalveolar lavage protein and neutrophil counts compared with baseline values was observed in untreated animals with sepsis, indicating acute lung injury. These variables exhibited no notable increase in NO30- and NO60-treated animals with sepsis and were significantly (P < .05) reduced compared with untreated animals with sepsis. The lung myeloperoxidase content was significantly (P < .05) elevated at 5 hours in all groups with sepsis compared with baseline values and the control and NO-treated control groups. The total phorbol myristate acetate-induced polymorphonuclear leukocyte oxidant burst at 5 hours was significantly (P < .05) decreased in the NO30- and NO60-treated animals with sepsis compared with untreated animals with sepsis. Untreated and NO30- and NO60-treated animals with sepsis showed a significant (P < .05) increase in pulmonary artery pressure at 30 minutes, followed by a progressive decline. These changes were significant (P < .05) compared with baseline values and the control groups. No significant (P < .05) difference in pulmonary artery pressure or systemic arterial pressure was found at any time between untreated and NO30- and NO60-treated animals with sepsis. CONCLUSIONS: The delayed administration of inhaled NO preserves alveolar-capillary membrane integrity in this porcine model of gram-negative sepsis. The inhibition of neutrophil transendothelial migration, rather than neutrophil rolling or tight adhesion, may be a critical mechanism by which inhaled NO produces this effect. Decreased oxidant production by activated neutrophils may be a secondary mechanism by which inhaled NO reduces acute lung injury.

Animals↗
PubMed1991

Administration of inhaled anesthesia with high-frequency oscillation: an in vitro study.

To assess administration of inhaled anesthesia during high-frequency oscillation, we evaluated the performance of a high-frequency oscillator that permitted incorporation of a precision vaporizer. The ventilator design used a single gas source for both vaporizer circuit and ventilatory support. The performance was evaluated in conjunction with a test lung device. The vaporizer performance was accurate when high-frequency, low-volume gas flow was used to provide source gas for the vaporizer. The ventilator provided accurate halothane delivery to the test lung device. Based on the results of this study, inhaled anesthesia can be accurately administered in conjunction with high-frequency oscillation. A single gas source that transverses the vaporizer before breathing circuit entrainment is critical for accurate results.

Anesthesia, Inhalation↗
PubMed1997

[Drug administration by inhalation systems].

Inhalant systems are often the drug administration method of choice for numerous respiratory diseases. The use of these systems is increasing due to their many advantages, one of which is the small quantity of medication they can deliver to a specific area. However, they also have their disadvantages, as inhalers require certain techniques that are not always followed. Inhalants may be propelled by a variety of methods: pressurized canisters, pumps, dry powder dispensers, nebulizers. Because each of these systems have their own administrating technique, the patient needs to be instructed in the proper use of the inhaler, with periodic follow-ups by health care workers to insure this.

Administration, Inhalation↗
PubMed1997

A toxicological review of lactose to support clinical administration by inhalation.

Although lactose is widely used in the pharmaceutical industry as an excipient in preparations given by several routes of administration, including by inhalation, there is no comprehensive review of its toxicological properties. This document seeks to review the available oral preclinical and clinical safety data from the literature, together with that generated by Fisons in animals using the inhalation route. In animal toxicity studies, lactose has been administered primarily by the inhalation and dietary routes to the rat, dog and/or primate. Adverse findings, such as abdominal distension and diarrhoea, have been demonstrated in rodent feeding studies. However, these changes are considered to be due to non-specific effects associated with high dietary doses of lactose, with a subsequent production of a dietary imbalance which results in physiological disturbances and an overload in the metabolic processes particularly involving calcium. These changes at high dietary intakes of lactose are considered to be of little relevance for man under the normal conditions of use of the material as an excipient in pharmaceutical formulations. No adverse local effects to the lung have been demonstrated in the animal studies using the inhalation route. Although the inhalation dose of lactose in the animal studies, of which most is subsequently swallowed, is markedly higher than the clinical dose, it is considerably less than consumed in animal studies using the dietary route. Consequently, it is not surprising that lactose is well tolerated by the inhalation route. In a small number of susceptible humans, intolerance to lactose is generally observed with oral intake of lactose, usually as a constituent of milk and is associated with lactase deficiency. Swallowed lactose at the levels present in inhaled preparations is unlikely to present any significant problems in patients with lactase deficiency. In conclusion, lactose is well recognized as a safe pharmaceutical excipient for use in oral or inhalation formulations and is not likely to constitute any significant toxicological hazard to man.

Administration, Inhalation↗
PubMed1991

Inhalation versus oral administration of acetone: effect of the vehicle on the potentiation of CCl4-induced liver injury.

Acetone potentiation of liver injury is greater when corn oil is given with acetone 18 h prior to a challenge with CCl4. This study aimed to further characterize the effects of the vehicle used to administer acetone on the severity of acetone-potentiated CCl4-induced liver injury. The more severe acetone-potentiated liver injury observed when corn oil was the vehicle does not seem to be due to greater liver acetone concentrations. When corn oil was used as the vehicle to administer acetone, liver and blood CCl4 concentrations were not significantly different from those where water was the vehicle. Therefore the relationship between blood or liver acetone concentration and plasma ALT activity for orally-administered acetone was modified by corn oil. Liver triglyceride concentration measured 18 h after a gavage of corn oil was significantly higher than that for the water-treated group. A direct effect of corn oil on liver, in particular a promotion of the propagation phase in the lipid peroxidation process induced by CCl4, is proposed to explain the increase in acetone-potentiated CCl4-induced liver injury.

Acetone↗