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PubMed2004

New drugs for management of diabetes: insulin analogues, inhaled insulin, pramlintide, and novel peptides.

Diabetes mellitus has reached epidemic proportions and contributes to considerable morbidity and mortality in the form of metabolic, microvascular, and macrovascular complications. Although there is no cure, large controlled studies demonstrate the importance of strict glycemic control in reducing progression of microvascular disease and associated morbidity. Insulin replacement is necessary for all patients with type 1 diabetes. In treatment of type 2 diabetes, more timely addition of insulin as patients fail to attain glycemic targets on combinations of oral agents has become widely accepted. Pharmacokinetic properties of human insulins limit their ability to mimic physiologic insulin secretion. Analog insulins (prandial and basal) are designed with improved physiologic pharmacokinetic characteristics to enable more simplified insulin dosage adjustments and a reduced risk for hypoglycemia. Inhaled administration has emerged as a promising route for noninvasive prandial insulin. Clinical trials are under way to further characterize safety and efficacy of inhaled insulin preparations. Despite numerous pharmacologic advancements, the majority of diabetic patients continue to have inadequate glycemic control. New information regarding biochemistry and pathophysiology of the disease is providing exciting opportunities for drug development. Promising new therapeutic classes include the synthetic analog of amylin (pramlintide), glucagon-like peptide (GLP-1) derivatives, and dipeptidyl peptidase IV inhibitors. Intriguingly, GLP-1 hormones may have important biologic actions aside from stimulating insulin release, including inhibition of gastric motility and acid secretion, suppression of glucagon secretion, and islet cell proliferation. Although additional studies are needed, perhaps these emerging agents will have greater efficacy and safety because of a higher degree of selectivity for their molecular targets.

Journal Article↗
PubMedDate not supplied

Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). DESIGN: Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. SETTING: University hospital clinical research unit. PATIENTS: Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > or = 50% predicted, Brasfield score > or = 15). INTERVENTIONS: Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (approximately 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. MEASUREMENTS AND MAIN RESULTS: After oral dosing, the mean +/- SD maximum peak concentration (Cmax) was 20.6 +/- 10.0 ng/ml at 3.2 +/- 1.2 hours in adults and 21.7 +/- 4.88 at 2.9 +/- 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 +/- 115 and 254 +/- 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 +/- 0.7 and 13.4 +/- 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 +/- 1.67 ng/ml at 0.5 +/- 0.2 hours and 1.37 +/- 1.21 ng/ml at 4.0 +/- 1.0 hours for adults, and 1.49 +/- 0.99 ng/ml at 0.5 +/- 0.1 hours and 1.52 +/- 0.81 ng/ml at 3.3 +/- 0.5 hours for adolescents. Estimated mean +/- SD dose nebulized was 1.91 +/- 0.66 and 2.28 +/- 0.30 mg in the adult and adolescent groups, respectively. Mean +/- SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 +/- 17.6 and 15.4 +/- 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. CONCLUSIONS: Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.

Administration, Inhalation↗
PubMed2004

Adrenomedullin in the treatment of pulmonary hypertension.

Adrenomedullin (AM) is a potent, long-lasting pulmonary vasodilator peptide. Plasma AM level is elevated in patients with primary pulmonary hypertension (PPH), and circulating AM is partially metabolized in the lungs. These findings suggest that AM plays an important role in the regulation of pulmonary vascular tone and vascular remodeling. We have demonstrated the effects of three types of AM delivery systems: intravenous administration, inhalation, and cell-based gene transfer. Despite endogenous production of AM, intravenously administered AM at a pharmacologic level decreased pulmonary vascular resistance in patients with PPH. Inhalation of AM improved hemodynamics with pulmonary selectivity and exercise capacity in patients with PPH. Cell-based AM gene transfer ameliorated pulmonary hypertension rats. These results suggest that additional administration of AM may be effective in patients with pulmonary hypertension. AM may be a promising endogenous peptide for the treatment of pulmonary hypertension.

Adrenomedullin↗
PubMed1993

Mechanisms of carcinogenicity of methyl halides.

Methyl chloride, bromide, and iodide are used as methylating agents. These compounds are mutagenic in short-term tests and do not require activation by exogenous S9 mix. In DNA-binding studies performed in rats and mice, 14C-labeled methyl chloride was given by inhalation, and methylation of DNA bases was examined. The compound did not lead to specific DNA adducts. In particular, methylation of DNA bases was not observed. In contrast, methyl bromide and methyl iodide, upon oral and inhalation administration to rats and mice, caused systemic DNA methylation. Specifically, 3-methyl-adenine, 7-methyl-guanine, and O6-methyl-guanine were formed. Long-term inhalation bioassays have been performed in rats and mice with methyl chloride and methyl bromide. Methyl chloride induced renal tumors, but only in male mice at the highest concentration tested (1000 ppm). Under these special conditions, a number of secondary effects occur subsequent to glutathione depletion in the target tissue, resulting in DNA damage (DNA-protein cross-links and probably DNA single-strand breaks). The particular coincidence of secondary high-dose effects precludes a risk extrapolation to man. Methyl bromide did not induce tumors in rats and mice when administered by inhalation. However, experimental data point to a possible local carcinogenic effect on the rat forestomach when the compound is given by gavage. A factor that accounts for the discrepancy between systemic DNA methylation and apparent noncarcinogenicity upon inhalation might be the preference of 7-N over O6 methylation of guanine. An extrapolation of the negative rodent inhalation bioassay of methyl bromide to man might be problematic because rodents metabolize methyl bromide very quickly whereas in humans there is a particular subpopulation that only poorly metabolizes the compound ("nonconjugators"). Such individuals can be characterized by incubation of erythrocytes with methyl chloride or methyl bromide and measurement of the substrate decline. Methyl iodide has been tested, with positive outcome, in early carcinogenicity bioassays not based on modern methodology. However, these results, along with the proven systemic methylating potency of methyl iodide, argue in favor of a carcinogenic effect of the compound.

Animals↗
PubMed1984

Toluene blood level following subcutaneous injection of toluene in the rat.

A model of toluene level in blood following subcutaneous injection of toluene mixed with polyoxyethylated-vegetable-oil vehicle was developed. The purpose was to provide a means of predicting dose received for subsequent toxicologic studies for any time and dose combination. The pharmacokinetics were of secondary interest. Using data from 111 rats, a four-parameter equation was devised to predict the time course of toluene blood level from 20-480 min post dosing, for dose levels of 50-1000 mg/kg. Blood concentrations rose at a rate which was independent of dose level. Maximum blood levels were uniquely determined by dose level. Blood levels fell at different rates depending upon dose level. Injection exposure, when compared to inhalation, has the advantages of (a) low expense, (b) low equipment requirements, and (c) simplicity. The disadvantage is, for some experiments, poor temporal stimulation of the normal route of administration, inhalation.

Animals↗
PubMed2006

Diabetes therapy trials with inhaled insulin.

Administration of insulin by inhalation was first attempted > 50 years ago. At that time, little was known concerning effective delivery systems and insulin formulations. The recent development of pulmonary delivery systems for the administration of insulin is driven by the reluctance of patients and their providers to initiate insulin earlier in the course of Type 2 diabetes, the desire to reduce the number of daily insulin injections for both Type 1 and 2 patients, and the recent emphasis on intensified glycaemic control including postprandial glycaemic control. The deep lung is a unique mucosal tissue having a surface area of > 100 m2 and is readily accessible both to the external environment and to drug delivery, provided that appropriate conditions are met. There have been four mid- to late-phase pulmonary insulin programmes using modern inhalation devices that will be reported in this paper. The programmes differ in the choice of delivery systems, the formulations of insulin and reported bioavailability, pharmacokinetic and glucodynamic profiles and adverse events. However, all systems successfully deliver insulin to the deep lung and biological effectiveness compares favourably with injected subcutaneous insulins.

Administration, Inhalation↗
PubMed2005

Sedation during voiding cystourethrography: comparison of the efficacy and safety of using oral midazolam and continuous flow nitrous oxide.

PURPOSE: We compare the efficacy and safety profile of oral midazolam and continuous flow 50% nitrous oxide (N(2)O) for alleviating anxiety and pain during voiding cystourethrography (VCU) in children. MATERIALS AND METHODS: This prospective, randomized clinical trial study was conducted in the radiology unit of a tertiary care center. Children older than 3 years scheduled for VCU were given either 0.5 mg/kg midazolam orally or continuous flow 50% N(2)O. Main outcomes were degree of anxiety and pain as assessed by the attending nurse and radiologist performing the test using a behavioral anxiety score, a distress score and an overall satisfaction score, side effects and recovery profile. RESULTS: The study included 47 children (89% girls) with a mean age of 6 years (range 3 to 15). There were 24 subjects in the midazolam group and 23 in the N(2)O group. Midazolam and N(2)O provided adequate anxiety and pain relief to perform the examination, yet children given N(2)O required less restraining and experienced a significantly shorter recovery time (29 +/- 10 vs 63 +/- 25 minutes, p <0.001). CONCLUSIONS: Continuous flow 50% nitrous oxide and oral midazolam are comparably safe and effective in reducing anxiety and distress during VCU in children older than 3 years. However, N(2)O provides a more rapid onset of sedating effect and has a shorter recovery time.

Administration, Inhalation↗
PubMed2005

Effects of vitamin C on liver enzymes and biochemical parameters in rats anesthetized with halothane.

Halothane is an important human and veterinary anesthetic, which produces free radicals during biotransformation. Occasionally, these free radicals may cause hepatic injury, especially in case of multiple halothane exposures over short periods. Vitamin C may protect cellular lipids and lipoproteins against oxidative damage by the free radicals. This study investigated the effects of vitamin C on liver enzymes and other biochemical parameters in rats anesthetized with halothane. One group of rats was used as a control, and saline (0.9% NaCl) was injected intraperitoneally into these animals as a placebo. The second group of rats was used as an anesthesia control group and was only anesthetized by halothane for 2 h. The third group was anesthetized by halothane and injected vitamin C intraperitoneally. Activities of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase enzymes were significantly increased (p < 0.05, p < 0.01, p < 0.05, respectively) by halothane anesthesia, but decreased (p < 0.05, p < 0.05, p < 0.05, respectively) with administration of vitamin C. Concentrations of triglycerides, cholesterol, total bilirubin and creatinine were statistically affected (p < 0.05, p < 0.01, p < 0.05, and p < 0.01, respectively) by injection of vitamin C. Values of erythrocyte counts, packet cell volumes, hemoglobin concentration, leukocyte counts, rates of neutrophils and lymphocytes were significantly affected (p < 0.01, p < 0.05, p < 0.05, p < 0.01, p < 0.001 and p < 0.01, respectively) by halothane anesthesia. The values of erythrocyte counts, leukocyte counts, neutrophil and lymphocyte rates were significantly decreased (p < 0.05, p < 0.05, p < 0.05, p < 0.01 and p < 0.01, respectively) with administration of vitamin C. Based upon these results, vitamin C may play an important role in the prevention of hepatic cellular injury inflicted by halothane anesthesia.

Administration, Inhalation↗
PubMed1993

Ba 679 Br, a new long-acting antimuscarinic bronchodilator: a pilot dose-escalation study in COPD.

Preclinical studies with Ba 679 Br have demonstrated a significantly longer duration of action than ipratropium bromide. Following inhalation of single doses, no systemic antimuscarinic effects were noted at doses likely to be bronchodilating in man. The objective of the present pilot-study of Ba 679 Br was to establish the dose-range for its bronchodilatory activity in a small number of chronic obstructive pulmonary disease (COPD) patients, before initiating a formal dose- and time-response study. Employing an open cross-over design, the efficacy of Ba 679 Br was tested, following single inhalational administration of five doses of increasing magnitude on separate days in six patients with COPD. A piezoelectric crystal was used, in order to nebulize an aqueous solution into a mist suitable for inhalation. There was a mean increase in forced expiratory volume in one second (FEV1) of 36% 30 min after inhaling ipratropium bromide 40 micrograms. Pulmonary function tests (FEV1, and specific airways conductance (sGaw)) were performed, at regular time intervals up to 24 h after test drug inhalation. The bronchodilatory activity of Ba 679 Br appeared to be dose-related in the dose-range tested (10-160 micrograms). A peak response was reached in 1.5-2 h, and persisted for 10-15 h in the majority of patients with return to baseline FEV1 approximately 19 h after dosing. No changes in physical examination, electrocardiogram (ECG) and laboratory safety tests from predose values were noted, and no serious adverse events were reported by the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchodilator Agents↗
PubMed1984

Safety and efficacy of salbutamol aerosol on Dermatophagoides farinae induced bronchospasm in asthmatic patients.

The effects of inhaled salbutamol in bronchial provocation with inhaled house dust mite allergen (HDM) were studied in 20 adult subjects with bronchial asthma and positive skin test to the allergen. There was a significant association between the skin test and the outcome of bronchial challenge, although the magnitude of the skin test reactivity was not significantly correlated with the degree of bronchial reactivity. Metered dose inhaler administration of salbutamol (200 gamma total) was started after antigen produced a fall in mean FEV1 to 31%. Salbutamol treatment returned the FEV1 within 5 min to 66%, and within 45 min to 91% of baseline in all but one patient. It appears that in most asthmatics inhaled salbutamol does significantly and immediately reverse HDM-induced bronchospasm.

Administration, Intranasal↗
PubMed1996

Ventilatory factors affecting inhaled nitric oxide concentrations during continuous-flow administration.

PURPOSE: Inhaled nitric oxide has been reported to be useful in acute respiratory distress syndrome and other lung diseases characterized by pulmonary hypertension and hypoxemia. The best site to inject the NO is still controversial, as is whether it can be affected by changes in ventilatory settings. The objective of this study was to examine the impact of various ventilator settings (tidal volume [Vt], inspiratory-to-expiratory [I:E] ratio, added dead space) in the final NO concentrations reached when NO is administered as a continuous flow near the endotracheal tube. METHODS: A test lung model was ventilated using a ServoVentilator 300 Siemens with square wave flow. A continuous flow of NO was administered between the Y piece and the endotracheal tube. The flow was adjusted with an NO precision flowmeter (range, 0.2 to 1.5 L/min) attached to a cylinder containing 800 ppm of NO. Actual NO concentrations in the lung model were measured by chemiluminescence (NOX 2000; Seres). The effects of changing Vt (from 300 to 1300 mL) and I:E ratio (from 1:4 to 2:1) and the addition of dead space (100 mL) were examined. RESULTS: At each step of the study, the measured NO concentration was higher than predicted. Biases from predicted NO concentration due to tidal volume were 17% at 1,300 mL Vt, 21% at 1,100 mL Vt, 25% at 900 mL Vt, 28% at 700 mL Vt, 35% at 500 mL Vt, and 48% at 300 mL Vt. Changes in I:E ratio induced increases in No concentration of 4% at 2:1, 5% at 1:1, 22% at 1:2, and 31% at 1:4. The addition of dead space enhanced these differences: 62% at 2:1, 104% at 1:1, 230% at 1:2, and 322% at 1:4. CONCLUSION: According to our lung model, continuous-flow administration of NO near the endotracheal tube is influenced strongly by changes in ventilatory settings.

Humans↗
PubMed1979

Comparative investigations on pirbuterol, salbutamol and placebo aerosols in bronchial asthma.

In a single blind crossover study 12 asthmatics received in randomised order single doses of pirbuterol (200 and 400 microgram), salbutamol (200 microgram) and placebo-aerosols, in order to determine the extent and duration of bronchodilator activity, the optimum dosage, the incidence, type and degree of side effects and the cardiovascular as well as hematologic, renal and hepatic functions after inhalative administration. All patients were checked by repeated pulmonary function studies, ECG and extensive laboratory tests. No significant differences were found between salbutamol 200 microgram and pirbuterol 400 microgram when lung functions were studied over 4 hr following inhalation. Pirbuterol 400 microgram and salbutamol 200 microgram were significantly better than pirbuterol 200 microgram. There were no side effects or changes of clinical relevance in pulse rate, blood pressure, ECG or laboratory test results. Pirbuterol is a well tolerated bronchodilator which appears to be of clinical importance in inhalative treatment of bronchospastic disease.

Adolescent↗
PubMed1999

Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans.

The purpose of this study was to evaluate the feasibility of intrapulmonary delivery of ABT-431, a selective D1 receptor agonist. Following intratracheal instillation of the drug solution, the lung bioavailability was found to be approximately 75% in dogs. An aerosol suspension formulation was then developed by dispersing the drug in tetrafluoroethane, HFC-134a, with the aid of poloxamer 124 and vitamin E. This ABT-431 MDI aerosol formulation showed about 40% of the particles emitted from the valve and actuator system to be under 5 microm in diameter. Also, the primary package (15 mL aluminum container, DF10/ACT-150 valve, and Micron-4-actuator with the orifice 0.4 mm) was satisfactory for accurate and reproducible dosimetry. Using tracheostomized beagle dogs, the C(max) following tracheal administration of 5 mg aerosolized ABT-431 was found to be 13.3+/-0.9 ng ml(-1) and the AUC(0-24) was estimated at 33.2+/-10.6 h ng ml(-1). The lung bioavailability of the aerosolized drug was 34% compared to intravenous injection in dogs. In humans, results from a single rising dose study demonstrated that rapid absorption of ABT-431 following oral inhalation administration resulted in a dose-dependent increase in the area under the plasma-time curve at dosage levels between 3.3 and 13.2 mg. There is a possibility of up to 25% absorption of the drug from human lung. Thus, pulmonary bioavailability of ABT-431 is significantly greater than that of oral administration. Also, these findings suggest that small and lipophilic compounds, especially with hepatic first pass effect, may be effectively delivered systemically using oral inhalation aerosols.

Absorption↗
PubMed1999

Inhaled nitric oxide fraction is influenced by both the site and the mode of administration.

OBJECTIVE: Inhaled nitric oxide (NO) can be delivered continuously or sequentially (= during inspiration) at different locations of the ventilation circuit. We have tested the influence of locations, modes of NO administration and the ratio of the inspiratory time over the respiratory cycle time (I/I + E ratio) on the accuracy of NO fractions, delivered by 2 devices: Opti-NO and Flowmeter. METHODS: We used a simplified lung model consisting of a ventilation circuit with a Y piece, a tracheal tube, a 150 ml dead-space volume and a 5 liter balloon. Three fractions (3, 6, 9 ppm) were administered continuously or sequentially, in controlled volume, in 4 different sites on the inspiratory branch above the Y piece: i) just after the water trap, ii) just before the Y piece; below the Y piece: iii) just after the Y piece, iv) into the endotracheal tube. In addition, different I/I + E ratios (25, 33, 50, 80%) were studied. The delivered NO fractions were measured in the balloon by chemiluminescence (CLD 700, Ecophysics). A linear regression analysis was used to test the relationship between administered and measured NO fractions for the 3 fractions (3, 6 and 9 ppm) in sequential and continuous modes. Intercept values were compared to zero and slopes to the identity line. RESULTS: When NO was administered in the continuous mode upstream the Y piece, NO fractions measured in the balloon corresponded to the administered fractions. In contrast, below the Y piece, the measured NO fractions were significantly lower than the administered NO fractions. In the sequential mode, above and below the Y piece, the delivered NO fractions were within the manufacturer's range. CONCLUSIONS: For the continuous NO delivery, locations above the Y piece are mandatory. However, locations below the Y piece imposes a sequential system, which can also be used for the sites located above the Y piece.

Administration, Inhalation↗
PubMed1995

m-xylene toxicokinetics in phenobarbital-treated rats: comparison among inhalation exposure, oral administration, and intraperitoneal administration.

Rats, pretreated with phenobarbital (PB) for 3 days (80 mg/kg/day), were challenged with m-xylene orally or intraperitoneally at a small (0.01 ml/kg or 0.081 mmol/kg) or a large (0.10 ml/kg or 0.814 mmol/kg) dose, or by 6-hr inhalation exposure at a low (40 ppm) or a high (400 ppm) concentration. The concentrations of m-xylene and its major metabolite, m-methyl hippuric acid (m-MHA), were measured over time in the blood and urine, respectively. PB treatment, which increased the hepatic metabolism of m-xylene in vitro about sixfold, had a significant effect on the metabolism of inhaled m-xylene (decreased blood m-xylene concentration together with increased urinary excretion of m-MHA) only at a high exposure concentration (400 ppm). On the other hand, the enzyme induction had a significant effect on the metabolism of orally administered m-xylene either at a small (0.081 mmol/kg) or a large (0.814 mmol/kg) dose, due to the first-pass metabolism that plays a great role in this route. When m-xylene was administered intraperitoneally, the effect of enzyme induction was shown only at the large dose, a finding which suggests that intraperitoneal administration is more similar to inhalation exposure than oral administration. However, in agreement with oral administration but in contrast to inhalation exposure, PB treatment increased the urinary excretion of m-MHA only shortly after intraperitoneal administration of m-xylene, with no significant increase occurring in the total amount of m-MHA excreted in the urine, despite the great difference in the blood m-xylene concentration between PB-treated and control rats.

Administration, Inhalation↗
PubMed1997

Conscious sedation.

Some patients are anxious about routine dental treatment; others, who may be able to cope with uncomplicated treatment, are worried by more unpleasant procedures such as minor oral surgery. Management approaches to anxiety vary according to its severity, the age of the patient, the degree of cooperation and the patient's medical history. Psychological approaches have been widely used and range from informal and common-sense methods to formal relaxation training and hypnosis. These techniques are safe, free from adverse effects and give the patient a sense of control. An increasing number of patients are managed with conscious sedation techniques in combination with local anaesthesia and the more severely anxious and uncooperative may require treatment under general anaesthesia. As patient awareness of the risk of anaesthesia and the availability of sedation have increased, so the popularity of conscious sedation for dentistry has increased.

Administration, Inhalation↗
PubMed2003

NORM workers: a challenge for internal dosimetry programmes.

The mining, milling and processing of uranium and thorium bearing minerals may result in radiation doses to workers. The control of occupational exposures from these natural sources of radiation imposes a challenge to regulators and radiation protection advisers. A survey pilot programme, which included six mines in Brazil and a monazite plant, was established, consisting of the collection and analysis of concentrations of uranium, thorium and polonium in urine, faeces and air samples. Results from workers were compared to background data from their families living in the same area and from residents from the population of Rio de Janeiro. Positive exposure results were identified among the coal miners, the niobium miners and the monazite sand workers. Difficulties in the application of internal dosimetry programmes are discussed in relation to the control of NORM workers.

Administration, Inhalation↗