David Donnell

Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant

BACKGROUND This study tested the hypothesis that there would be improved asthma control with increasing doses of beclomethasone dipropionate (BDP) formulated in hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP, this study also tested the hypothesis that HFA-BDP would provide more effective control of asthma than CFC-BDP. METHODS In this multicenter, randomized, parallel-group blinded study, asthmatic subjects who had deterioration in asthma control after discontinuation of inhaled corticosteroids were randomized to receive one of 6 possible treatments: 100 microg/d, 400 microg/d, or 800 microg/d of HFA-BDP or 100 microg/d, 400 microg/d, or 800 microg/d of CFC-BDP for 6 weeks. Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep disturbance scores, morning and evening peak expiratory flows, and daily use of inhaled beta-agonist for symptom control on diary cards were assessed over 6 weeks of treatment. RESULTS Three hundred twenty-three patients were randomized to the 6 treatment groups, which had similar demographics and baseline lung function. There were significantly larger changes from baseline at week 6 in FEV(1) percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The FEV(1) percent predicted dose-response curve for HFA-BDP was shifted to the left compared with the dose-response curve for CFC-BDP. By using the Finney bioassay method, it was calculated that 2.6 times as much CFC-BDP would be required to achieve the same improvement in FEV(1) percent predicted as HFA-BDP (95% confidence interval, 1.1-11.6). All treatment groups except the 100 microg/d CFC-BDP group tolerated study drug well. Ten (17%) of 59 patients in this group reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports of increased asthma symptoms were classified as severe), or both, and 8 patients withdrew from the study (3 for adverse events related to asthma). CONCLUSIONS Increasing doses of inhaled corticosteroids lead to improved lung function and asthma control. Moreover, the reformulation of BDP in HFA enables effective asthma control at much lower doses than CFC-BDP.

Twenty-eight-day Double-blind Safety Study of an HFA-134a Inhalation Aerosol System in Healthy Subjects

A 28‐day double‐blind parallel group study has been conducted to compare the safety and tolerability of HFA‐134a, a chlorofluorocarbon‐free propellant in a pressurized metered‐dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C).

Atypical molecular pharmacology of a new long-acting β2-adrenoceptor agonist, TA 2005

The molecular pharmacology of a new putative long-acting bronchodilator TA 2005 (8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxy-phenyl)- 1-methylethyl]amino]ethyl]carbostyril hydrochloride) has been compared with that of the reference compounds isoprenaline and salbutamol in both methacholine (3 x 10(-6) M) precontracted guinea pig tracheal smooth muscle relaxation and in bovine trapezium muscle binding experiments. TA 2005 appeared very potent compared with isoprenaline and salbutamol (pD2 values of 9.29 vs. 7.65 and 7.10 respectively). For isoprenaline and salbutamol a shallow displacement curve was observed and addition of the non-hydrolysable GTP analogue guanylyl-imidodiphosphate (GppNHp) gave a rightward shift (pKd,high and pKd,low values of 7.3 and 6.1 vs. 7.0 and 5.4 respectively). For TA 2005 a steep displacement curve was found with only one binding state even without GppNHp (pKd,high value of 8.2). The long duration of action of TA 2005 might be explained by tight binding of this compound to the beta 2-adrenoceptor. The extent of tight binding for TA 2005 was extremely large. The molecular basis of the tight agonist binding phenomenon for TA 2005 seems to be of different origin than for isoprenaline. It is hypothesized that a different mechanism of activation of the beta 2-adrenoceptor may be involved for TA 2005.

Adrenal Effects and Pharmacokinetics of CFC-free Beclomethasone Dipropionate: a 14-Day Dose-Response Study

Since equivalent efficacy is achieved with lower doses of the reformulated beclomethasone dipropionate in the chlorofluorocarbon (CFC)‐free propellant HFA‐134a (HFA) than with the original CFC‐beclomethasone dipropionate formulation, it is possible the HFA‐beclomethasone dipropionate may have less safety concerns than the CFC formulation. Despite its chronic use, the steady‐state pharmacokinetics of beclomethasone dipropionate has never been studied before. This double‐blind study examined adrenal effects and pharmacokinetics after 14 days of dosing with HFA‐beclomethasone dipropionate.

Clinical equivalence of a novel non-chlorofluorocarbon-containing salbutamol sulfate metered-dose inhaler and a conventional chlorofluorocarbon inhaler in patients with asthma

BACKGROUND New formulations of non-chlorofluorocarbon-containing propellants for pressurized metered-dose inhaler delivery systems must be developed in response to the forthcoming ban on chlorofluorocarbon (CFC) production. OBJECTIVE This study compared the bronchodilator effects of 100, 200, and 300 micrograms (base equivalent) of salbutamol in a novel CFC-free propellant system (Airomir in the 3M CFC-Free System; 3M Pharmaceuticals, St. Paul, Minn.; 108 micrograms of salbutamol sulfate or 90 micrograms of salbutamol base equivalent per inhalation) with that of 100 and 200 micrograms of salbutamol base in a conventional CFC propellant system (Ventolin, CFC-11/12; Allen and Hanburys, Division of Glaxo Inc., Research Triangle Park, N.C.; 90 micrograms of salbutamol base per inhalation) and placebo. METHODS Twenty-six patients with chronic, stable asthma, who had a forced expiratory volume in 1 second (FEV1) between 50.0% and 75.0% of predicted normal value, entered this randomized, double-blind, double-dummy, 6-period, crossover study. FEV1 was measured before and at multiple time points (ranging from 10 to 480 minutes) after administration of one, two, and three inhalations of salbutamol/CFC-free (100, 200, and 300 micrograms); one and two inhalations of salbutamol/CFC (100 and 200 micrograms); and placebo. Safety parameters included adverse events, heart rate, blood pressure, physical examinations, electrocardiograms, and clinical laboratory tests. Parametric analysis of variance models appropriate for a 6-period crossover design were used, along with multiple comparisons according to Tukeys method. RESULTS All active treatments produced significantly (p < 0.0001) greater bronchodilation than placebo. The bronchodilator effect, as measured by FEV1 (peak percent change, peak as a percent of predicted value, duration, and area under the curve) after two inhalations of salbutamol/CFC-free was clinically comprable to two inhalations of salbutamol/CFC, with no clinically meaningful differences in safety parameters between the two delivery systems or between different dose levels. CONCLUSION These results suggest that salbutamol/CFC-free may offer a suitable alternative for salbutamol/CFC when the need arises to change from CFC-containing salbutamol products.

Cytochrome P450 metabolic intermediate complex of nefopam.

NADPH‐catalysed biotransformation of nefopam in liver microsomes obtained from phenobarbitone‐pretreated rats leads to the formation of an inactive cytochrome P450 metabolic intermediate (MI) complex. This complex can be detected spectrophotometrically by an absorbance maximum at 459 nm. The extent of the in‐vitro MI complexation of 33 μm nefopam, a cyclic analogue of orphenadrine, was almost equal to the extent of the in‐vitro MI complexation of 33 μm tofenacine, the mono‐N‐demethylated metabolite of orphenadrine. The time course of the MI complexation of nefopam and studies with two of its major metabolites suggest an initial biotransformation, which has to occur before MI complexation can take place. Maximal MI complexation of nefopam occurred at approximately 25 μm, whereas the MI complexation could not be detected at 100 μm nefopam.

Interaction of Nefopam and Orphenadrine with the Cytochrome P‐450 and the Glutathione System in Rat Liver

Nefopam, a cyclic analogue of orphenadrine, exhibits a type I (substrate) and a type II (ligand) interaction with ferri‐cytochrome P‐450 in control and phenobarbitone induced rat hepatic microsomes respectively. In‐vitro metabolism of nefopam in phenobarbitone‐induced microsomes leads to the production of a reactive metabolite which complexes with cytochrome P‐450. In contrast to the known complexation of orphenadrine, complexation by nefopam can be inhibited by glutathione (GSH, 0·1‐1·0 mm). However, in‐vivo administration of nefopam to rats does not diminish the GSH content of liver cytosol nor increase oxidized glutathione levels nor alter the activities of GSH transferase and GSH peroxidase. In‐vivo administration does not lead to cytochrome P‐450 induction nor cytochrome P‐450 complexation as has been shown for orphenadrine. Finally, nefopam inhibits the NADPH dependent endogenous H2O2 production in both control and phenobarbitone‐induced microsomes.

Solid-state stereochemistry of nefopam hydrochloride, a benzoxazocine analgesic drug

The solid-state structures of (±)- and (+)-nefopam hydrochloride (1), an analgesic agent, were determined by single-crystal X-ray diffraction analysis. (±)-Nefopam hydrochloride gave crystals belonging to the monoclinic P21/c space group, and at 298 K: a= 11.766(1), b= 7.741 (1), c= 16.907(3)A, β= 97.43(1)°, V= 1 527.0(7)A3, Z= 4, R(F)= 0.0336, and Rw= 0.0452. (+)-Nefopam hydrochloride monohydrate gave crystals belonging to the orthorhombic P212121 space group, and at 298 K: a= 9.651 (2), b= 19.747(2), c= 8.504(2)A, V= 1 620.7(7)A3, Z= 4, R(F) 0.0432, and Rw= 0.0690 for the (1S,5S)-model versus R(F)= 0.0442, and RW= 0.0700 for the (1R,5R)-model. The nefopam·HCl diastereoisomer found in the chiral crystal was also found in the racemic modification: (1S,5S) in (+)-(1)·H2O and (1R,5R), (1S,5S) in (±)-(1). The geometry of the nefopam·HCl molecule in both crystals is similar, and is that of a boat-(flattened chair) eightmembered ring. The N-methyl group is in an equatorial-like orientation, the oxydimethyleneamino moiety is in a gauche conformation, and the phenyl group resides in a relatively sterically unhindered exo-type position trans to the methyl. The major difference between the (±)-(1) and (+)-(1)·H2O molecular geometries is in the pitch of the phenyl ring. Energy minimization calculations on a series of nefopam·HCl boat-(flattened chair), twist-chair-(flattened chair), and twist-boat-(flattened chair) conformations were made by empirical force field methods using the MOLMEC molecular mechanics program. These calculations have shown that the (1R,5R), (1S,5S)-exo-phenyl–equatorial-methyl boat-(flattened chair) model for nefopam is the lowest energy structure in the series. Its geometry is analogous to that observed for crystalline (±)-(1) and (+)-(1)·H2O. This calculated molecular structure together with that of the axial N-methyl epimer correspond to the stereochemistry of the minor and major N-protonated solution species, respectively, upon dissolution of crystalline (±)-(1) or (+)-(1)·H2O in dichloromethane. The relatively small calculated energy difference (ca. 0.5 kcal mol–1) between the two epimers, which differ via diastereoisomerization through a prototropic shift/nitrogen inversion, is completely consistent with the magnitudes of the n.m.r. observed equilibrium ratios both in acidic aqueous medium or in dichloromethane solution (ca. 1:1 and ca. 3:2, respectively). The other calculated conformational models for nefopam·HCl geometry are not consistent with the n.m.r. data.

A new radioligand binding assay for cytochrome P450IID1 (CYP2D1) in rat liver microsomes: A tool to predict sparteine/debrisoquine type polymorphism of drugs

[3H]-Mepyramine ([3H]-pyrilamine) has a high affinity for cytochrome P450IID1 (CYP2D1) in rat liver microsomes, the isoenzyme involved in the oxidative metabolism of debrisoquine. Drugs known to interact with this enzyme, as either substrate or inhibitor, displaced [3H]-mepyramine. Compounds specific for other P450 isoenzymes did not displace [3H]-mepyramine. Drugs that are positive in this binding assay can be either substrates or inhibitors of CYP2D1 and warrant further research to investigate possible polymorphism. Substrates could reach toxicological concentrations, and inhibitors can have drug interactions with known CYP2D6 substrates. Although care should be taken in the extrapolation from rat to human, since CYP2D1 and CYP2D6 have clear differences, this rapid, easy-to-perform and inexpensive assay has predictive value for the sparteine/debrisoquine type of polymorphic behavior of compounds and could be used at an early stage in drug development.