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Biomedical subjects

D Donnell

Publications and source records attributed to D Donnell.

34 records · Page 2Linked to original sources
PubMed1995

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 Tukey's 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.

Administration, Inhalation↗
PubMed1994

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.

Animals↗
PubMed1994

A functional beta-2 adrenoceptor-mediated chronotropic response in isolated guinea pig heart tissue: selectivity of the potent beta-2 adrenoceptor agonist TA 2005.

Responses were measured of the highly potent beta-2 adrenoceptor agonist TA 2005, a new bronchodilator, on isolated guinea pig right and left atria and papillary muscle. The main objectives of the study were to investigate the selectivity of the compound and to determine whether guinea pig isolated heart tissues could be used as a model for investigating mechanisms of clinical cardiac side effects. It was found that the inotropic responses in all tissues were mediated by the beta-1 adrenoceptor only. TA 2005 was a partial agonist for the inotropic response compared with I-isoprenaline. For the right atrial chronotropic response, however, TA 2005 exerted a biphasic effect and reached 84% of the I-isoprenaline response. The first phase was mediated by the beta-2 adrenoceptor, whereas the second phase was beta-1 adrenoceptor mediated. Approximately 64% of the TA 2005 chronotropic response was exerted via the beta-2 adrenoceptor. Addition of the beta-2-selective antagonist ICI 188.551 blocked the beta-2 adrenoceptor-mediated response, providing only a monophasic response. Addition of the beta-1-selective antagonist ICI 89.406 resulted in further separation of the phases. The finding that a beta-2-mediated chronotropic response exists on the right atrium of the guinea pig sheds new light on selectivity studies. It is suggested that quantification of beta-1/beta-2 selectivity of beta adrenoceptor agonists be performed not on the basis of measurement of guinea pig right atrial chronotropism but rather on the basis of measurement of guinea pig left atrial inotropism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1993

Solution- and solid-state structures of N-desmethylnefopam hydrochloride, a metabolite of the analgesic drug.

The solid-state structure of (+/-)-N-desmethylnefopam hydrochloride (1), a metabolite of the analgesic drug, was determined by single-crystal X-ray diffraction analysis. Compound 1 gave crystalline prisms belonging to the orthorhombic Pcab space group, and at ambient temperature (293 K), a = 9.939(2), b = 14.479(1), c = 20.148(3) A, V = 2899.5(8) A3, Z = 8, R(F) = 0.045, and Rw(F) = 0.025. The benzoxazocine ring of crystalline 1 is twisted into the boat-flattened (chair) [BfC] conformation, the phenyl ring resides in a relatively sterically unhindered exo-type ring position, whereas the O atom and NCH2Ar occupy sterically hindered positions between "boat" and "chair" regions. Dissolution of BfC crystalline 1 in CD2Cl2 solvent affords a dynamic conformational equilibrium (involving the putative twist-chair-flattened (chair) conformer) as shown by line broadening and weighted time-averaged vicinal coupling constants [-OCH2CH2N- segment] in the 1H NMR spectrum. The solution-state weighted time-averaged 50(1) degrees O-CH2-CH2-N dihedral angle, calculated by the R-ratio method, shows that the BfC conformation is the major contributor to time-averaged structure.

Analgesics↗
PubMed1993

Solid-state stereochemistry and activity of 3-methylnefopam diastereomers: manipulation of eight-membered ring conformations in analogues of the non-narcotic analgesic drug.

The solid-state structures of (+/-)-(1R,3S,5S)/(1S,3R,5R)- and (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-methylnefopam hydrochloride, epimeric 3-methyl derivatives of the non-narcotic analgesic drug, were determined by single-crystal X-ray diffraction analyses. (+/-)-(1R,3S,5S)/(1S,3R,5S)-3-Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2(1)/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) A, beta = 93.06 degrees, V = 3234(2) A3, Z = 8, R(F = 0.070, and Rw(F) = 0.053. (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2(1)2(1)2(1), and at 92 K, a = 9.261(2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) A3, Z = 4, R(F) = 0.034, and Rw(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)-racemic modification had twist-chair-(flattened chair) [TCfC] conformational geometries for the eight-membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 A in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-epimers were found in the same boat-(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight-membered ring conformations of the two 3-methylnefopam diastereomers differ in the -N+H(CH3)CH2CH-fragment chair or boat arrangement vis-a-vis the adjacent flattened region. In both 3-methyl diastereomers, the C(3)-methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo-position, and the -OCH(Ph)-o-C6H4- fragment occupied the flattened region of the eight-membered ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

Atypical molecular pharmacology of a new long-acting beta 2-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.

Adrenergic beta-Agonists↗
PubMed1992

Solid-state structure of orphenadrine hydrochloride and conformational comparisons with diphenhydramine hydrochloride and nefopam hydrochloride.

The solid-state structure of (+-)-orphenadrine hydrochloride [(CH3)2NCH2CH2OCH(o-CH3C6H4)(Ph).HCl], a skeletal muscle relaxant drug, was determined by single-crystal X-ray diffraction analysis. Orphenadrine hydrochloride gave crystals belonging to the monoclinic P2(1)/n space group, and at low temperature (92 K), the following parameters were found: a = 6.923 (4), b = 7.508 (5), c = 33.22 (3) A, V = 1720 (3) A3, Z = 4, R(F) = 0.109, and Rw(F) = 0.131. Data were collected from poor crystalline material because of the low volume of the needle-shaped crystals (0.025 x 0.025 x 0.15 mm3). A molecular mechanics model was calculated by using an input structure based on atomic coordinates of the crystallographically determined molecular structure. The resulting molecular mechanics model and the structure determined by X-ray crystallography have the same molecular conformation. Whereas both solid-state (+-)-orphenadrine hydrochloride and diphenhydramine hydrochloride [(CH3)2NCH2CH2OCH(Ph)2.HCl] have synclinal N-C-C-O and antiperiplanar NC-C-O-CAr2 torsion angles, the former has a helical arrangement for Ar2CH, as expected, and the phenyl rings in the latter are disposed in a nonhelical, "open-book" arrangement.

Diphenhydramine↗
PubMed1989

Stereoisomer differentiation for the analgesic drug nefopam hydrochloride using modeling studies of serotonin uptake area.

Equatorial and axial N-methyl diastereomers of the analgesic drug nefopam hydrochloride were differentiated using a hypothetical model of the serotonin (5-hydroxytryptamine) uptake area. Both diastereomers were placed within the hypothetical model area to form van der Waals interactions involving the phenyl group of nefopam, but only in the case of the equatorial N-methyl epimer was the +N--H bond able to be oriented towards the proposed hydrogen-bonding site. A comparison of equatorial N-methyl nefopam hydrochloride enantiomers in the proposed two-site binding mode points to less severe nonbonding steric interactions for the (+)-(1S,5S)-enantiomer compared with the (-)-(1R,5R)-isomer.

Models, Biological↗
PubMed1989

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.

Aminopyrine N-Demethylase↗
PubMed1987

Nefopam excretion in human milk.

Human milk and plasma samples were obtained from five healthy nursing mothers who were taking nefopam hydrochloride (60 mg four-hourly) for post-episiotomy pain. Concentrations of nefopam were quantified in milk and plasma paired samples, taken daily from birth for 5 days, by a specific paired-ion reverse phase h.p.l.c. method. Although nefopam was present in human milk in an equivalent concentration to plasma (milk: plasma ratio 1.2 +/- 0.7, mean +/- s.d.), the likely infant exposure was less than 0.05 mg kg-1 day-1 which, on a body weight basis, would be less than 3% of the maternal dose.

Adult↗
PubMed1987

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 microM nefopam, a cyclic analogue of orphenadrine, was almost equal to the extent of the in-vitro MI complexation of 33 microM 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 microM, whereas the MI complexation could not be detected at 100 microM nefopam.

Animals↗
PubMed1986

Conformation of nefopam hydrochloride, a novel analgesic.

The solid state structures of (+/-)- and (+)-nefopam hydrochloride (3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine hydrochloride, 1) were determined by single crystal X-ray diffraction analysis. (+/-)-Nefopam hydrochloride gave crystals belonging to monoclinic P21/c space group, and at 298 K: a = 11.766 (1) A, b = 7.741 (1) A, c = 16.907 (3) A, beta = 97.43 (1) degrees, V = 1527.0 (7) A3, Z = 4, R = 0.0336, and Rw = 0.0452. (+)-Nefopam hydrochloride monohydrate gave crystals of the orthorhombic P2(1)2(1)2(1) space group, and at 298 K: a = 9.651 (2) A, b = 19.747 (2) A, c = 8.504 (2) A, V = 1620.7(7) A3, Z = 4, R = 0.0432, and Rw = 0.0690 for the (1S,5S)-model. The diastereoisomer found in the chiral crystal was also found in the solid racemic modification: (1S,5S) in the monohydrate of (+)-1 and (1R,5R)/(1S,5S) in (+/-)-1. 1H and 13C[1H] NMR spectroscopy revealed two distinct, major and minor, N-protonated species in CD2Cl2 solution differing in the stereochemistry of the N-methyl group. The molecular structures of the crystals of (+/-)-1 and (+)-1 X H2O (a) indicate a modified boat-chair conformation of the eight-membered ring with an equatorial N-methyl group, caused by two sp2-hybridized ring atoms, and (b) correspond to the stereochemistry of the minor species in solution.

Crystallization↗
PubMedDate not supplied

Clinical and pharmacological review of the efficacy of orphenadrine and its combination with paracetamol in painful conditions.

Orphenadrine citrate, a monomethylated derivative of diphenhydramine, has been used as a muscle relaxant and as an analgesic both alone or as a constituent of combination products. Data on the efficacy of orphenadrine alone and in combination with paracetamol for painful conditions are evaluated in the present review. From the available animal data it is concluded that the antinociceptive effect of orphenadrine has been clearly demonstrated but data have also clearly indicated that it has muscle relaxant properties. Human placebo-controlled studies have shown some support for the view that orphenadrine on its own acts as a mild analgesic in painful conditions associated with muscle spasm. Although only a small number of well-controlled studies have been completed with the combination product of orphenadrine/paracetamol, each supports the view that the combination has superior efficacy over paracetamol alone. There is no doubt that the combination product is more efficacious than placebo.

Acetaminophen↗
PubMedDate not supplied

Inhaled corticosteroid delivery systems: clinical role of a breath-actuated device.

Several devices have been developed to overcome the need to co-ordinate actuation with inhalation required during use of a pressurised metered dose inhaler (MDI) and to improve drug delivery to the lung. These include spacer attachments for MDIs, dry powder inhalers and breath-actuated MDIs. The breath-actuated Autohaler (3M Pharmaceuticals) is a compact, multidose inhaler device that, unlike dry powder inhalers, does not rely on the patient's inspiratory effort to aerosolise the dose of medication. Due to its simple operation, the Autohaler is suitable for patients unable to operate a conventional MDI efficiently, including the elderly, children, patients with arthritis and patients with low inspiratory flow rates. The mandatory replacement of chlorofluorocarbon propellants with non-ozone-depleting propellants has given the opportunity to improve drug delivery characteristics of MDIs. Recently, a formulation of beclomethasone dipropionate in hydrofluoroalkane-134a (HFA-BDP), has been developed in a conventional MDI that delivers most of the emitted dose to the lung. Drug deposition studies show that the HFA-BDP formulation in the Autohaler device has a similar lung deposition pattern to drug delivered from the MDI, when used correctly, and dose delivery is consistent across a wide range of inspiratory flow rates. Furthermore, HFA-BDP Autohaler has similar clinical benefits to CFC-BDP Autohaler but at less than half the dose. HFA-BDP Autohaler offers a useful CFC-free delivery option for patients challenged by the conventional MDI device.

Administration, Inhalation↗
PubMedDate not supplied

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.

Adolescent↗