Combined intervention programme reduces inappropriate prescribing in elderly patients exposed to polypharmacy in primary care.

PURPOSE: To evaluate the effect of a combined or a single educational intervention on the prescribing behaviour of general practitioners (GPs). The primary endpoint was effect on inappropriate prescribing according to the Medication Appropriateness Index (MAI). METHODS: General practitioners were randomised to either (1) a combined intervention consisting of an interactive educational meeting plus feedback on participating patients' medication, (2) a single intervention with an interactive educational meeting or (3) a control group (no intervention). Elderly (>65 years) patients exposed to polypharmacy (>or=5 medications) were identified and approached for inclusion. Data on medications prescribed over a 3-month period were collected, and the GPs provided detailed information on their patients before and after the intervention. A pre- and post-MAI were scored for all medications. RESULTS: Of the 277 GPs invited to participate; 41 (14.8%) volunteered. Data were obtained from 166 patients before and after the intervention. Medication appropriateness improved in the combined intervention group but not in the single intervention group. The mean change in MAI and number of medications was -5 [95% confidence interval (CI) -7.3 to -2.6] and -1.03 (95% CI -1.7 to -0.30) in the combined intervention group compared with the group with the educational meeting only and the no intervention group. CONCLUSIONS: A combined intervention consisting of an interactive educational meeting plus recommendations given by clinical pharmacologists/pharmacists concerning specific patients can improve the appropriateness of prescribing among elderly patients exposed to polypharmacy. This study adds to the limited number of well-controlled, randomised studies on overall medication appropriateness among elderly patients in primary care. Important limitations to the study include variability in data provided by participating GPs and a low number of GPs volunteering for the study.

Effects of five different airway smooth muscle relaxants on inhibitory neurotransmission in isolated guinea-pig trachea in vitro.

Pharmacodynamic effects produced by terbutaline (10 nM), theophylline (10 microM), sodium nitroprusside (30 nM), levcromakalim (0.3 microM) or isradipine (1 nM) on frequency-dependent relaxations induced by electric field stimulation of either proximal or distal parts of isolated guinea-pig trachea were studied in vitro. Preparations were depleted for tachykinins by capsaicin, pretreated with atropine (0.1 microM) and contracted by histamine (2 microM). Drug effects were studied in preparations with combined adrenergic and inhibitory non-adrenergic non-cholinergic (NANC) innervation and in preparations with inhibitory NANC innervation either with or without additional treatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (100 microM). In preparations with combined adrenergic and inhibitory NANC innervation terbutaline, sodium nitroprusside, levcromakalim and isradipine significantly reduced relaxant responses to electric field stimulation in proximal preparations, whereas distal preparations were only affected by terbutaline. In preparations with inhibitory NANC innervation without L-NAME pretreatment, terbutaline significantly enhanced relaxant responses to electric field stimulation only in distal preparations, whereas theophylline, sodium nitroprusside and levcromakalim significantly augmented responses to electric field stimulation in both proximal and distal preparations. In preparations with inhibitory NANC innervation pretreated with L-NAME, theophylline significantly inhibited relaxant responses in distal preparations, whereas sodium nitroprusside, levcromakalim and isradipine significantly augmented relaxant responses to electric field stimulation in proximal preparations. It was concluded that drugs used in the present study can modulate the effects of inhibitory autonomic and NANC neurotransmission in isolated guinea-pig trachea. Furthermore, it was shown that some variation in drug effects exists in relation to proximal and distal parts of guinea-pig trachea.

Interaction between prostaglandins and selective phosphodiesterase inhibitors in isolated guinea-pig trachea in vitro.

The possible interaction between spontaneously synthesized relaxant prostaglandins and the relaxation produced by three different isoenzyme-selective phosphodiesterase inhibitors was investigated in the isolated guinea-pig trachea in vitro. The relaxant action of siguazodan (phosphodiesterase III inhibitor), rolipram (phosphodiesterase IV inhibitor) and zaprinast (phosphodiesterase V inhibitor) was investigated in preparations with either spontaneously tone alone or in preparations with spontaneous tone and additionally stimulated with histamine (1 microM). In addition, relaxant effects were assessed in preparations without spontaneous tone (inhibited by indomethacin 2 microM) and precontracted with histamine (1 microM) or prostaglandin F2 alpha (10 microM), either alone or in the presence of a non-relaxant concentration (20 nM) of prostaglandin E2. All three phosphodiesterase inhibitors preferentially relaxed preparations with spontaneous tone and showed increased relaxant effects in preparations with spontaneous tone and additionally stimulated with histamine compared to preparations contracted by histamine alone. This enhanced relaxing effect observed in the presence of initial spontaneous tone was mimicked by exogenous application of prostaglandin E2 to indomethacin treated preparations either precontracted by histamine or prostaglandin F2 alpha. Furthermore, the study revealed marked differences in the relaxant profiles of siguazodan, rolipram and zaprinast, differences which most likely are related to the functional importance of the phosphodiesterase isoenzymes inhibited by these drugs. It is concluded that endogenously synthesized relaxant prostaglandins and exogenously applied prostaglandin E2 are capable of enhancing the relaxant action of the phosphodiesterase inhibitors siguazodan, rolipram and zaprinast and that cyclooxygenase inhibition is an important way to avoid this interaction in experimental studies of airway smooth muscle relaxants in isolated guinea-pig trachea in vitro.

In vitro studies on the interactions of beta2-adrenoceptor agonists, methylxanthines, Ca2+-channel blockers, K+-channel openers and other airway smooth muscle relaxants in isolated guinea-pig trachea.

Pharmacodynamic interactions in vitro between different types of airway smooth muscle relaxants were systematically and quantitatively evaluated by using a new methodological technique. Relaxant concentration-effect curves for terbutaline, theophylline, cromakalim, sodium nitroprusside and isradipine were obtained in isolated guinea-pig trachea contracted by histamine (1 microM). The effects of three different fixed concentrations of each airway smooth muscle relaxant were initially attained and concentration-effect curves for combinations with increasing concentrations of either one of the other relaxants were produced. Based on pharmacodynamic parameters obtained by non-linear regression analysis of experimental data for the relaxants alone theoretical concentration-effect curves for predicted additive interaction were constructed by using the isobolic method. Synergistic (over-additive) interaction was defined as existing when data points and derived pharmacodynamic parameters obtained with combinations of the relaxants showed statistically significant deviation from the predicted additive interaction curve and its functional parameters. Significant synergistic interaction with terbutaline was found for both theophylline (70 or 200 microM), cromakalim (0.1, 0.3 or 1 microM), sodium nitroprusside (30 or 100 nM) and isradipine (1, 3 or 10 nM). Theophylline showed synergistic interaction with cromakalim (0.1, 0.3 or 1 microM), sodium nitroprusside (10 nM) and isradipine (1, 3 or 10 nM). Interactions between cromakalim and sodium nitroprusside (10, 30 or 100 nM) were also synergistic, whereas cromakalim and isradipine (1, 3 or 10 nM) produced only additive interaction. Possible mechanisms underlying the interactions are discussed on basis of existing knowledge with special regards to phosphodiesterase isoenzymes, K+ and Ca2+ channels.

Involvement of K+ channels in the relaxant effect of vasoactive intestinal peptide and atrial natriuretic peptide in isolated guinea-pig trachea.

The possible contribution of K+ channel activation to airway smooth muscle relaxation induced by vasoactive intestinal peptide (VIP) and atrial natriuretic peptide (ANP) was investigated in isolated guinea-pig trachea. Concentration-relaxation (CR) curves were assessed in preparations precontracted by 30 mM K+, 124 mM K+ or histamine either alone or in the presence of a K+ channel blocker: iberiotoxin (IbTX), glipizide, tetraethylammonium (TEA) or Ba2+. VIP completely relaxed contractions induced by histamine but had a lower effectiveness against those induced by 30 mM K+ and 124 mM K+. IbTX and TEA shifted the CR curve for VIP 5 and 14 times to the right, respectively. Glipizide and Ba2+ did not significantly antagonize the action of VIP. ANP relaxed contractions induced by histamine and 30 mM K+ but failed to relax those elicited by 124 mM K+. IbTX and TEA shifted the CR curve for ANP 8 and 46 times to the right, respectively. Glipizide and Ba2+ suppressed the maximal effect produced by ANP, and glipizide also shifted the CR curve to the left. The K+ channel opener levcromakalim relaxed tracheal contractions induced by histamine and 30 mM K+ but not those induced by 124 mM K+. Glipizide caused a 5-fold rightward shift of the CR curve for levcromakalim whereas IbTX shifted the curve to the left and increased the maximal relaxant effect. The Ca2+ channel blocker isradipine completely relaxed contractions induced by 30 mM K+ and 124 mM K+ but only partially relaxed those contracted by histamine. All four K+ channel blockers increased the maximal relaxant effect and shifted the CR curve for isradipine to the left. The results suggest that airway smooth muscle relaxation produced by VIP and ANP involves activation of large-conductance Ca(2+)-activated K+ channels (BKCa) and further that ANP may possibly activate other types of K+ channels additional to BKCa.

Inhibition by cromakalim, pinacidil, terbutaline, theophylline and verapamil of non-cholinergic nerve-mediated contractions of guinea-pig isolated bronchi.

Contractions induced by electrical field stimulation of sensory non-cholinergic excitatory nerves in guinea-pig isolated bronchi are due to the release of substance P (SP) and related tachykinins. Release of such neuropeptides are thought to play a pathophysiological role in asthma. Two K+ channel openers cromakalim (pD2 = 6.45; Emax = 95%) and pinacidil (pD2 = 6.06; Emax = 87%) were shown to concentration-dependently inhibit non-cholinergic nerve-mediated contractions in guinea-pig bronchi in vitro. Cromakalim (pD2 = 6.27; Emax = 25%) and pinacidil (pD2 = 6.03; Emax = 25%) each had a much lower inhibitory efficacy against contractions induced by exogenously applied SP but the same potency as found against contractile responses to non-cholinergic neurostimulation. Also the beta 2-adrenoceptor agonist terbutaline (pD2 = 8.29; Emax = 83%), the xanthine derivative theophylline (pD2 = 4.19; Emax = 100%) and the Ca2+ blocker verapamil (pD2 = 5.55; Emax = 100%) suppressed responses to non-cholinergic neurostimulation. Terbutaline (pD2 = 6.32; Emax = 74%), theophylline (pD2 = 3.25; Emax = 71%) and verapamil (pD2 = 4.01; Emax = 100%) had a 10-100-fold lower inhibitory potency against SP-induced contractions but each drug showed about the same efficacy as found against nerve-mediated contractions. Glibenclamide (1 microM) reversed the inhibitory effects of cromakalim and pinacidil on neurally-mediated contractions but did not influence the effects of terbutaline, theophylline and verapamil. The results demonstrate that cromakalim, pinacidil, terbutaline, theophylline and verapamil inhibit non-cholinergic excitatory neurotransmission in guinea-pig bronchi and suggest that they act preferentially at a pre-junctional site.

Effects of antidiabetic sulphonylureas, cromakalim and their interaction in guinea-pig isolated tracheal smooth muscle.

Glibenclamide, glipizide and glibornuride showed dual effects in guinea-pig isolated trachea. The drugs antagonized the relaxant response to the K+ channel opener cromakalim (order of effectiveness: glibenclamide > glipizide > glibornuride) and at concentrations of 1-1000 microM produced airway smooth muscle relaxation (order of potency: glibenclamide > glipizide = glibornuride). Gliclazide, tolbutamide and chlorpropamide did not antagonize cromakalim nor did the two latter drugs produce tracheal relaxation. The sulphonylureas and cromakalim were compared as airway relaxants against a panel of different spasmogens. The order of tissue responsiveness for the sulphonylureas was: spontaneous tone = LTD4 > PGF2 alpha = histamine = 30 mM K+ > carbachol and for cromakalim: spontaneous tone = LTD4 = PGF2 alpha = histamine > carbachol > 30 mM K+. Glibenclamide, but not cromakalim, relaxed contractions induced by 124 mM K+. Phentolamine and Ba2+, which are reported blockers of ATP-regulated K+ channels, failed to influence sulphonylurea-induced airway smooth muscle relaxation. Glibenclamide reversed tracheal relaxation produced by cromakalim, whereas cromakalim failed to reverse relaxation induced by glibenclamide. The mechanism for the additional property of sulphonylureas to relax airway smooth muscle is unclear, but the results do not support a role for involvement of cromakalim-sensitive K+ channels.

Smooth muscle relaxant effects of propofol and ketamine in isolated guinea-pig trachea.

The effects of anesthetics on airway smooth muscle tone are important in the management of patients with asthma. In the present study we evaluated the effect of propofol and ketamine on isolated guinea-pig tracheal preparations mounted for recording isometric contractile force. In a concentration-dependent way both drugs produced 100% relaxation irrespective of whether tracheal tone was spontaneous or induced by carbachol, histamine, prostaglandin F2 alpha, 30 mM K+ or 124 mM K+. The relaxant potency of propofol was dependent of the formulation of the drug used. Propofol showed an about 3 times higher potency when solubilized with hydroxypropyl-beta-cyclodextrin compared with an oil-in-water emulsion of the drug (Diprivan). Propofol had the greatest potency on tracheal preparations with spontaneous tone (EC50 = 4.0 +/- 0.9 microM). Ketamine preferentially relaxed contractions elicited by carbachol (EC50 = 120.8 +/- 5.2 microM) and had a lower potency than propofol when tone was spontaneous or induced by other tracheal spasmogens. Since propofol was a more effective tracheal relaxant in vitro than ketamine, the possibility that propofol, like ketamine, may inhibit bronchoconstriction during anesthesia should be studied further.

Effects of K+ channel blockers on the relaxant action of dihydralazine, cromakalim and nitroprusside in isolated rabbit femoral arteries.

The relaxant responses to dihydralazine and the influence of different K+ channel blockers were studied in isolated rabbit femoral arteries. The prototype K+ channel opener, cromakalim, and nitroprusside, which does not produce relaxation by K+ channel activation were used for comparison. Dihydralazine was most effective on contractions induced by noradrenaline (EC50 = 1.1 microM; Emax = 95%) and relaxed the contractions elicited by 20 mM K+ (EC50 = 2.0 microM; Emax = 81% in preference to 124 mM K(+)-induced contractions (EC50 = 30.1 microM; Emax = 54%). Cromakalim, but not nitroprusside, also selectively relaxed 20 mM K(+)-induced contractions. In noradrenaline-contracted arteries, glibenclamide (10 microM) completely suppressed the relaxant response to cromakalim but did not influence the vasorelaxation produced by dihydralazine or nitroprusside. Tetraethylammonium (8 mM) and Cs+ (4 mM) shifted the concentration-relaxation curve for dihydralazine 2-fold to the right, whereas Ba2+ (0.1 mM), 4-aminopyridine (5 mM) and procaine (0.1 mM) failed to influence dihydralazine-induced responses. Tetraethylammonium (8 mM) shifted the concentration-relaxation curve for cromakalim and nitroprusside 6-fold to the right and suppressed the maximal relaxant effects by about 30%. It is concluded that dihydralazine produces vascular smooth muscle relaxation by a mechanism different from the opening of glibenclamide- and ATP-sensitive K+ channels.

Antidiabetic sulfonylureas relax isolated rabbit coronary arteries.

Antidiabetic sulfonylureas completely relaxed isolated rabbit coronary arteries contracted by prostaglandin F2 alpha. The order of potency was glibenclamide (EC50 = 4.75 microM) greater than glipizide = glibornuride = tolbutamide = chlorpropamide. The drugs also relaxed the contractions induced by 30 mM K+ but much less potently. The effectiveness of the drugs as vascular smooth muscle relaxants did not correlate with their ability to antagonize the vasorelaxant action of cromakalim. Sulfonylurea-induced vasorelaxation probably involves mechanisms other than an interaction with ATP-regulated K+ channels.