Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs.

The opioid agonist properties of (+/-)-methadone are ascribed almost entirely to the (-)-methadone enantiomer. To extend our knowledge of the pharmacological actions of methadone at ligand-gated ion channels, we investigated the effects of the two enantiomers of methadone and its metabolites R-(+)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium perchlorate (EDDP) and R-(+)-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline hydrochloride (EMDP), as well as structural analogs of methadone, including (-)-alpha-acetylmethadol hydrochloride (LAAM) and (+)-alpha-propoxyphene, on rat alpha3beta4 neuronal nicotinic acetylcholine receptors (nAChRs) stably expressed in a human embryonic kidney 293 cell line, designated KXalpha3beta4R2. (+/-)-methadone inhibited nicotine-stimulated 86Rb+ efflux from the cells in a concentration-dependent manner with an IC50 value of 1.9 +/- 0.2 microM, indicating that it is a potent nAChR antagonist. The (-)- and (+)-enantiomers of methadone have similar inhibitory potencies on nicotine-stimulated 86Rb+ efflux, with IC50 values of approximately 2 microM. EDDP, the major metabolite of methadone, is even more potent, with an IC50 value of approximately 0.5 microM, making it one of the most potent nicotinic receptor blockers reported. In the presence of (+/-)-methadone, EDDP, or LAAM, the maximum nicotine-stimulated 86Rb+ efflux was markedly decreased, but the EC50 value for nicotine stimulation was altered only slightly, if at all, indicating that these compounds block alpha3beta4 nicotinic receptor function by a noncompetitive mechanism. Consistent with a noncompetitive mechanism, (+/-)-methadone, its metabolites, and structural analogs have very low affinity for nicotinic receptor agonist binding sites in membrane homogenates from KXalpha3beta4R2 cells. We conclude that both enantiomers of methadone and its metabolites as well as LAAM and (+)-alpha-propoxyphene are potent noncompetitive antagonists of alpha3beta4 nAChRs.

Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors.

Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated (86)Rb(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [(3)H]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.

NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance.

A model proposing that N-methyl-D-aspartate (NMDA) receptor and opioid receptor mechanisms overlap and interact within the same dorsal horn nociceptive neurons makes several predictions. First, hyperalgesia should be associated with opioid tolerance. Second, both hyperalgesia and tolerance to opioid-analgesia should be blocked by an NMDA-receptor antagonist. Results from our laboratory and others support these predictions and point to several clinical implications. One is that, in addition to preventing tolerance and dependence, combining NMDA-receptor antagonists with both opioid and nonopioid analgesics may increase their analgesic potency. Preclinical animal studies demonstrate these advantages and underscore the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs.

MorphiDex pharmacokinetic studies and single-dose analgesic efficacy studies in patients with postoperative pain.

MorphiDex (MS:DM), a 1:1 (weight:weight) ratio of morphine sulfate (MS) to dextromethorphan hydrobromide (DM), is under clinical development for the treatment of moderate to severe pain. The enhancement of MS analgesia by DM is due to a pharmacodynamic interaction, not an effect on MS blood levels or a pharmacokinetic interaction between MS and DM, or their metabolites. Peak blood levels were achieved at approximately 1 hour, similar to MS in solution, resulting in a rapid onset of effect. As the dose was increased, dose-proportionality was linear. Food reduced the peak concentration in blood (Cmax) but not the extent of the absorption. Single-dose, double-blind, placebo-controlled studies in patients suffering from moderate to severe postoperative pain after third-molar oral surgery or orthopedic surgery demonstrated a significantly greater analgesic effect for MS:DM over MS alone with an 8-hour duration of effect. MS:DM is an effective treatment of moderate to severe pain.

Effects of the combined oral administration of NSAIDs and dextromethorphan on behavioral symptoms indicative of arthritic pain in rats.

The effects of combined single oral treatments with non-steroidal anti-inflammatory drugs (NSAIDs) and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan (DM) on arthritic pain were examined in a rat model of adjuvant-induced arthritis. Although 12.5-100 mg/kg doses of DM alone produced no reliable effects, treatments with ibuprofen (IB, 50 and 100 mg/kg but not 12.5 or 25 mg/kg) produced mild analgesia in arthritic rats as determined using the Randall-Sellito test. IB showed a dose-response relationship which appeared to plateau at doses of 50 and 100 mg/kg. Adding 50 mg/kg DM to each IB dose resulted in significantly greater analgesic activity than IB alone at doses of 25, 50 and 100 mg/kg. A similar interaction between 50 mg/kg DM and 50 mg/kg IB occurred with respect to spontaneous pain behavior. Adding 25 mg/kg DM to 25 mg/kg IB likewise increased analgesia as measured by both the Randall-Sellito and spontaneous pain behavior tests (both P < 0.05). Five more NSAIDs were evaluated using the Randall-Sellito test, which included naproxen (NP), piroxicam (PIR), etodolac (ET), diclofenac (DC), and ketorolac (KE). For all six NSAIDS, the addition of 50 mg/kg DM reliably increased their analgesic potency, as indicated by reliable increases in previously effective NSAID doses (all six NSAIDs) as well as previously ineffective NSAID doses (IB, NP, DC, and PIR). These data demonstrate that DM greatly potentiates the analgesic activity of IB, DC, NP, PIR, ET, and KT and increases the peak effect over the NSAIDs alone. Similiar to DM's previously demonstrated enhancement of opioid analgesia in acute pain, the combination of DM and an NSAID may represent a novel analgesic approach to improved management of arthritic pain.

Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats.

Combined oral administration of morphine sulfate (MS) and the over-the-counter antitussive drug and N-methyl-D-aspartate receptor antagonist dextromethorphan (DM) prevented the development of tolerance to the antinociceptive effects of MS (15, 24, or 32 mg/kg) in rats. This combined oral treatment regimen also attenuated signs of naloxone-precipitated physical dependence on morphine in the same rats. A wide range of ratios of MS to DM (2:1, 1:1, and 1:2) were effective for preventing the development of morphine tolerance and dependence. In addition, we provide evidence that under certain circumstances DM increases the acute antinociceptive effects of MS. All of these results indicate that oral treatment that combines DM with opiate analgesics may be a powerful approach for simultaneously preventing opiate tolerance and dependence and enhancing analgesia in humans.

Midodrine treatment for patients with hemodialysis hypotension.

Hypotension is the principal complication of chronic hemodialysis. Autonomic insufficiency is thought to be a primary contributing cause of hemodialysis hypotension. We treated patients who experience hemodialysis hypotension with midodrine, a selective alpha-1 adrenergic pressor agent in an initial effort to assess potential efficacy. Twenty-one patients who experienced severe hypotension during hemodialysis participated in this study. To qualify, patients had to exhibit a fall of > or = 30 mmHg in systolic blood pressure with associated clinical symptoms during hemodialysis. The lowest intra- and post-dialysis blood pressures were monitored for five consecutive hemodialysis treatment periods before receiving midodrine, as a baseline. After the patients were titrated to a maintenance midodrine dose, the lowest intra- and post-dialysis blood pressure data were again collected for five consecutive dialysis treatments. Hemodialysis blood pressures on midodrine treatment were compared to baseline to evaluate the effect of midodrine. Midodrine given at a mean treatment dose of 8 mg (range 2.5-25) significantly increased the mean (+ or - SE) minimal systolic pressure from 93.1 "+ or - " 3.8 to 107.1 + or - 3.2 mmHg (p <0.01) and elevated the mean diastolic pressure from 52.3 + or - 2.9 to 57.9 + or - 2.3 mmHg during hemodialysis. Also, the post-dialysis blood pressures (systolic/diastolic) were significantly increased from 115.6 + or - 3.1/62.3 + or - 2.1 to 129.9 + or - 3.9/68.1 + or - 1.7 mmHg (p <0.01 and 0.05, respectively). No apparent clinical or laboratory abnormalities were observed. Oral midodrine appears to be a safe and effective therapy for the treatment of hemodialysis hypotension.

Combined modality treatment with ternary Cu(II) complexes and X rays.

Ternary Cu(II) complexes with bidentate malonato- and heterocyclic amine ligands were tested with regard to cytotoxicity and potentiation of x-ray induced cell killing in V79 cells. Two lead complexes were also tested in a tumor assay using the MTG-B murine adenocarcinoma model growing in the flanks of female C3H/HeJ mice. One complex, [2,2'-bipyridyl malonatoCu(II)] (RL-5077), produced sensitizer enhancement ratios (SER's) of 1.8 (hypoxic conditions) and 1.0 (oxic conditions) in vitro when irradiation followed 1 hr exposure to the drug at 100 microM. When RL-5077 was administered at doses of 1/2 (11.65 mg/kg) or 1/4 (5.25 mg/kg) the maximum tolerated dose (MTD), 15 min prior to a locally delivered dose of 20 Gy, enhancement ratios (ER's) of 1.6 and 2, respectively, resulted. The second lead complex, [1,10 phenanthroline (malonato)Cu(II)hydrate] (RL-5027), produced SER's of 1.8 and 1.2 under hypoxic and oxic conditions, respectively, at a concentration of 25 microM. Injection of RL-5027 (5 mg/kg) resulted in toxicity without enhancement in combination with radiation. Analogues of these two complexes have been synthesized in an effort to optimize the potentiation of radiation effects while minimizing toxicity to drug alone and increasing water solubility of the drug. Further studies of the structure-activity relationship of Cu(II) ternary complexes using in vitro radiosensitization as the endpoint have identified four classes of ligands with varying biological activity and have supplied information about the effects of group substitution on solubility, toxicity, and radiation potentiation. This group of complexes represents a new class of radiopotentiators that deserves further investigation into its potential for clinical use.

Celiprolol, atenolol and propranolol: a comparison of pulmonary effects in asthmatic patients.

Celiprolol, a new beta-adrenoceptor antagonist, blocks serotonin- and methacholine-mediated bronchoconstriction in animals, even in the presence of propranolol. In two, randomized, placebo-controlled, 5-way crossover trials, the pulmonary effects of celiprolol 200 and 400 mg, propranolol 40 mg and atenolol 100 mg were compared in 34 asthmatic patients. Pulmonary function was measured after single doses of each agent, and again following subsequent, graded doses of albuterol or isoproterenol aerosol. Changes in one-second forced expiratory volume (FEV1) and maximal midexpiratory flow rate (FEF25-75) prior to albuterol or isoproterenol were positive after placebo and both doses of celiprolol. Propranolol, and to a lesser extent, atenolol, caused significant reductions in both measures of pulmonary function. Overall changes in FEV1 following each drug plus isoproterenol or albuterol were positive, in the rank order, celiprolol approximately placebo greater than atenolol greater than propranolol. Propranolol pretreatment caused a significant reduction in the effect of bronchodilator. Unlike atenolol and propranolol, celiprolol was highly bronchosparing and did not antagonize sympathomimetic bronchodilators.

Effects of high doses of celiprolol in asthmatic patients.

Sixteen normotensive asthmatic patients received single doses of 400 and 600 mg of celiprolol and 100 mg of atenolol in this placebo-controlled, double-blind crossover study. Pulmonary function was assessed by spirometry. Changes in forced one-second expiratory volume (FEV1) and mid-maximal expiratory flow (MMEF) following both doses of celiprolol were indistinguishable from the effects of placebo, whereas atenolol caused a significant reduction in both measurements of pulmonary function. Graded doses of albuterol, a beta 2-selective sympathomimetic administered at 15-min intervals starting 3 h after each treatment, as expected, caused bronchodilation. The overall bronchodilatory effects of this combined, beta-blocker plus albuterol treatment on pulmonary function were greatest after celiprolol 600 mg, followed in order by celiprolol 400 mg, placebo, and atenolol. Celiprolol 400 mg and 600 mg neither caused bronchoconstriction nor antagonized albuterol in this acute study. Because of its bronchosparing properties, even at high doses, celiprolol may offer an advantage over other, similar agents in the treatment of hypertension and angina in asthmatics.

Effect of orally administered celiprolol in patients with chronic atrial fibrillation.

The heart rate increase induced by dynamic exercise in patients with chronic atrial fibrillation is competitively attenuated by beta-blockade. The influence of oral celiprolol on exercise induced tachycardia was evaluated in 23 patients with chronic stable atrial fibrillation in a dose-titration study. This was succeeded by a placebo-controlled double-blind, crossover multi-center trial. During the dose-titration phase each patient underwent a single-blind three week dose escalation period-taking celiprolol 200 mg once daily for one week, celiprolol 400 mg once daily for the third week. After a one week placebo washout, patients then entered a double-blind crossover phase, consisting of one week each of placebo or celiprolol according to a pre-determined randomization. After one week of placebo washout, each patient was crossed-over. In 21 patients celiprolol reduces exercise-induced increased heart rate by approximately 35% when compared with placebo. These results indicate that celiprolol should be effective in controlling the exercise-induced increase in heart rate in patients with chronic atrial fibrillation. In addition, results of 24 h ambulatory ECG monitoring (Holtor monitoring) indicate that celiprolol reduces the ventricular premature contractions.

Clinical cardiac electrophysiologic study of celiprolol.

The objective of the study was to evaluate the acute effect of intravenous celiprolol on the electrophysiologic properties of the cardiac conduction system in man and to assess potential problems in terms of its causing heart block or sinus bradycardia. Eight patients with controlled coronary artery disease and hypertension but without conduction system disease were studied. All cardiac drugs e.g., digoxin, sympathomimetics and other beta blockers were discontinued prior to entering the study. Surface ECG leads I, AVF, and Vi were applied to each patient, and the ECG was continuously displayed on an oscilloscope. A quadripolar stimulating electrode (7F) was inserted percutaneously and positioned in the high right atrium and a tripolar or bipolar His bundle recording catheter was positioned cross the tricuspid valve. The atrial and His bundle electrograms were recorded on a direct writing recorder. After completion of the baseline electrophysiologic (EP) measurements, in an open fashion, celiprolol (0.1 mg/kg) was administered intravenously at the rate of 1 mg/min into each of the five patients. The complete battery of the EP measurements were repeated immediately following completion of the infusion. Preliminary data in eight patients demonstrated no significant effect of celiprolol on the cardiac conduction system.

Comparison of the acute hemodynamic effects of intravenous celiprolol and propranolol in patients with suspected coronary disease.

The acute hemodynamic effects of intravenously administered celiprolol and propranolol were compared in 18 patients, 12 with coronary obstruction in the presence or absence of reduced LV function and six with no significant cardiac disease. The study was performed using a single blind, randomized design with celiprolol (0.07 and 0.14 mg/kg) and propranolol (0.07 mg/kg) in six patients per treatment group. The hemodynamic parameters obtained via right and left heart catheterization were measured at baseline and at 5 and 10 min after drug infusion (1.0 mg/min). Propranolol produced a significant fall in left ventricular Vmax, left ventricular dP/dt and cardiac output. In contrast, celiprolol either caused no change or significantly increased these parameters. These results indicate that celiprolol has an acute hemodynamic profile which differs significantly from that of propranolol.

Effect of celiprolol, a new beta 1-alpha 2 blocker, on the cardiovascular response to exercise.

The pharmacodynamics of beta blockade with single oral doses of celiprolol 200 and 400 mg, compared with placebo, atenolol 50 and 100 mg, propranolol 80 and 160 mg, metoprolol 100 and 200 mg, and pindolol 5 and 10 mg, were evaluated in an open, incomplete-block study design employing 11 healthy male volunteers. Each subject received five of the 11 possible treatments at weekly intervals. The maximal rate-pressure product (RPP) induced by standardized treadmill exercise was measured 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after each treatment. During the course of the exercise test, heart rate and systolic blood pressure were recorded at one-minute intervals for five minutes. The maximal RPP, heart rate, and the maximum change from baseline were calculated for each exercise period. The data were analyzed using absolute reduction and percentage reduction of these parameters. All of the beta blockers tested produced significant decreases (P less than .05) in the exercise RPP, ranging from 16% reduction for celiprolol 200 mg to 47% reduction for propranolol 160 mg at peak response. Celiprolol 400 mg reduced the RPP by 31% at peak effect and did not differ significantly from the other treatments. Celiprolol 400 mg and atenolol 100 mg were the only agents that significantly reduced the RPP 24 hours posttreatment (20.7% and 21.7%, respectively) compared with placebo. Celiprolol 400 mg was the only agent to significantly reduce exercise heart rate 24 hours posttreatment (26.6 beats, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

The bronchosparing effect of celiprolol, a new beta 1- alpha 2-receptor antagonist on pulmonary function of propranolol-sensitive asthmatics.

Twelve normotensive asthmatics who demonstrated bronchoconstriction after a single oral dose of 80 mg of propranolol received (according to a double-blind, randomized, crossover design) placebo, celiprolol 200 mg, and celiprolol 400 mg at intervals of at least three days. Pulmonary function parameters were measured by whole body plethysmography just before treatment and hourly for three hours. Thereafter, terbutaline (0.5 mg), a beta2 agonist, was administered in aerosol form at 15-minute intervals for a total of five doses. This design permitted a safety assessment of the effect of placebo and celiprolol on resting pulmonary function and the evaluation of any interaction between this beta blocker and terbutaline. Propranolol 80 mg produced a statistically significant decrease in a forced one second expiratory volume and forced vital capacity, and a pronounced rise in airways resistance as compared with either dose of celiprolol or with placebo (P less than .001). The effect of celiprolol was not statistically distinguishable from placebo. Terbutaline caused further net bronchodilation after administration of celiprolol and placebo but, even at supratherapeutic doses, failed to restore pulmonary function parameters to baseline levels after treatment with propranolol. The bronchosparing effect of celiprolol may be due to its unique pharmacologic profile, which includes cardioselectivity, modest beta 2-agonist activity, and alpha 2-receptor blockade.

Pharmacokinetics and clinical pharmacology of indapamide.

Indapamide is a new antihypertensive diuretic agent indicated for the treatment of hypertension and edema. Indapamide shows an alteration in vascular reactivity to calcium and other agonists, suggesting the possibility of a direct vascular effect. The drug is recommended in doses of 2.5 to 5 mg once a day. It is rapidly and completely absorbed from the gastrointestinal tract, resulting in maximal blood levels in approximately 2.3 hours. Coadministration of indapamide with food or antacids does not reduce bioavailability. Linear proportionality of blood concentration with increasing doses is evident following both single and multiple doses. Other pharmacokinetic parameters are not dose related. Indapamide is widely distributed in the body with extensive binding to erythrocytes. Binding to plasma proteins is approximately 76%. Disappearance of indapamide from the blood is biphasic, with a terminal half-life of approximately 16 hours. Renal clearance represents less than 10% of the total systemic clearance of the parent drug, showing the dominant role of hepatic clearance. Studies of 14C-labeled indapamide in humans demonstrate that 70% of the radioactivity is excreted in urine and 23% in feces. Indapamide is extensively metabolized; less than 7% of the dose is excreted in urine as unchanged compound. Studies of patients with renal impairment showed little or no accumulation of indapamide in the blood in comparison to patients with normal renal function. Clinical studies demonstrate that indapamide has diuretic properties. Free water clearance studies indicate a site of action in the cortical diluting segment of the distal tubules. No adverse effect of indapamide on renal function is evident in normal volunteers, hypertensive patients, or geriatric hypertensive patients, as determined by glomerular filtration rate or effective renal plasma flow. Hemodynamic studies of indapamide in patients with mild to moderate hypertension show a significant (p less than 0.05) decrease in mean blood pressure (16%) and total peripheral resistance (15%). No other significant hemodynamic effects are evident. The data suggest that indapamide may produce antihypertensive activity through a dual mechanism of action--diuretic and direct vascular. Additionally, it appears to be safe even for patients with impaired renal function.

Double-blind oral analgesic study of butorphanol in musculoskeletal pain: a comparison with codeine and placebo.

Butorphanol tartrate (4 mg and 8 mg) was compared to codeine phosphate (60 mg) and placebo for oral analgesic activity and side-effects employing a double-blind design in ninety-three out-patients suffering from moderate to very severe musculoskeletal pain. The study duration was 72 hours with medication administered every 4 to 6 hours (four times daily) for a total of twelve doses per patient. The results demonstrate that both the 4 mg and 8 mg doses of butorphanol were significantly better (p less than 0.u5) than placebo. While codeine 60 mg also proved active, it appears to be less efficacious than the high dose of butorphanol. The peak effect appeared to be evident in 1 to 2 hours. Butorphanol may be at least seven times more potent than codeine on a milligram basis. Although no serious side-effects were observed, butorphanol appeared to present a greater incidence of side-effects than codeine and placebo in this study.