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At least 865 records · Page 48Linked to original sources
PubMed1990

Prevention of myocardial reperfusion injury in experimental coronary revascularization following ischemic arrest by a novel antiinflammatory drug, ONO-3144.

The cardioprotective effects of a novel antiinflammatory drug, ONO-3144 (ONO), on ischemic-reperfused myocardium were investigated using an in situ pig heart model. Heart was subjected to 2 h of regional ischemia, with the final 1 h having superimposed global cardioplegic arrest followed by 1 h of reperfusion. ONO (20 microM) was administered after the arrest at the onset of reperfusion. Left ventricular developed pressure (LVDP), maximum rate of rise of left ventricular pressure (LV dp/dt), and left ventricular end-diastolic pressure (LVEDP) were measured under isovolumic conditions to assess cardiac contractility and compliance. ONO improved LVDP and LV dp/dt, and reduced LVEDP after 60 min of reperfusion compared to control. This drug also improved segment shortening and end-diastolic length significantly after 15 and 60 min of reperfusion. Slight improvements in oxygen consumption and creatine kinase (CK) release were also noted. In addition, ONO reduced lipid peroxidation and thromboxane formation but enhanced the production of prostaglandins. In vitro studied demonstrated ONO to be effective scavengers for both hydroxyl (OH.) and hypohalite (OCL.) radicals. The results suggest that myocardial reperfusion injury that developed after ischemic arrest was reduced significantly by ONO. This drug inhibited such injury, probably by directly scavenging potentially harmful radicals such as OH. and OCI., which are generated in ischemic-reperfused myocardium.

Animals↗
PubMed1991

AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels.

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.

Animals↗
PubMed1991

Cardiovascular and renal actions of AHR-16303B, an antagonist of 5-HT2 receptors and calcium channels, in hypertensive and normotensive rats.

The cardiovascular and renal responses to AHR-16303B, a novel antagonist of 5-hydroxytryptamine (5-HT2) receptors and calcium channels, were examined in spontaneously hypertensive (SHR) and normotensive rats (NTR) and compared with verapamil and ritanserin. In SHR, AHR-16303B (10-300 mg/kg orally, p.o.) produced dose-related reductions in mean arterial blood pressure (MABP), accompanied by modest isokaliuretic diuresis and unchanged heart rate (HR). In NTR, 10-30 mg/kg p.o. AHR-16303B had no effect on MABP or renal excretory function; 100 and 300 mg/kg reduced MABP but had only transient effects on HR; 100 mg/kg produced antidiuresis in NTR. Both strains of rats tolerated doses of AHR-16303B as high as 300 mg/kg. In both SHR and NTR, verapamil (10-100 mg/kg p.o.) produced dose-related reductions in MABP, antinatriuresis at 60 and 100 mg/kg, and variable effects on HR. Oral ritanserin had no effect on MABP of SHR or NTR at 3 or 10 mg/kg. AHR-16303B is unique in that it simultaneously antagonizes 5-HT2 receptors and produces safe and effective reduction of elevated BP without altering HR or triggering renal compensatory antidiuresis. At effective 5-HT2/calcium antagonistic doses, AHR-16303B has no effect on cardiorenal homeostasis in normotensive animals.

Administration, Oral↗
PubMed1994

Electrophysiologic effects of alprafenone on canine cardiac tissue.

We studied the actions of the propafenone derivative alprafenone on transmembrane action potentials (APs) of canine Purkinje fibers (PF) and ventricular and atrial muscle. In PF with normal maximum diastolic potentials (MDPs), alprafenone (5 x 10(-8)-1 x 10(-6) M) produced concentration-dependent decreases in AP amplitude (APA), Vmax, AP duration (APD), and conduction velocity. The effects on Vmax were use dependent. The decrease in PF APD was the result of the drug's action on the slope of phase 2. In contrast to its effect on PF, alprafenone induced a significant increase in APD in ventricular epicardial and endocardial muscle and had no effect on atrial APD. In PF, alprafenone prolonged the effective refractory period (ERP) with respect to APD, and at high [K+]0, prolonged refractoriness beyond repolarization. Alprafenone decreased Vmax and slow-response APA. It had no effect on normal automaticity or isoproterenol (ISO)-induced automaticity, but significantly suppressed BaCl2-induced abnormal automaticity at low levels of membrane potential. Alprafenone inhibited both early and delayed afterdepolarizations and eliminated triggered activity. We conclude that alprafenone's range of actions is consistent with that of other effective antiarrhythmic drugs and is very similar to that of propafenone.

Animals↗
PubMed1985

Stability of bupropion and its major metabolites in human plasma.

Bupropion (BUP) is a new, monocyclic, second-generation antidepressant with efficacy comparable with that of the tricyclics but possessing a more favorable side-effect profile. Therapeutic drug monitoring services are expected to be widely available following the marketing of BUP, yet relatively little has been published on its clinical pharmacokinetics. The purpose of this study was to assess the drug's plasma stability and to determine the best storage conditions for conducting pharmacokinetic studies of BUP and its major metabolites. Human plasma was spiked with known concentrations of BUP and its major basic metabolites, threo-amino alcohol (TB), erythro-amino alcohol (EB), and hydroxy metabolite (HB), and incubated under varying conditions of temperature and pH. BUP showed a log linear degradation that was both temperature and pH dependent. BUP half-life in pH 7.4 plasma stored at 22 and 37 degrees C was 54.2 and 11.4 h, respectively. Incubation at 37 degrees C, pH 2.5 to 10, for 48 h had minimal effect on metabolite concentrations. These results indicate that drug degradation must be considered in studies involving the incubation of plasma for protein binding determinations and the collection and storage of plasma samples for drug concentration analysis during therapeutic drug monitoring.

Antidepressive Agents↗
PubMed1984

Comparative investigation of the antiarrhythmic effect of propafenone (Rytmonorm) and lidocaine in patients with ventricular arrhythmias during acute myocardial infarction.

Propafenone, a new class I antiarrhythmic drug, given as a bolus injection followed by oral medication, or lidocaine were given to 20 consecutive patients admitted with chest pain suggesting acute myocardial infarction and showing high grades, i.e. multiform, pairs or R-on-T premature ventricular complexes or short runs of ventricular tachycardia. Before institution of therapy the mean number (+/- 1 SD) of premature ventricular contractions (PVCs) per hour was 169 +/- 123 in the lidocaine group and 324 +/- 440 in the propafenone group. During the next 24 hours lidocaine reduced the numbers of PVCs by 73% and propafenone by 75%. The mean number (+/- 1 SD) of 5-minute periods with high grade PVCs was 4.3 +/- 2.9 in the lidocaine group and 5.8 +/- 4.5 in the propafenone group. During therapy this number was equally reduced in both groups to 2.4. One patient in the lidocaine group developed ventricular fibrillation and three patients in the propafenone group were excluded because of increasing numbers of PVCs. One patient in the propafenone group showed a torsade-de-pointes ventricular tachycardia.

Aged↗
PubMed2001

Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-alpha or interleukin-6.

TK5048 and its derivatives, AM-132, AM-138, and AM-97, are recently developed antimitotic (AM) compounds. These 1-phenylpropenone derivatives induce cell cycle arrest at the G2 / M phase of the cell cycle. TK5048 inhibited tubulin polymerization in human lung cancer PC-14 cells in a concentration-dependent manner. In a polymerization assay using bovine brain tubulin, AM-132 and AM-138 were quite strong, AM-97 was moderately strong, and TK5048 was a relatively weak inhibitor of tubulin polymerization. A murine leukemia cell line resistant to a sulfonamide antimitotic agent, E7010, which binds to colchicine-binding sites on tubulin, was cross-resistant to the in vitro growth-inhibitory effect of AM compounds. Inhibition of tubulin polymerization is therefore one of the mechanisms of action of these AM compounds against tumor cells. To profile the antitumor effect of AM compounds, the in vivo antitumor effect of AM-132 was evaluated against cytokine-secreting Lewis lung carcinoma (LLC). Tumor-bearing mice were treated with intravenous AM-132 using three different treatment schedules. LLC tumors expressing tumor necrosis factor-alpha (TNF-alpha), granulocyte macrophage colony-stimulating factor (GM-CSF), or interleukin (IL)-6 were very sensitive to AM-132. In particular, LLC tumors expressing IL-6 were markedly reduced by AM-132 treatment, and showed coloring of the tumor surface and unusual hemorrhagic necrosis. These results suggest a combined effect of AM-132 and cytokines on the blood supply to tumors.

Animals↗
PubMed1980

A controlled comparison of oxyfedrine, isosorbide dinitrate and placebo in the treatment of patients suffering attacks of angina pectoris.

1 In a group of 23 patients with documented ischaemic heart disease who experienced angina pectoris, oral oxyfedrine (24 mg three times daily) was compared with isosorbide dinitrate (10 mg three times daily) and placebo in a double-blind double-crossover clinical trial. 2 Isosorbide dinitrate appeared no better than placebo, either in terms of symptomatic relief or ECG responses to exercise. Thirty eight per cent of patients complained of headaches and 28% had to cease taking the drug for this reason. 3 Oxyfedrine produced statistically significant improvements in both symptom level (P < 0.01) and ECG ST-segment responses to exercise (P < 0.01). The only side effect noted was a reversible loss of taste sensation by one patient. 4 Neither drug produced any adverse changes in any haematological or biochemical parameters. 5 Oxyfedrine is, therefore, to be preferred to isosorbide dinitrate, being both much better tolerated and more efficacious.

Adult↗
PubMed1980

Oxyfederine and propranolol--a controlled trial in angina pectoris.

1 A double-blind-crossover randomised trial was performed to compare the effects of oxyfedrine (maximum dose 32 mg three times daily), propranolol (maximum dose 120 mg three times daily) and placebo in 30 patients with chronic stable angina pectoris. Assessment was by means of symptom level, ECG responses to graded exercise and haematological and biochemical investigation. 2 Oxyfedrine and propranolol resulted in similar significant improvements in symptom level (P < 0.05 in both cases), and ST index (propranolol P < 0.02; oxyfedrine P < 0.05). Neither drug produced any significant changes in haematologaical or biochemical investigations and only infrequent minor side effects were noted. 3 These results indicate that oxyfedrine is a safe and well-tolerated drug with an efficacy comparable with that of propranolol in the treatment of patients with angina pectoris.

Adult↗
PubMed1983

Effects of bupropion, nomifensine and dexamphetamine on performance, subjective feelings, autonomic variables and electroencephalogram in healthy volunteers.

Bupropion, a novel antidepressant, has been compared with nomifensine and dexamphetamine in a controlled double blind trial in 12 healthy volunteers. Signals detected in an auditory vigilance test were increased by dexamphetamine 5 and 10 mg when compared with lactose dummy, but unaffected by bupropion 100 and 200 mg and nomifensine 100 mg. Auditory reaction time was decreased by dexamphetamine but unaffected by bupropion and nomifensine. Heart rate was increased after all active treatments but the largest rise followed dexamphetamine 10 mg which differed from both lactose dummy and all other active treatments. Systolic blood pressure was higher after dexamphetamine 10 mg than all other treatments, none of which differed from lactose. No changes occurred in diastolic blood pressure. Pupil size increased after dexamphetamine 10 mg but no changes followed other treatments. Visual analogue scales showed that subjects were more alert, attentive, proficient, excited, interested and elated after dexamphetamine but no changes followed bupropion or nomifensine. Subjects were able to recognise that they had received an active drug only after dexamphetamine 10 mg. Increased activity was seen in the 7.5-13.5 Hz and 13.5-26 Hz frequency bands of the electroencephalogram after dexamphetamine 10 mg but not after bupropion or nomifensine. These findings in man suggest that neither of these two, non-sedative antidepressants possess amphetamine-like stimulant activity, and are discussed in relation to the animal pharmacology of the drugs.

Adult↗