Vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy.

The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis, an iron-dependent form of cell death triggered by the aberrant accumulation of lipid peroxides. Inhibitors of the cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, are thus potential anticancer agents. However, the efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy might thus provide the basis for effective cancer treatment. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). Oxyfedrine contains a structural motif required for covalent inhibition of aldehyde dehydrogenase (ALDH) enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion.

Effects of oxyfedrin: a beta-adrenoreceptor stimulant, on infarct size following acute coronary artery ligation.

Regional left ventricular blood flow and the extent of myocardial ischaemia were studied after acute coronary artery occlusion in open-chest dogs before and after infusion of oxyfedrin, a beta-adrenergic stimulant. Regional blood flow was measured with radioactive tracer microspheres and local tissue injury was estimated by the S-T segment elevation in epicardial electrocardiograms. Animals receiving oxyfedrin were divided into two groups: 1 and 2. Oxyfedrin was infused intravenously in a dose of 0.80 to 0.94 mg.kg-1 in dogs of group 1 and 1.45 to 1.60 mg.kg-1 in dogs of group 2. The rate of infusion in the animals of both groups was 0.61 mg.min-1. Oxyfedrin caused further S-T segment elevation over ischaemic myocardium and increased the extent of ischaemic injury in group 1 dogs. Conversely, in this same group of dogs, the blood flow was unchanged in low flow regions ( less than 0.3 cm3.g-1.min-1) and increased in higher flow areas, inside the ischaemic region. In the animals of group 2, oxyfedrin caused further S-T segment elevation over ischaemic myocardium and increased the extent of ischaemic injury. Concomitantly, blood flow was significantly reduced both inside and outside the ischaemic region. These observations in dogs of group 1 (ie increased blood flow inside the ischaemic region by infusion of oxyfedrin, in flow zones higher than 0.3 cm3.g-1.min-1, with a further S-T segment elevation over ischaemic myocardium, and an increase in the extent of ischaemic injury) may be explained by a primary effect of oxyfedrin on oxygen demands with secondary changes in blood flow.

Clinical pharmacokinetics of vasodilators. Part II.

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Beta-adrenoceptor sensitivity of brown and white adipocytes after chronic pretreatment of rats with reserpine.

The effect of pretreatment with reserpine (1.0 mg/kg i.p. daily for 7 days) on beta-adrenoceptor-mediated responses has been measured in epididymal white and interscapular brown adipocytes, left atria and vas deferens of rats in order to investigate the classification of the receptors and whether they are innervated. Lipolysis was measured in adipocytes, and from the same rats, the beta 1-adrenoceptor-mediated positive inotropic responses of isolated paced left atria and beta 2-adrenoceptor-mediated inhibition of field stimulation-induced contraction of the vas deferens were examined. The agonists used were isoprenaline, oxyfedrine (atria only) and (except in brown adipocytes) ritodrine, which was a partial agonist in white adipocytes, atria and vas deferens. Atria and brown adipocytes exhibited beta-adrenoceptor supersensitivity after reserpine pretreatment, whereas vas deferens and white adipocytes did not. Reserpine-induced reductions in food intake and body weight did not appear to influence beta-adrenoceptor-mediated lipolysis, since restriction of the diet equivalent to that of reserpine-treated rats produced no change in white adipocyte sensitivity. Responses mediated via beta 1-, but not beta 2-adrenoceptors, display supersensitivity after chronic depletion of neuronal catecholamines with reserpine and this is evidence for innervation of this receptor subtype. Thus, atrial beta 1-adrenoceptors are assumed to be innervated, whereas vas deferens beta 2-adrenoceptors are not. The present results are consistent with histochemical evidence that brown, but not white, adipocyte beta-adrenoceptors are innervated. However, they are not compatible with conventional receptor classification studies, which suggest that rat brown and white beta-adrenoceptors are similar--either both beta 1 or both atypical.

Alifedrine, a positive inotropic agent that moderately reduces the severity of ischaemia and reperfusion-induced ventricular arrhythmias.

The effects of alifedrine, a positive inotropic agent, were examined in greyhounds anaesthetised with chloralose. An intravenous dose of 0.3 mg kg-1 resulted in a substantial increase in myocardial contractility (increased dP/dtmax, cardiac output and stroke volume) without significantly affecting heart rate. The effects of alifedrine on the severity of arrhythmias resulting from both coronary artery occlusion and reperfusion were also determined. A mild antiarrhythmic effect was observed during early ischaemia when the incidence of ventricular tachycardia was reduced from 90% in controls to 50% in treated dogs. There was also a significant reduction in the number of extrasystoles appearing as ventricular tachycardia (from 511 +/- 138 to 151 +/- 84). The total number of extrasystoles during the first 30 min of ischaemia was also reduced, although not significantly, from 846 +/- 193 to 527 +/- 86. Following release of a 40 min coronary artery occlusion there was a marked reduction in reperfusion-induced ventricular fibrillation from 75% in controls, to 37% in the alifedrine-treated dogs. The overall survival from the combined occlusion-reperfusion insult was increased from 20% in controls to 50%. These results suggest that alifedrine has an unusual and useful spectrum of pharmacological activity in that it combines antiarrhythmic activity with an ability to improve cardiac function.

Haemodynamic effects of intravenous and oral alifedrine in patients with cardiac failure.

A randomized, double-blind, double-crossover, placebo-controlled haemodynamic study was undertaken in patients with Grade II/III (NYHA) cardiac failure to examine the acute effects of intravenous alifedrine, 20 mg and 40 mg (17 patients), and oral 40 mg alifedrine (8 of these patients). Patients received single doses of alifedrine and placebo on separate days, with invasive monitoring. Alifedrine resulted in a significant (p less than 0.001), dose-dependent increase in cardiac output. The peak effect (+23% with 20 mg i.v., +42% with 40 mg i.v. and +29% with 40 mg orally) was seen approximately 1 hour after intravenous administration (with about half of these increases still apparent at 3 hours) but developed progressively over 3 hours after oral administration. There were significant reductions (p less than 0.001) in peripheral resistance (peak mean changes -21% with 20 mg i.v., -31% with 40 mg i.v. and -23% with 40 mg orally), but little (less than +/- 6%) observed change in arterial pressure. With intravenous alifedrine, there were significant increases in stroke volume (+19% with 20 mg, +35% with 40 mg, p less than 0.001) with little (5%) change in heart rate (+3% and +7%, respectively, N.S.). With the 40 mg oral dose, there was a small increase in heart rate (+12%, p less than 0.005) associated with a 19% (N.S.) increase in stroke volume. Peak haemodynamic responses to 40 mg alifedrine orally were 50% to 75% of those seen after administration of the same dose intravenously. When assessed 3 hours after administration, responses to the two routes of administration were similar. There were no clinically or statistically significant changes in arterial (non-invasive), pulmonary artery, pulmonary capillary or right atrial pressures with any dose of alifedrine. No significant arrhythmias were noted clinically with the doses studied. Alifedrine, therefore, is an interesting agent, available both orally and intravenously, which is well tolerated and appears to produce marked acute increases in cardiac output with little change in heart rate or blood pressure. Further studies should determine whether these effects are maintained during longer-term therapy and clarify the relative contributions of positive inotropic and peripheral vasodilator activity to the effects observed.

Echocardiographic evaluation of acute administration of oxyfedrine in patients with coronary artery disease.

In order to assess the effects of oxyfedrine in ischaemic heart disease, echocardiographic evaluation of left ventricular function was performed 2,5,10,15 and 20 minutes after the intravenous administration of 12 mg oxyfedrine in 15 patients with coronary artery disease without angiographic abnormalities of left ventricular wall motion. The following parameters were measured: heart rate, mean arterial blood pressure, internal dimension in diastole (LVIDd) and in systole (LVIDs) of the left ventricule and the percentage shortening of the LVID (%LVID). There was a significant increase in %LVID (peak 10 minutes after drug administration; p less than 0.001) indicating improved left ventricular function, associated with slight changes in pre-load (LVIDd) and in heart rate, and no variation in mean blood pressure. No abnormalities of contraction were observed after the administration of oxyfedrine. These results suggest that oxyfedrine exerts a direct positive inotropic effect of the myocardium in patients with significant coronary artery stenoses.

Derivative and graphical procedures for correction of irrelevant UV spectrophotometric absorption in changeable matrixes.

The application of direct zero-order UV spectrophotometric and graphical or derivative background correction methods to selected pharmaceutical preparations shows their relative advantages in different situations. The assay of the active components in a changeable matrix is a problem with formulations having a limited shelflife. Although the standard three-point correction procedures can provide accurate data, there are practical problems if the irrelevant absorption band is such that only the derivative approach gives enough resolving power for reliable qualitative and quantitative determinations.

[Experimental myocardial infarct in computerized tomography]. / Der experimentelle Myokardinfarkt im Computertomogramm.

The findings on computer tomography after ligation of the coronary artery of a dogs heart are described. The ischaemic area can be differentiated from normal myocardium by its hypo-dense appearance. The localisation and size of the ischaemic area correlates with the scintigraphic findings. The known morphological and functional changes after intravenous oxyfedrin (positively inotropic, increased myocardial blood-flow) can also be seen on the computer tomogram (after oxyfedrin: myocardial thickening, reduction in cross-sectional area of the left ventricle, improved contraction, increased density of the ischaemic area). This confirms the possible diagnostic role of CT in the elucidation of changes in the left ventricle in the course of coronary disease.

Antimicrobial potentiality of a new non-antibiotic: the cardiovascular drug oxyfedrine hydrochloride.

Ten cardiovascular drugs, having diverse pharmacological action, were screened for possible antimicrobial property against known eight sensitive bacteria, belonging to Gram positive and Gram negative types. Although five drugs failed to show antimicrobial activity and three had moderate antimicrobial action, oxyfedrine HCl and dobutamine were seen to possess pronounced antimicrobial property. Oxyfedrine was further tested in vitro against 471 strains of bacteria from two Gram positive and fourteen Gram negative genera. The minimum inhibitory concentration (MIC) of oxyfedrine was determined by agar dilution method, which ranged from 50-200 microg/ml in most of the strains, while some strains were inhibited at even lower concentrations. In animal experiments, this compound was capable of offering significant protection to Swiss strain of white mice, challenged with 50 median lethal dose (MLD) of a virulent strain of Salmonella typhimurium at concentrations of 15, 30 and 60 microg/mouse. The in vivo results were highly significant according to chi-square test.

Relative bioavailability of DL-oxyfedrine HCl after single-dose oral administration of tablets as compared to equimolar solutions.

The pharmacokinetics and comparative bioavailability of oxyfedrine after single-dose oral administration of oxyfedrine*HCl tablets in comparison to an equimolar aqueous solution of oxyfedrine*HCl were investigated in 12 healthy male subjects. Six of them received 96 mg DL-oxyfedrine*HCl as tablets and solution and the remaining 6 subjects received 16 mg DL-oxyfedrine*HCl as tablets and solution in a randomized cross-over design. For evaluation of the relative bioavailability of the tablet formulation, the main metabolite norephedrine (expressed as hydrochloride) was analyzed in plasma for all 12 subjects. Furthermore, for determination of the parent drug, samples of whole blood were analyzed for DL-oxyfedrine*HCl. Relevant concentrations of the parent drug were found only in the high dosage group. There was no evidence of dose-linearity referring to AUC and Cmax of norephedrine between 16-mg and 96-mg doses of DL-oxyfedrine*HCl. The relative bioavailability of the tablet formulation after administration of 16 mg DL-oxyfedrine*HCl, based on the metabolite norephedrine*HCl was for AUC: 85.37% within a 90% confidence interval of 69.29-105.17% and for Cmax: 78.79% within a 90% confidence interval of 59.19-104.90%. The figures for the 96 mg dose strength were: AUC: 107.85% (90.06-129.15%) and for Cmax: 74.74% (62.48-89.42%).

Effects of thiofedrine on platelet aggregation, thromboxane B2 and 6-keto-PGF1 alpha in rats.

Thiofedrine inhibited rat platelet aggregation and intraplatelet thromboxane B2 (TxB2) generation induced by arachidonic acid. The IC50 values were 0.18 and 0.21 mmol/l, respectively. Thiofedrine, 1.25-5.00 mg/kg i.v., showed a significant inhibition of rat platelet aggregation and intraplatelet TxB2 generation induced by arachidonic acid, with ID50 values of 2.4 and 3.3 mg/kg. Thiofedrine, 0.5-2.0 mg/kg i.v., reduced TxB2 generation but increased 6-keto-PGF1 alpha formation in rat plasma.

Influence of thiofedrine on platelet aggregation, intraplatelet cyclic cAMP and malondialdehyde in rats.

Platelet aggregation and cyclic adenosine monophosphate (cAMP) production were studied by turbidimetry and competitive protein binding assay, respectively, in rats. Thiofedrine (Thi) significantly inhibited adenosine diphosphate (ADP)-induced and thrombin-induced platelet aggregation in vitro, with IC50 values of 0.56 and 0.16 mmol/l, respectively. In vivo, Thi 1.25-5.0 mg/kg i.v. significantly inhibited ADP-induced platelet aggregation at rate of 17.1-40.3%. Thi caused a dose-dependent increase in cAMP levels in rat washed platelets. Malondialdehyde (MDA) levels in rat platelets were measured by colorimetry. Thi had an inhibitory effect on thrombin-induced platelet MDA production. The results suggest that the antiaggregatory action of Thi may be related to metabolism of arachidonic acid (AA) and elevation of cAMP levels.

Evaluation of the clinical electrophysiological effects of antianginal drugs without specific antiarrhythmic properties.

The authors have studied the electrophysiological effects of four antianginal drugs: oxyfedrine, nifedipine, dipyridamole and carbochromene. These drugs demonstrated different and sometimes contrasting effects on sinus node function, atrial refractoriness and atrioventricular conduction. These effects may constitute an indication or a contraindication in different clinical pictures and should be considered in the choice of treatment of patients with coronary artery disease.

[The effects of oxyfedrine on the hemodynamics of patients with acute myocardial infarction]. / Effetti dell'ossifedrina sull'emodinamica in pazienti con infarto miocardico acuto.

In 16 patients with acute transmural myocardial infarction the effect of 8 mg of intravenous oxyfedrine followed by an infusion of 0.3 mg/kg body weight per hour on haemodynamics of the pulmonary and systemic circulation and dynamic cardiac indices was investigated. Cardiac rate, systemic arterial blood pressure, minute volume, cardiac output, and tension-time index remained unchanged on the whole. On the other hand oxyfedrine produced a persistant significant decrease of the mean and diastolic pulmonary artery pressure, pulmonary capillary pressure, and of the contraction and pressure-increase time. These effects were also demonstrable in patients previously treated with digitalis. No cardiac arrhythmias were observed. The positive inotropic effect of oxyfedrine is suggested as reason for these changes.

Effect of intravenous oxyfedrine on exercise in patients with ischaemic heart disease.

In a double blind crossover trial, acute effects of 8 mg intravenous oxyfedrine were compared with those of placebo in 18 patients with stable effort angina assessed by treadmill exercise testing. In the resting state, oxyfedrine caused an increase in heart rate (84 +/- 23 to 103 +/- 19 bpm, p less than 0.01), systolic blood pressure (123 +/- 16 to 133 +/- 20 mmHg, p less than 0.01) and double product (11 x 10(3) +/- 2 x 10(3) to 13.7 x 10(3) +/- 3.1 x 10(3), p less than 0.01) as compared to placebo. However, these parameters were not significantly different at the end of first or second stage of the treadmill test (p = NS). Time to one mm ST segment depression was increased with oxyfedrine as compared to placebo (1.5 +/- 1.5 to 1.9 +/- 1.5 minutes, p less than 0.05). Oxyfedrine did not increase the total duration of exercise (4.1 +/- 1.0 to 4.7 +/- 2.2 minutes, p = NS) or time to ischaemic symptoms (2.7 +/- 1.3 to 2.9 +/- 1.9 minutes, p = NS). The total work done was significantly more on oxyfedrine 312 +/- 189 joules/kg to 370 +/- 209 joules/kg, p less than 0.01) as also the double product achieved (20.6 x 10(3) +/- 6.1 x 10(3) to 22.5 x 10(3) +/- 6.4 x 10(3), p less than 0.01). It is concluded that intravenous oxyfedrine improves exercise capacity in patients with stable effort angina presumably by reducing myocardial ischaemia.

[Pharmacology of 1-phenylaminoethylamino-3-(phenoxy)propanol derivatives with beta-adrenergic action]. / Zur Pharmakologie von 1-Phenylaminoethylamino-3-(phenoxy)propanolderivaten mit beta-adrenerger Wirkung.

In the framework of a screening test of new phenoxyalkanolamines the authors tested derivatives with the basic structure Ph1--NHCH2CH2NHCH2CH(OH)CH2--OPh2 for beta-adrenergic blocking activity and sympathicomimetic action on the spontaneously beating atrial preparation from the guinea-pig and on the circulation of the cat. Derivatives with the substituents 2,5-dimethyl, 2-nitro, 3-nitro, 2,6-dimethyl and 2-chloro at Ph1 produced in the atrial preparation a some 3- to 10fold stronger beta 1-adrenergic blockade than propranolol. In in vivo experiments on the cat, all of these compounds had a potent sympathicomimetic effect on the heart, so that they may be classified as specific beta-adrenergic antagonists. The addition of 4-nitro, 3-methyl and 4-ureido at Ph2 reduces the beta-adrenergic blockade and suppresses the sympathicomimetic action. 1-(3',4'-Dimethoxyphenylethylamino)-2-hydroxy-3-phenoxypropane and its derivates showed a similar behaviour as described by Hoefle [8]. 1-[beta-(3-Nitrophenylamino)ethylamino]-2-hydroxy-3-phenoxypropane hydrochloride exhibited a particularly strong and long-lasting sympathicomimetic effect. Studies on the dog revealed a specific beta 1-mimetic action; in the effective dose range of 10-30 micrograms/kg i.v., a positive inotropic effect prevailed, and the effect on heart rate was but small. No beta-adrenergic blockade or mimetic action on the peripheral vascular system was observed.

Oxyfedrine in myocardial stunning.

Effect of oxyfedrine (OXF)(1 mg/kg) administered just before reperfusion (post-treatment) was investigated in a canine model of myocardial stunning. In the saline-treated animals, myocardial stunning was evidenced by fall in MAP, decrease in LV peak (+) dP/dt, rise in LVEDP and incomplete regeneration of myocardial ATP, after reperfusion. OXF was found to be effective in preventing the haemodynamic and metabolic changes associated with myocardial stunning.

[Enhanced cytotoxic effect of Adriamycin and vincristine against PC-6 (human lung cancer cell line) and Hattori (human breast cancer cell line)].

Enhancements of cytotoxic effects of adriamycin (ADM) and vincristine (VCR) on PC-6 (lung cancer cell line) and Hattori (breast cancer cell line) were investigated by concomitant use of a calmodulin inhibitor: nicardipine, antiplatelet agents: oxyfedrine and trimethazidine and an antihypertensive agent: trichlormethiazide. Nicardipine increased the cytotoxic activity of both drugs but other agents did not produce any significant increase. Nicardipine increased the cytocidal effect of VCR on PC-6 about 2-fold and on Hattori about 3-fold. Furthermore, it also increased the effect of ADM on Hattori about 2-fold. Thus, nicardipine enhanced the cytocidal activity of VCR more remarkably than that of ADM.

[Suppressor activity changes in human T-lymphocytes as affected by adreno- and cholinotropic substances]. / Izmenenie supressornoi aktivnosti T-limfotsitov cheloveka pod vliianiem adrenokholinotropnykh veshchestv.

The influence of oxyfedrine (beta-adrenoagonist) and carbocholine (cholinoagonist) on the functional activity of Con A-induced suppressor T-lymphocytes in healthy persons and in bronchial asthma patients was studied. Oxyfedrine at a concentration of 10 micrograms/ml (10(-5) M) was shown to induce a significant increase in the suppressing activity of both normal lymphocytes and those obtained from bronchial asthma patients. The repeated incubation of lymphocytes with carbocholine at a concentration of 5 micrograms/ml (10(-6) M) led to the removal of the suppressing effect of normal lymphocytes and to the increase of the activating effect of lymphocytes from bronchiae asthma patients.