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.

In vitro and in vivo synergism between tetracycline and the cardiovascular agent oxyfedrine HCl against common bacterial strains.

The cardiovascular drug oxyfedrine HCl revealed noteworthy in vitro antibacterial action against 501 strains of Gram positive and Gram negative bacteria. It also offered significant protection to mice challenged with a mouse-virulent bacterial strain. Prompted by such results, the present study was carried out to ascertain whether this drug could augment the efficiency of an antibiotic when used in combination with it. For this purpose, ten bacterial strains were selected, which were sensitive to oxyfedrine as well as to six antibiotics, like benzyl penicillin, chloramphenicol, ciprofloxacin, erythromycin, streptomycin and tetracycline. Distinct and statistically significant (p<0.01) synergism was observed between oxyfedrine and tetracycline by disc diffusion tests, compared with their individual effects. The fractional inhibitory concentration (FIC) index of this combination, evaluated by checkerboard analysis, was 0.37, which confirmed synergism between the pair. This synergistic drug duo was further dispensed to infected mice. The results of the mouse-protection tests advocated that the combination was significantly synergistic (p<0.0001), according to Student's 't' test. Hence, the capacity of extended antibiotic therapy in several microbial diseases may be improved with the help of this synergistic drug pair, and the study might throw light on newer directions to contest drug-resistant bacterial infections.

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.

[The subcellular pathophysiology of heart failure due to toxic-allergic myocarditis and the action of refracterin on intracardiac hemodynamics and the functional state of the 3 subcellular cardiomyocyte systems responsible for the act of contraction-relaxation]. / Subkletochnaia patofiziologiia nedostatochnosti serdtsa, obuslovennoi toksiko-allergicheskim miokarditom, i deistvie refrakterina na vnutriserdechnuiu gemodinamiku i funktsional'noe sostoianie trekh subkletochnykh sistem kardiomiotsita otvetstvennykh za akt sokrashchenie--rasslablenie.

It is shown that cardiotropic drug refracterin promotes recovery of cardiac contraction and relaxation, their coordination destroyed in cardiac failure (CF) caused by 10-day toxico-allergic myocarditis (TAM). Pumping capacity of the heart returns to normal after normalization of functional activity of three systems of cardiomyocyte responsible for contraction-relaxation: contractile proteins, energy supply and calcium transport. The key process is refracterin-related reestablishment of normal content and proportion of adenyl nucleotides and creatininephosphate and regulation role of phosphorylation and energy of metabolic processes in the cells and their interaction. Thus, refracterin effectiveness lies in its ability to interfere in intracellular metabolic processes in the myocardium, to reestablish normal homeostasis of the systems responsible for contraction-relaxation function and eventually to remove left ventricular cardiac dysfunction.

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.

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.

Effects of the novel beta-adrenergic partial agonist alifedrine on cardiac performance in dogs with acute ischemic left ventricular failure.

Acute ischemic left ventricular failure was induced in dogs by coronary embolization with plastic microspheres, resulting in reduced cardiac output (CO), increased left ventricular end-diastolic pressure (LVEDP), pulmonary capillary pressure (PCP), and total peripheral resistance (TPR). Intravenous (i.v.) administration of alifedrine, a beta-adrenergic partial agonist (0.3 mg/kg as bolus and 0.3 mg/kg/h as infusion), significantly improved performance of the failing heart. Left ventricular contractility was increased up to 50%, heart rate (HR) up to 28%, and CO up to 30%. LVEDP, PCP, and TPR were markedly decreased. Myocardial oxygen consumption was increased only to a minor degree despite the positive inotropic effect; coronary flow was augmented up to 26%. Thus, alifedrine in this model markedly improved left ventricular function by balanced stimulation of the myocardium and reduction of pre- and afterload.

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.

Myocardial biosynthesis of prostacyclin and the influence of cardiac loading and drugs.

Cardiac tissue from different parts of hearts from guinea pigs and rabbits have the capacity to rapidly synthesize prostacyclin (PGI2). Auricles show a higher PGI2-formation than ventricles. Addition of the endoperoxide PGH2 markedly enhanced the myocardial PGI2-biosynthesis. Furthermore many cardiotonic drugs induced a significant rise, but eicosanoids or cyclooxygenase inhibitors a marked reduction of the cardiac PGI2-formation. Acute pressure overload by graduated aortic stenosis, ischemia by coronary ligation or pacing with high frequency reduced the cardiac contractility. After aortic stenosis the myocardial PGI2-biosynthesis is lowered, but increased after coronary ligation or pacing. Under these conditions indomethacin, PGE1, iloprost, verapamil and trapidil markedly reduced the PGI2-biosynthesis and exert a protective effect in regard to cardiac damage. The results indicate that pathophysiological changes significantly influence the PGI2-biosynthesis of the heart. The drug induced inhibition of the myocardial PGI2-formation parallels a cardioprotective effect of these substances.

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.

[Mechanism of action of oxyfedrine as a partial beta receptor agonist]. / Zum Wirkmechanismus von Oxyfedrin als partieller Betarezeptorenagonist.

To investigate a possible dual action of oxyfedrine on beta-adrenergic receptors, hemodynamics and systolic time intervals were studied in 12 healthy volunteers during intravenous infusion of isoprenaline. The dose was titrated to a mean target heart rate of 113 bpm corresponding to an average dose of 6.16 micrograms/min. After return to baseline hemodynamics, oxyfedrine was administered as an intravenous bolus of 8 mg and the protocol was repeated. Compared to baseline, the percentage changes induced by isoprenaline at doses of 2.73 and 6.16 micrograms/min before and after (in parentheses) oxyfedrine were: heart rate: +33/+83% (+19/+62%); cardiac output: +90/153% (+30/+71%); systolic blood pressure: +16/+20% (+6/+7%); stroke volume: +42/+38% (+10/+6%); peripheral vascular resistance: -50/-63% (-31/-50%); cardiac work: +86/+148% (+19/+54%); pre-ejection period: -40/-56% (-27/-45%); isovolumic contraction time: -56/-79% (-29/-63%); systolic ejection rate: +67/+103% (+27/+52%); tension time index: +32/+50% (+7/+20%). Thus, the dose-dependent hemodynamic effects of isoprenaline were significantly attenuated by oxyfedrine pre-treatment with a shift of the dose-response curve to the right; this was attributed to a beta-antagonistic property of oxyfedrine. The results indicate that, in view of its well-known beta-stimulating effects, oxyfedrine exerts a dual action on adrenergic beta-receptors consistent with partial agonistic activity. Thereby, the different profiles of hemodynamic and metabolic actions of oxyfedrine compared to those of pure beta-agonistic agents can be explained as well as its beneficial therapeutic effects in patients with coronary heart disease.

Oxyfedrine and propranolol. A comparative experimental approach to protect myocardium against isoprenaline-induced myocardial necrosis.

Myocardial necrosis was produced in rats by isoprenaline (ISP) administration (85 mg X kg-1 s.c.) for two consecutive days. Rats sacrificed at 12, 24, 30, 36 and 48 h, respectively, after the last injection of ISP showed a marked increase in serum enzymes, viz. creatine phosphokinase (CPK), lactic dehydrogenase (LDH) and aspartate transaminase (AST) and tissue content of lactate. In addition, there was a significant reduction in the glycogen content of myocardium and the activity of enzyme phosphofructokinase (PFK) was changed in biphasic fashion, i.e. initial enhancement of activity was followed by a persistent fall. All these changes were present along with typical infarct-like necrosis as seen microscopically. Both oxyfedrine (OXF, 2, 4 and 8 mg X kg-1 i.m.) and propranolol (PROP, 1, 2 and 4 mg X kg-1 i.m.) administered for 5 days before and two days during ISP administration were effective in providing protection. However, with 8 mg X kg-1 dose of PROP sporadic high mortality was observed. Serum AST and CPK levels in OXF (4 and 8 mg X kg-1) and PROP (2 and 4 mg X kg-1) pretreated animals returned back to the range of controls. Unlike OXF, the LDH level in PROP pretreated rats, though reduced significantly, remained always higher than the control values. The beneficial effect of OXF on myocardial glycolytic flux was dose-dependent. 8 mg X kg-1 of OXF increased (31%) the glycogen content significantly (p less than 0.01) and the activity of enzyme PFK and tissue lactate content were brought back to normal. PROP did not exhibit dose-dependent reduction in the lactate content of the myocardium and it was never restored back to the range of control values.(ABSTRACT TRUNCATED AT 250 WORDS)

[The importance of increased prostaglandins and prostacyclin for the effect of oxyfedrin in isolated guinea pig heart preparations]. / Zur Bedeutung einer vermehrten Freisetzung von Prostaglandinen und Prostazyklin für die Wirksamkeit von Oxyfedrin an isolierten Herzpräparaten des Meerschweinchens.

In isolated perfused heart preparations of guinea pigs coronary dilating and positive inotropic doses of oxyfedrine induce a significant increase of the release of prostaglandin-like substances (PLS) and prostacyclin (PGI2). Indometacin as an inhibitor of prostaglandin biosynthesis (140 mumol/l) enhances after a 10 min lasting perfusion contraction force and coronary flow of the hearts but inhibits PGI2-formation. Under these conditions oxyfedrine loses its positive influence on inotropism, coronary flow and PGI2-efflux. Indometacin (140 mumol/l) also completely abolishes the increase of cardiac performance of isolated auricle preparations by oxyfedrine (50 mumol/l). These findings agree with former results and indicate an involvement of the PLS- and PGI2-biosynthesis in the antianginal efficacy of oxyfedrine.

[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.