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.

Physiological changes induced by chromium stress in plants: an overview.

This article presents an overview of the mechanism of chromium (Cr) stress in plants. Toxic effects of Cr on plant growth and development depend primarily on its valence state. Cr(VI) is highly toxic and mobile whereas Cr(III) is less toxic. Cr-induced oxidative stress involves induction of lipid peroxidation in plants that cause severe damage to cell membranes which includes degradation of photosynthetic pigments causing deterioration in growth. The potential of plants with the adequacy to accumulate or to stabilize Cr compounds for bioremediation of Cr contamination has gained engrossment in recent years.

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.

Efficiency of refracterin in patients with chronic cardiac insufficiency caused by coronary heart disease.

Composite preparation refracterin administered in a dose of 300 mg/day for 3 days in addition to routine therapy significantly improved the results of treatment of severe cardiac insufficiency of ischemic genesis compared to placebo. Improvement of clinical status of patients is determined by positive dynamics of systolic and diastolic functions of the left ventricle.

Efficiency and mechanisms of the antioxidant effect of standard therapy and refracterin in the treatment of chronic heart failure in elderly patients with postinfarction cardiosclerosis.

Refracterin therapy of patients with chronic heart failure caused by coronary heart disease and postinfarction cardiosclerosis markedly promoted improvement in the pulmonary and systemic circulation in comparison with patients receiving traditional therapy. The mean functional class of chronic cardiac failure decreased by 43% under the effect of refracterin vs. 27% decrease in the group receiving traditional therapy. After 1-month refracterin course the end-systolic and end-diastolic sizes of the left ventricle decreased by 12 and 7%, respectively, ejection fraction increased by 7.2% in comparison with the initial level, total oxidant activity and MDA content in the plasma decreased significantly, while total antioxidant activity, catalase and SOD activities, cytochrome C, NADH, and NADPH levels increased. The prooxidant-antioxidant system was shifted towards antioxidants, which attests to activation of the defense and adaptive mechanisms after administration of refracterin, which is especially important in elderly patients with initially decreased reserve potentialities of the antioxidant defense system.

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.

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.

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.

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.

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%).

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.

[Effects of oxyfedrine on high blood viscosity and myocardial necrosis induced by epinephrine and ice water stress in rats].

Acute high blood viscosity (HBV) and myocardial necrosis was established by epinephrine (Epi) and ice water stress in rats. Effects of iv oxyfedrine (Oxy) on HBV, plasma viscosity (PV), hematocrit, erythrocyte electrophoretic time (EET), and fibrinogenic viscosity (FV) were studied in model. Results showed that Oxy 1 mg.kg-1 iv markedly decreased the arterial and venous blood HBV at shear rates of 700 s-1 and 70 s-1, respectively (P < 0.01). There were significant differences in the alleviation of HBV among 3 groups (Oxy 0.01, 0.1, and 1 mg.kg-1 iv). The above doses markedly decreased the HBV, PV, and FV, and shortened the EET. Effects of iv Oxy on the myocardial necrosis rat model were scrutinized under the light and electron microscopes. Oxy iv 1 mg.kg-1.d-1 x 1, 3, and 5 d prevented or mitigated the occurrence and development of myocardial necrosis. The structure of heart mitochondria and myofibrils were clearly discernible. This action may be related to the alleviation of HBV by Oxy.

Effects of oxyfedrine on regional myocardial blood flow in patients with coronary artery disease.

Medical treatment of angina pectoris is largely based on the use of beta-blocking agents, calcium antagonists, and nitrates. Oxyfedrine, an amino ketone derivative and partial agonist at beta receptors, has been shown to have potent antianginal properties and to increase coronary blood flow in normal and ischemic myocardial regions in experimental studies. We assessed the effects of intravenous oxyfedrine on regional myocardial blood flow, using positron emission tomography (15-oxygen water), in six patients with chronic stable angina, positive exercise tests, and documented coronary artery disease. Myocardial blood flow was measured in all patients before (baseline) and 10 minutes after the intravenous administration of a single bolus (0.11-0.13 mg/kg) of oxyfedrine. Compared to baseline, heart rate and systolic blood pressure remained almost unchanged after the administration of oxyfedrine. Mean baseline myocardial blood flow was 0.90 +/- 0.15 ml/g/min in areas supplied by arteries with significant coronary stenosis and 1.08 +/- 0.19 ml/g/min in areas supplied by nonstenotic coronary vessels (p less than 0.05). After the administration of oxyfedrine, myocardial blood flow increased significantly in both the regions supplied by stenotic vessels (by 25%; from 0.90 +/- 0.15 to 1.20 +/- 0.31 ml/g/min; p = 0.002) and in areas supplied by angiographically normal coronary vessels (by 22%; from 1.08 +/- 0.19 to 1.38 +/- 0.49 ml/g/min; p less than 0.05). The results of this study indicate that in patients with coronary artery disease, intravenous oxyfedrine significantly increases regional myocardial blood flow, both in areas supplied by critically obstructed vessels and in areas supplied by normal or less severely narrowed coronary arteries.

[Ageusia as the aftereffect of oxyfedrine use]. / Ageusia jako nastepstwo ubocznego dzialania oksyfedryny.

Out of oxyfedrine++ side effects known up to the present (mild agitation, stupor, heat sensation, pains in the epigastrium++, skin allergy) 24 cases of ageusia appearing usually after 4 weeks of treatment with oxyfedrine++ were presented. Disturbances of taste are found to be unpleasant for patients, and result in remarkable exacerbation of their general feeling. The complaints subside completely after finishing treatment, and the time of taste disorder withdrawal is prolonged according to the time of oxyfedrine++ treatment.

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.

[Use of beta 1-adrenostimulants in circulatory failure in patients with chronic inflammatory lung diseases]. / Primenenie beta 1-adrenostimuliatorov pri nedostatochnosti krovoobrashcheniia u bol'nykh s khronicheskimi vospalitel'nymi zabolevaniiami legkikh.

In 34 patients with chronic cor pulmonale, the drugs from a group of beta-adrenostimulants, nonachlazinum and oxyphedrinum, were tested for effects on their hemodynamics, pulmonary ventilation function, blood gas composition and acid-base balance. In patients with circulatory failure due to lung diseases, nonachlazinum and oxyphedrinum were found to exert a pronounced positive intropic action, to contribute to an increase in cardiac output. The agents may be included into the multimodality therapy of patients with decompensated chronic cor pulmonale.

[The pathogenesis of psoriasis]. / K voprosu o patogeneze psoriaza.

Ildamen has a positive effect on the course of psoriasis in patients with cardiovascular diseases. Its effect in psoriasis appears to be explained by its stimulating action on skin beta-adrenoreceptors. The study carried out by the authors confirms the contribution of beta-adrenoreceptors to the pathogenesis of psoriasis.