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The overexpression of ABCB1 in cancer cells is a major factor contributing to the development of multidrug resistance (MDR) and treatment failure in cancer patients. Therefore, re-sensitization of MDR cancer cells to anticancer drugs remains an important aspect in chemotherapy. The progress in developing clinically applicable synthetic inhibitors of ABCB1 has been slow, mostly due to complications associated with intrinsic toxicities and unforeseen drug-drug interactions. Here, we explored the drug-repositioning approach for cancer therapy by targeting ABCB1-mediated MDR in human cancer cells. We found that DPI-201106, a positive inotropic agent, selectively inhibits the drug efflux function of ABCB1, and in doing so, re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs. Furthermore, the ATPase activity of ABCB1 and docking analysis of DPI-201106 in the drug-binding pocket of ABCB1 were determined to confirm the interaction between DPI-201106 and ABCB1 protein. In summary, we revealed an additional action and a potential clinical application of DPI-201106 to reverse ABCB1-mediated MDR in human cancer cells, which may be beneficial for cancer patients who have developed multidrug resistance and no longer respond to conventional chemotherapy, and should be further investigated.

A concise enantioselective synthesis of (S)-903, an inotropic agent, is described in nine linear steps and 95% ee based on asymmetric dihydroxylation of cinnamate ester and Co-catalyzed multifunctional reduction of several functional groups leading to the construction of core tetrahydroquinolin-3-ol, as the key steps.

Background: Mesenchymal stem cell (MSC)-treatment has shown clinical benefits in various diseases, however the poor viability of engrafted MSC limits therapeutic potential. Apelin-13 is a potent inotropic agent that, when administered in conjunction with MSCs treatment, improves survival and

Conformationally restricted analogues of the positive inotropic agent 1 have been synthesized in order to determine its biologically active conformation. Comparison of the distance maps (as a tool for the allowed conformations) with the biological activity give new insights in the biologically active conformation of this class of positive inotropic agents.

The synthesis of ethyl or methyl esters of 2-substituted 5-acetyl-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids 2a-d, f and 5 by reaction of sodium acetoacetamide with ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates and ethyl 2-ethoxymethylene-4,4,4-trifluoro-3-oxobutanoate, respectively, has been described. These esters routinely gave the corresponding carboxylic acids by alkaline hydrolysis followed by acidification. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria and on contractile activity of electrically-driven left atrium from reserpinetreated guinea pigs. Among the tested compounds, ethyl 5-acetyl-1,6-dihydro-6-oxo-2-phenyl-3-pyridinecarboxylate was found to be more potent and more effective than milrinone as a positive inotropic agent, while only marginally affecting the frequency rate.

Putative 5-HT 4 receptors were investigated in isolated piglet left atria and papillary muscles. In atrial tissues, 5-hydroxytryptamine (5-HT) was a potent positive inotropic agent with a pD 2 of 6.7. Its effects were antagonised in a selective and competitive manner by the 5-HT 4 receptor antagonist, SDZ 205-557, with a pA 2 of 7.3. In contrast to atrial tissues, piglet papillary muscles were virtually unresponsive to 5-HT 10 −8 −10 −3 M, suggesting that functional cardiac 5-HT 4 receptors are not present in ventricular tissue.

Triiodothyronine is an important regulator of cellular metabolism and may have potential use as an inotropic agent The aim of this study was to determine the effects of cardiopulmonary bypass on thyroid function in infants weighing less than 5 kg. Serial measurements of triiodothyronine, thyroxine, and thyroid-stimulating hormone were made in 10 infants and corrected for the effects of hemodilution. We demonstrated a fall in triiodothyronine and thyroxine levels, with some recovery after 3 to 6 hours. An additional decrease then occurred, reaching a trough at 48 hours (representing a fall of 78% for triiodothyronine and 57% for thyroxine) before hormone levels returned to normal at 5 to 7 days. Thyroid-stimulating hormone concentrations increased and decreased, predating and complementing exactly the changes in triiodothyronine and thyroxine. These results are quantitatively and, for thyroid-stimulating hormone, qualitatively different from those previously reported in adults. In two patients who died, however, and in one who had a particularly difficult postoperative course, no increase in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations was found after a trough had been reached at 48 to 72 hours, which suggests abnormal function at the hypothalamopituitary level. (J T horac C ardiovasc S urg 1992;103:800-5)

To assess whether an inotropic agent may affect quality of life in severe heart failure, a double-blind, placebo-controlled crossover study was performed in 10 patients over three periods of 3 weeks, including an initial control period of 3 weeks and periods on placebo or enoximone, 150 mg t.d.s. Quality of life was assessed by a questionnaire following initial training of patients to evaluate their symptoms after certain stresses, by visual analogue scales of symptoms, and by objective assessments during graded exercise. Daily dyspnoea score decreased from 33.2 +/- 2 (placebo) to 27.7 +/- 4 (enoximone) (P less than 0.01) and daily fatigue score decreased from 14.8 +/- 2.5 (placebo) to 12.6 +/- 2 (enoximone) (P less than 0.05). There were also significant beneficial responses in the mean daily NYHA class and in the duration of a walking test. Self-assessed global quality of life score increased from 2.7 +/- 0.6 (placebo) to 3.6 +/- 0.8 (enoximone) (P less than 0.05). It was concluded that over periods of 3 weeks, enoximone significantly improved self-assessed quality of life.

The purpose of this study was to examine the inotropic effects of nitroprusside (NP), a direct nitric oxide (NO) donor, in isolated rat hearts. Langendorff-perfused hearts (n = 5), paced at 6 Hz, were subjected to 15 min of equilibration (EQ) followed by infusion of NP, producing a coronary artery concentration of 1 x 10(-5) M. Coronary flow, left ventricular developed pressure (DP), end-diastolic pressure, and contractility and compliance (+/- dP/dt) were monitored throughout the experiment by a computerized data acquisition system. Myocardial oxygen consumption (MVO2) was measured at the end of EQ and after 2 1/2 min of NP infusion. Myocardial efficiency was calculated as the quotient of DP divided by MVO2. Values are expressed as the mean +/- SEM. Paired t tests were used to calculate statistical significance. Values for parameters monitored at end EQ and at 2 1/2 min NP infusion showed that there was a 93% increase in coronary flow, 18, 17, and 16% increases in developed pressure, contractility, and compliance, respectively, no significant change in end-diastolic pressure, a 49% increase in myocardial oxygen consumption, and a 21% decline in myocardial efficiency (P < 0.05 for all differences). We conclude that in the isolated rat heart, NO behaves as a positive inotrope.

Background: Little is known about the specific components which underpin changes in ventricular–vascular interaction occurring in response to the inotropic agent dobutamine during postnatal growth. This study examined this question using wave intensity analysis. Methods: Anesthetized open-chest lambs aged 1–2 days (n= 9), 7–10 days (n= 8) and 6–8 weeks (n= 9) were instrumented with an aortic micromanometer tomeasure blood pressure (P) and an ultrasonic flow probe to obtain aortic blood velocity (U). Haemodynamicswere recorded during an incremental dobutamine infusion (0.5–10 g/(kgmin)). Wave intensity (dIW) was calculated as the product of the rates of change of P andUwith customized software using ensemble-averaged signals. Forward and backward components of dIW were determined after calculation of wave speed. R d a s a s p v ( r i i ( C v d a a

Two small, randomized, blind clinical trials comparing the administration of triiodothyronine with that of placebo have been carried out in patients undergoing myocardial revascularization. In patients with a left ventricular ejection fraction of 40% (study II), triiodothyronine administration resulted in significantly improved stroke volume (p

A new inotropic agent, TA-064, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol, was shown to have strong effects in experimental animals. Its effectiveness and associated adverse effects were tested in humans invasively (n = 6) and noninvasively (n = 17). Increasing doses of intravenous infusion (1, 2, and 4 micrograms/kg/min) increased plasma levels to 15, 35, and 82 ng/ml, respectively, resulting in marked increases in the peak rate of left ventricular pressure rise (dP/dt) (1,450 +/- 63 to 3,042 +/- 349 mm Hg/s) (mean +/- standard error of the mean [SEM], p less than 0.01) and the ratio of dP/dt to left ventricular pressure at a developed pressure of 40 mm Hg (25 +/- 3 to 39 +/- 2 s-1) (p less than 0.01), with a reduction in left ventricular end-diastolic pressure (12 +/- 2 to 4 +/- 1 mm Hg) (p less than 0.01). Minimal or no changes were seen in heart rate and left ventricular systolic pressure. After a single oral dose (10 mg), the plasma level reached its peak at 90 minutes (16 +/- 9 ng/ml, n = 17). A positive inotropic effect was confirmed echocardiographically in both healthy volunteers (n = 8) and patients with congestive heart failure (CHF) (n = 9) who were maximally treated with conventional regimens: increase in mean velocity of circumferential fiber shortening (healthy volunteers: 1.29 +/- 0.05 to 1.60 +/- 0.11 circ/s [p less than 0.05]; patients with CHF: 0.69 +/- 0.08 to 0.93 +/- 0.09 circ/s [p less than 0.01]), ejection fraction (healthy volunteers: 68 +/- 2 to 75 +/- 2% [p less than 0.05], patients with CHF: 37 +/- 4 to 45 +/- 5% [p less than 0.01]) without change in heart rate. The cardiac index was increased only in the CHF group (2.71 +/- 0.22 to 3.21 +/- 0.24 liters/min/m2) (p less than 0.05). No significant untoward effects were observed. Thus TA-064 is a potent inotropic agent and can be used either parenterally or orally. Salutary effects can be expected in patients with congestive heart failure who are treated with digitalis and diuretic agents.

Histamine, a positive inotropic agent which elevates cyclic AMP, was tested for ability to induce Ca 2+ channels in 3 preparations of embryonic (16-day-old) chick ventricular myocardial cells whose fast Na + channels were blocked by tetrodotoxin or voltage inactivated in 25 mM K + . In such inexcitable cells, histamine (10 −6 M) rapidly (1–3 min) induced slowly rising, overshooting, plateau-like responses accompanied by contractions. Mn 2+ , D600, of H 2 -receptors blocking agents abolished the slow responses. These results suggest that the positive inotropic action of histamine, like that of catecholamines, is mediated by an increased availability of slow Ca 2+ channels.

The hemodynamic and neurohumoral effects of cummulative intravenous doses of piroximone (MDL 19205), a noncatecholamine, nonglycoside, imidazole derivative with positive inotropic and vasodilating properties, were studied in eight patients with severe congestive heart failure. A dose of 1.25 mg/kg in seven patients and 1.75 mg/kg in one patient increased cardiac index by 75% from 1.96 to 3.41 liters/min per m2 and decreased systemic vascular resistance (-41%), right atrial (-66%) and pulmonary wedge pressure (-35%) (all p less than 0.005). Mean arterial pressure was slightly reduced from 78 to 71 mm Hg (p less than 0.05) and forearm blood flow increased by 42%. Plasma norepinephrine decreased from 830 to 542 pg/ml (p less than 0.05) and plasma renin activity tended to increase. In four patients, dobutamine (15 micrograms/kg per min) produced a comparable increase in cardiac index (+100%), but less decrease in pulmonary wedge pressure (-21 versus -41%, p less than 0.05 versus piroximone) and, unlike piroximone, significantly increased heart rate (+22%, p less than 0.05 versus piroximone) and heart rate-blood pressure product (+30%, p less than 0.01 versus piroximone). In four other patients, a single intravenous dose of piroximone (1 mg/kg) resulted in a 35% increase in the first derivative of left ventricular pressure (dP/dt) from 796 to 1,068 mm Hg/s (p less than 0.01). Thus, piroximone is a potent inotropic agent with an acute hemodynamic profile that may be more favorable than that of dobutamine. Because the drug is orally absorbed, clinical trials of chronic efficacy are indicated.

RO 2–2985, a potent inotropic agent, produces prolonged increases in left ventricular pressure and coronary and renal blood flow in conscious dogs. To evaluate these effects, 18 dogs were chronically instrumented with aortic or left ventricular pressure catheters, or both, and coronary and renal pulsed Doppler flow probes; 14 to 25 days later, after control values were recorded, sufficient blood was removed from each dog to reduce mean aortic pressure to 40 to 50 mm Hg or left ventricular pressure to 50 to 65 mm Hg during a 15 minute period. This pressure was maintained by withdrawal or addition of blood as necessary for an additional 30 minutes. The animals were then separated into two groups; one group was given RO 2–2985, the other an equivalent amount of drug solvent. Measurements were then made for 75 minutes or until death occurred. Retransfusion was performed in those animals living at 75 minutes. All 10 animals that received RO 2–2985 lived. After the drug injection, blood pressure and coronary and renal blood flow increased. Only one of eight animals receiving the solvent alone lived. The remaining control animals showed progressive deterioration in pressure and flow until death. The data show that RO 2–2985 decreased mortality and increased blood flow in the coronary and renal beds during hemorrhage-induced hypotension.

The effects of TA-064[(-)-α-(3,4-dimethoxyphenethylaminomethyl) -4-hydroxybenzylalcohol], an orally active inotropic agent, on myocardial oxygen consumption(MVO2) and left ventricular(LV) size were investigated in six anesthetized(N2O and halothane) dogs. LV pressure and LV inner diameter were measured by a micromanometer and ultrasonic-dimension gauges, respectively.