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1.
The property of aerobic glycolysis commonly possessed by malignant cells points to a weakness in oxidative metabolism which has been equated in some tumours with partial uncoupling of oxidative phosphorylation. The suggestions are made, first, that this endogenous defect may account for spontaneous cell death
, and, second, that its accentuation would inflict extensive tumour injury upon sensitive neoplasms. Certain drugs not in current use for the treatment of malignant disease are known to be able to interfere selectively with energy metabolism in sensitive tumours to such an extent that widespread necrotisation ensues. The drugs activate an endogenous destructive mechanism that appears to require oxygen. Liminal therapy, the maintenance of continuous destructive pressure on sensitive growths in such a manner that maximal anti-tumour activity in terms of interference with energy production is not achieved at any one time, and under conditions in which the oxygen supply is only partly depleted, is put forward as a possible means of achieving complete and selective tumour destruction
. 相似文献
2.
Danny D. Shen James P. Hosler Richard L. Schroder Daniel L. Azarnoff 《Journal of pharmacokinetics and pharmacodynamics》1980,8(1):53-68
The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t1/2) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given-orally, the area under the plasma concentration-time curve (AUC) and systemic availability () in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acidlabile metabolites was similar to the t1/2 of H. The AUCs for metabolites were 4–12 times larger than for the parentdrug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective ofroutes of administration or the acetylator status.This study was supported in part by Grant RR 828 from United States Public Health Service and a Research Starter grant from the Pharmaceutical Manufacturers Association Foundation, Inc. (D. D. S.). 相似文献
3.
H. Liedholm E. Wåhlin-Boll A. Hanson I. Ingemarsson A. Melander 《European journal of clinical pharmacology》1982,21(5):417-419
Summary The concentrations of real and apparent (= real hydralazine + acid-labile hydrazones) hydralazine in maternal and umbilical plasma obtained at delivery of 6 women treated with hydralazine and atenolol for pregnancy hypertension were measured by gas chromatography. In one of the patients, the concentrations of the same substances were subsequently measured in breast milk. Apparent hydralazine reached higher levels in umbilical than in maternal blood. The concentration of real hydralazine seemed to be at least as high in the fetus as in the mother. On the other hand, even though the fraction of real (i.e. presumably active) hydralazine was greater in milk than in plasma, the total concentration was smaller, and the estimated dose per milk feed of 75ml would not exceed 0.013mg. Thus, hydralazine treatment of the pregnant woman would expose her fetus to effective concentrations of the drug, but breast feeding would not result in a clinically relevant concentration in the infant. 相似文献
4.
Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC
0
) was 18.2% lower (p<0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p>0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC
0
of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p<0.01). 相似文献
5.
Kwadwo A. Yeboah Amy Allspaw Akram Al-Makki Brian M. Shepler 《Clinical therapeutics》2018,40(9):1592-1595
Purpose
Several antihypertensive medications have been associated with various forms of sexual dysfunction. We present a case report of a premenopausal patient with hydralazine-associated amenorrhea.Methods
The Naranjo adverse drug reaction probability scale was used to assess causality. We also performed a literature search on PubMed to find publications that report hydralazine-associated amenorrhea.Results
The Naranjo scale generated a score of 6, suggesting a probable relationship between amenorrhea and hydralazine therapy. No publications associating hydralazine with amenorrhea were identified.Implications
A probable relationship exists between hydralazine and the development of amenorrhea. 相似文献6.
Jay N. Cohn M.D. 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》1994,8(1):119-122
Summary Vasodilator drugs, particularly intravenously infused nitroprusside and an orally administered combination of hydralazine and isosorbide dinitrate, exert a profoundly favorable hemodynamic effect in the setting of heart failure complicating a prior myocardial infarction. Although these oral drugs also may relieve symptoms and improve exercise tolerance, the long-term benefits appear to be related to inhibition or reversal of the left ventricular dilation that results in a progressive fall in left ventricular ejection fraction. The long-term efficacy of both ACE inhibitors and hydralazine-nitrate in symptomatic heart failure makes the vasodilator combination a rational alternative to an ACE inhibitor and possibly an effective agent for cotherapy with an ACE inhibitor. Trials are needed to test the additive efficacy of this vasodilator combination and to develop other safe and effective drugs that target the progressive remodeling process in heart failure. 相似文献
7.
Chr. Krgaard Nielsen E. Arrigoni-Martelli 《Basic & clinical pharmacology & toxicology》1981,49(5):427-431
Abstract: Ring preparations of rabbit aorta were contracted by potassium (127 mM). Pinacidil (P 1134), a new vasodilator (2.3×10−5 M), the calcium antagonists verapamil (3.4×10−7 M), nifedipine (3.4×10−9 M) and hydralazine (1.9×104 M) relaxed the preparation by 50%. 50% relaxation of noradrenaline-contracted tissues was obtained with pinacidil, 6.8×10−5 M, verapamil, 2.4×10−4 M and hydralazine, 1.9×10−3 M. At 2×10−7 M concentration nifedipine was almost inactive. In ring preparations of rabbit aorta exposed to calcium-free medium and then depolarized with potassium (127 mM), pinacidil, 5×10−5 M and nifedipine, 10−8 M significantly inhibited the contractions by cumulative addition of calcium. Hydralazine, 10−3 M had no effect. Noradrenaline-induced contractions in calcium-free medium or in presence of increasing amounts of calcium were significantly inhibited by nifedipine, 10−8 M and hydralazine, 10−3 M. Pinacidil, 10−4 M had no effect. Pinacidil, 1.3×10−5 M and verapamil, 2.0×10−5 M inhibited by 50% the serotonin-induced increase of perfusion pressure of isolated rabbit ear artery. The noradrenaline effect in this preparation were 50% inhibited by pinacidil, 2.4×10−4 M and by verapamil, 8.8×10−5 M. Hydralazine, 10−3 M exerted minor inhibitory effect. It is suggested that interference with calcium influx contributes to the vasodilator activity of pinacidil. 相似文献
8.
M. B. Murphy A. J. Scriven M. J. Brown R. Causon C. T. Dollery 《European journal of clinical pharmacology》1982,23(6):479-482
Summary To determine whether inhibition of sympathetic activity is a factor in calcium antagonist induced hypotension, plasma noradrenaline was measured after intravenous infusion of hydralazine (25 mg) and the calcium antagonist nifedipine (4 mg) in 6 hypertensive males. The resultant reduction in mean blood pressure (12.4% and 14.2% respectively) was accompanied by similar increases in heart rate and plasma noradrenaline concentration. These results suggest that calcium slow channel blockade does not inhibit noradrenaline release from sympathetic nerves and that nifedipine induced hypotension is independent of such a mechanism. 相似文献
9.
P. K. Zachariah S. G. Sheps A. Schirger L. D. Fisher C. Shub J. B. Collins R. E. Spiekerman 《European journal of clinical pharmacology》1986,31(2):133-141
Summary Forty-three patients with mild essential hypertension were randomized into two double-blind studies: pinacidil vs. placebo or pinacidil vs. hydralazine. Pinacidil (62±18 mg/day) decreased office systolic and diastolic blood pressures from 145 to 137 mm Hg and from 98 to 89 mm Hg, respectively, after 6 weeks of therapy. Similarly, hydralazine (128±28 mg/day) reduced supine systolic blood pressure from 140 to 134 mm Hg and supine diastolic blood pressure from 93 mm Hg to 84 mm Hg. Significant tachycardia was not noted with either drug. Ambulatory blood pressure was monitored for 24 h during the placebo-washout and efficacy phases with both pinacidil and hydralazine. Mean 24-h blood pressure was 128 systolic and 81 diastolic with pinacidil and 121 systolic and 76 diastolic with hydralazine. Reduction in awake hypertensive diastolic blood pressure was significant for both pinacidil and hydralazine. Normal sleep diastolic blood pressure was not reduced by pinacidil but was reduced by hydralazine. Side-effects with both drugs included edema, headache, and palpitations. These data demonstrate that pinacidil is as effective an antihypertensive agent as hydralazine. 相似文献
10.
Jiang Y Huang Y Cheng C Lu W Zhang Y Liu X Zou L Ben Q Shen A 《Experimental and molecular pathology》2011,91(3):768-774
No proven targeted therapy is currently available for the treatment of triple-negative breast cancer (TNBC). Ligand activation of peroxisome-activated receptor (PPAR)γ induces antitumor effects in cancer but not obviously in TNBC. In TNBC cells, combined treatment with thiazolidinedione and demethylation drugs Hydralazine up-regulated protein and mRNA levels of PPARγ. Besides, the combination of two drugs promote antiproliferative and apoptotic effects in TNBC cells and decrease the proliferation index in the tumor xenografts. Taken together, our results suggest that multidrug regimens including a combination of Thiazolidinedione and Hydralazine may provide a therapeutic advantage in TNBC. 相似文献