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At least 19 recordsLinked to original sources
PubMed1979

Pharmacokinetics of hydralazine, apparent hydralazine and hydralazine pyruvic acid hydrazone in humans.

Hydralazine is an antihypertensive vasodilator agent. Lack of specific assay techniques for its measurement have delayed elucidation of its pharmacokinetic profile. This study compares the plasma profiles of hydralazine, measured both by a specific and by a previously published nonspecific assay and of a major plasma metabolite, hydralazine pyruvic acid hydrazone. After po and iv administration of hydralazine, peak hydralazine levels were lower (7-33%) and plasma half lives were shorter (15-31%) when measured by the specific technique. The mean plasma half life of the pyruvic acid hydrazone was 156 min and mean urinary clearance, 28 ml/min. The plasma profile of hydralazine and of the major metabolite, the pyruvic acid hydrazone, do not appear to correspond to the duration of antihypertensive effect of administered hydralazine.

Acetylation↗
PubMed1977

Comparative evaluation of the in vitro effects of hydralazine and hydralazine acetonide on arterial smooth muscle.

1. Dose-response relationships to K+ were determined in isolated strips of rabbit aorta. 2. K+ contractures were induced by 30 mM K+ in paired strips from individual animals. The effects of hydralazine and hydralazine acetone hydrazone (hydralazine acetonide) on these contractures were studied. 3. Hydralazine and hydralazine acetonide both produced dose-dependent decreases of K+-induced tone. Threshold concentrations for hydralazine were 11.89 +/- 4.5 X 10(-5) M (mean +/- s.d.) and for hydralazine actonide 9.7 +/- 4.6 X 10(-5) M (0.5 less than P less than 0.4). 4. The magnitude of the effect of hydralazine acetonide was greater than that of hydralazine at all concentrations above threshold, as reflected in a significant difference (P less than 0.05) in the slopes of dose-response curves to the two treatments. The vasodilator effects of hydralazine and the acetonide were terminated by washout of the bath. 5. The differences in effect were not due to instability of hydralazine under in vitro conditions. 6. It is concluded that hydralazine acetonide has intrinsic activity on vascular smooth muscle which differs significantly from that of the parent compound and that this may contribute to the hypotensive effects which follow administration of the parent compound.

Animals↗
PubMed1986

Hydralazine inhibits vascular reactivity by a mechanism independent of vascular prostaglandin biosynthesis: role of thromboxane synthetase in blocking hydralazine actions.

To explore the mechanism of action of hydralazine on vascular reactivity of small vessels we have examined its actions in the isolated perfused mesenteric vascular bed. In buffer perfused preparations hydralazine inhibited responses to nondepolarizing stimuli at concentrations comparable to those achieved in vivo. Inhibition of cyclo-oxygenase activity enhanced hydralazine's action as did inhibition of thromboxane synthetase. Hydralazine stimulated mesenteric vascular bed prostaglandin biosynthesis (6-keto PGF1a and PGE2 determined by radio-immunoassay) and stimulated aorta PG12 synthesis (monitored by platelet bioassay). Extracellular calcium opposed hydralazine's action by a mechanism sensitive to cyclo-oxygenase inhibition. Concentrations of hydralazine substantially greater than those effective in the perfused vascular bed were required to demonstrate inhibition of platelet aggregation and ram seminal vesicles cyclooxygenase activity. These data indicate: Hydralazine acts directly on the smooth muscle to attentuate responses to nondepolarizing stimuli. Hydralazine does not inhibit vascular reactivity by a PG12 dependent mechanism although it stimulates prostaglandin biosynthesis. Reduction of vascular bed prostaglandin and thromboxane A2 biosynthesis enhances hydralazine actions. Hydralazine appears to act at a thromboxane A2 sensitive site however it is not a nonselective prostaglandin antagonist. Hydralazine is effective at concentrations which do not inhibit either platelet aggregation or ram seminal vesicle cyclooxygenase. These data suggest that hydralazine is a potent direct acting vasodilator which stimulates prostaglandin biosynthesis and whose potency may in turn be attenuated by the production of proconstrictory prostaglandins.

Animals↗
PubMed1980

Prospective study of immune response to hydralazine and development of antideoxyribonucleoprotein in patients receiving hydralazine.

To examine the relationship between the immune responses to hydralazine, a drug known to induce systemic lupus erythematosus, and to deoxyribonucleoprotein (DNP) we followed prospectively 21 hypertensive patients treated with hydralazine for the first time. Within one year, antibodies to hydralazine developed in 16 of these patients and anti-DNP in seven of these. In one patient whose serum had a positive antinuclear antibody test prior to treatment, a mild hydralazine systemic lupus erythematosus syndrome developed preceded by rises in the levels of both anti-hydralazine and anti-DNP. Studies by radioimmunoassay on serums of three additional patients, not followed in this study but known to have hydralazine-induced systemic lupus erythematosus, revealed no evidence for either (1) cross-reactivity between anti-DNP and anti-hydralazine or (2) antibodies specific for a hydralazine-DNP complex. In some way, perhaps related to the mechanism by which carrier molecules enhance the immunogenuity of haptens, hydralazine increases the antigenicity of DNP. This effect depends on the development of immunity to hydralazine as well.

Antibodies↗
PubMed1995

Triplex-DNA stabilization by hydralazine and the presence of anti-(triplex DNA) antibodies in patients treated with hydralazine.

Hydralazine is an antihypertensive drug that elicits andti-nuclear antibodies in patients as an adverse effect. We investigated the ability of hydralazine to promote/stabilize the triplex DNA form of poly(dA).2poly(dT). Under conditions of low ionic strength, the polynucleotide melted as a double helix with a melting temperature (Tm) of 55.3 degrees C. Hydralazine destabilized this duplex form by reducing its Tm to 52.5 degrees C. Spermidine (2.5 microM), a natural polyamine, provoked the triplex form of poly(dA)-.2poly(dT) with two melting transitions, Tm1 of 42.8 degrees C corresponding to triplex-->duplex+single-stranded DNA and Tm2 of 65.4 degrees C, corresponding to duplex melting. Triplex DNA thus formed in the presence of spermidine was further stabilized by hydralazine (250 microM) with a Tm1 of 53.6 degrees C. A similar stabilization effect of hydralazine was found on triplex DNA formed in the presence of 5 mM Mg2+. CD spectra revealed conformational perturbations of DNA in the presence of spermidine and hydralazine. These results support the hypothesis that hydralazine is capable of stabilizing unusual forms of DNA. In contrast with the weak immunogenicity of DNA in its right-handed B-DNA conformation, these unusual forms are immunogenic and have the potential to elicit anti-DNA antibodies. To test this possibility, we analysed sera from a panel of 25 hydralazine-treated patients for anti-(triplex DNA) antibodies using an ELISA. Our results showed that 72% of sera from hydralazine-treated patients contained antibodies reacting toward the triplex DNA. In contrast, there was no significant binding of normal human sera to triplex DNA. Taken together our data indicate that hydralazine and related drugs might exert their action by interacting with DNA and stabilizing higher-order structures such as the triplex DNA.

Adolescent↗
PubMed1981

Relationship between immune response to hydralazine and to deoxyribonuclease in patients receiving hydralazine.

In a prospective study of 21 hypertensive patients receiving hydralazine for 1 year, we found a close relationship between development of antibodies to deoxyribonucleoprotein (DNP) and to hydralazine but no evidence for cross-reactivity between antibodies to these two antigens. Of 8 patients who developed increased levels of antiDNP, 7 also developed antibodies to hydralazine. Inhibition of the reaction between DNP and antiDNP as measured by radioimmunoassay in 3 patients with hydralazine lupus could not be achieved with large amounts of hydralazine. However, antibodies to DNP produced in guinea pigs immunized with hydralazine conjugates could be inhibited with hydralazine in accordance with previous studies by others on rabbits. In the human, antibodies to DNP which develop during hydralazine administration are not due to cross-reactive antibodies nor do they appear as a result of immune response to an in vivo hydralazine DNP conjugate.

Animals↗
PubMed1991

Metabolism of hydralazine by activated leukocytes: implications for hydralazine induced lupus.

Hydralazine is associated with a lupus-like syndrome. There is evidence that many drug hypersensitivity reactions are due to reactive metabolites. Incubation of hydralazine with activated neutrophils or monocytes led to the production of phthalazinone, phthalazine and 3 unidentified metabolites. Formation of the metabolites, with the exception of phthalazine, required activation of the leukocytes. Using radiolabelled hydralazine, covalent binding to activated neutrophils was observed. Oxidation of hydralazine catalyzed by myeloperoxidase (MPO) produced the same metabolites and covalent binding to protein. We conclude that hydralazine is metabolized by activated leukocytes to a reactive metabolite which may be associated with hydralazine induced lupus.

Chromatography, High Pressure Liquid↗
PubMed1978

Interference in assays for hydralazine in humans by a major plasma metabolite, hydralazine pyruvic acid hydrazone.

The present study showed that published spectrophotometric and GLC methods for hydralazine in plasma do not distinguish between the drug and a major plasma metabolite, hydralazine pyruvic acid hydrazone. These methods involve the acid treatment of the sample, which hydrolyzes that hydrazone back to hydralazine. A specific GLC assay for the hydrazone was developed and involves its selective extraction from plasma and transformation to 3-trifluoromethyl-s-triazolo[3,4-a]phthalazine. This derivative could be sensitively measured by GLC using an electron-capture detector. With this procedure, it was shown that most "apparent hydralazine" in plasma is the hydrazone, which forms rapidly from hydralazine and endogenous pyruvic acid. Previous work indicated that the hydrazone was inactive when administered intravenously to rabbits.

Chromatography, Gas↗
PubMed1986

Treatment of hypertension during pregnancy with hydralazine monotherapy or with combined therapy with hydralazine and pindolol.

Forty-four consecutive patients referred for treatment because of hypertension (greater than 150/90 mmHg) occurring during pregnancy were randomly allocated to one of two treatment groups, hydralazine alone (n = 21) or hydralazine combined with pindolol (n = 23). Satisfactory blood pressure control (diastolic pressure less than 90 mmHg) was achieved in 86% of patients receiving hydralazine alone and 91% of those on combined therapy. Although the treatment did not lower the overall incidence of hypertensive complications it appeared to delay the onset of such complications until successful surgical intervention was possible. Fetal outcome was similar in both groups and there was no perinatal mortality in this high-risk population. Although blood pressure control was similar in both groups of patients, combined therapy with hydralazine and pindolol can be considered to be superior to hydralazine monotherapy, since in patients treated with the combination the incidence and intensity of troublesome side-effects was markedly lower.

Adult↗
PubMed1979

Pharmacokinetics and cardiovascular effects in rabbits of a major hydralazine metabolite, the hydralazine pyruvic-acid hydrazone.

The hydrazone of hydralazine and pyruvic acid (HPH) has been recognized as a quantitatively important metabolite of hydralazine in human plasma. We evaluated the disposition of [14C] HPH after its i.v. administration to normal, anephric and probenecid-pretreated rabbits. Renal clearance of HPH in normal rabbits exceeded the glomerular filtration rate by a factor of 3 to 4 and accounted for 80 to 90% of the total body clearance. Active tubular secretion was established by the effect of probenecid pretreatment to reduce the renal clearance of HPH by 80%. Total body clearance of HPH in anephric rabbits was 10% of that of normal animals, emphasizing the minor importance of metabolic conversion for the overall disposition of HPH. HPH in a maximum dose of 50 mumol/kg i.v. had no hypotensive effect in renal hypertensive rabbits and did not interfere with the subsequent hypotensive response to hydralazine. This HPH dose produced plasma levels at least 50 times in excess of those reported in humans after administration of therapeutic doses of parent hydralazine. HPH is consequently of negligible clinical significance, despite the relatively high plasma concentration of this metabolite which occurs after administration of parent hydralazine.

Animals↗
PubMed1980

Hydralazine-pyrimidine interactions may explain hydralazine-induced lupus erythematosus.

Hydralazine, the prototypic drug that induces systemic lupus erythematosus, reacts with thymidine and deoxycytidine. Analysis of a reaction mixture of therapeutic concentrations of hydralazine with labeled thymidine reveals at least four labeled products. At higher concentrations, hydralazine reacts with labeled deoxycytidine to form at least three labeled products. Formation of these products is markedly enhanced by exposure to ultraviolet light. The reaction of hydralazine with thymidine and deoxycytidine may be in part responsible for initiating drug-induced systemic lupus erythematosus.

DNA↗
PubMed1989

Pharmacokinetics and biotransformation of hydralazine acetone hydrazone, a metabolite of hydralazine, in the rat.

The pharmacokinetics of hydralazine acetone hydrazone (HAH), which is a metabolite of hydralazine (HP), was investigated after iv administration to rats. Plasma concentrations of HAH, HP, and hydralazine pyruvic acid hydrazone (HPH) were simultaneously determined by a specific HPLC method. A five-compartment pharmacokinetic model was presented to elucidate the disposition of HAH and two products, HP and HPH. The parameters used in the model were obtained by administering each of the three compounds (10 mg/kg) separately. The proposed model described the experimental data well and the model parameters were close to the model-independent values. After HP administration, HPH appeared rapidly in plasma, but the HPH availability from HP amounted to only 17.8 +/- 3.7%, based on the comparison between the area under the plasma concentration curves of formed and iv HPH. The formation of HP from HAH in the systemic circulation was demonstrated, but formed HP disappeared rapidly. The fraction of HAH available to the systemic circulation as HPH was extremely low (7.8 +/- 2.2%), indicating that the conversion of HAH to HP was not so extensive. The present results support the hypotheses that HPH is formed via the direct reaction of HAH with pyruvic acid and that the secondary formation is mediated by conversion to HP.

Animals↗
PubMed1976

Studies on hydralazine. III. Bioavailability of hydralazine in man.

The bioavailability of orally administered hydralazine was assessed in 4 healthy subjects after separate administration of a single oral or intravenous dose (0.3 mg-kg-1). Comparison of the areas under the serum concentration-time curves showed that 26-55% of the oral dose was available to the systemic circulation as unchanged drug. The 0-24 h excretion of the drug in urine was rapid: 11.4-14.1% of the dose after intravenous administration, and 2.0-3.6% after an oral dose. Acetylation of hydralazine leads to formation of 3-methyl-s-triazolo-3,4, aphthalazine (MTP) and a gas-liquid-chromatographic method for its measurement in urine was developed. After oral and intravenous administration, 0.8-1.2% and 1.4-2.3% of the dose, respectively, were recovered within 24 hours from urine as MTP. After oral administration there was a relative increase in the amount of MTP in every subject, which indicates route-dependent metabolism. The lower bioavailability of oral hydralazine could be explained in terms of first-pass metabolism.

Acetylation↗
PubMed1981

Short- and long-term effects of hydralazine and combined hydralazine-prenalterol therapy in severe chronic congestive heart failure.

The hemodynamic benefits of combined administration of prenalterol (P) with hydralazine (H) were evaluated in ten patients with severe chronic heart failure. Single administration of 100 mg H increased cardiac index (CI) from 2.3 to 3.0 l/min/m2, whereas pulmonary capillary wedge pressure (PWC) remained unchanged. After 3--4 weeks of treatment with 200 mg H hemodynamic improvementt was maintained (CI: 2.9 l/min/m2). Additional administration of P caused further augmentation of CI (3.3 l/min/m2). After long-term treatment with the combination of H and P sustained augmentation of CI (3.2 l/min/m2), and, furthermore, a slight but significant decrease of PCW were observed (p less than 0.05 vs. chronic single H-therapy). Five patients were able to perform exercise testing; H improved maximal exercise capacity and exercise hemodynamics in three patients. Further improvemen was observed after combined treatment (H + P) in three of five patients. It is concluded, the prenalterol may enhance the effectiveness of hydralazine therapy in congestive heart failure by providing concomitantly the principal actions of the vasodilator and positive inotropic agent used separately. Furthermore, the results indicate that oral long-term administration of hydralazine and prenalterol can produce sustained beneficial improvement.

Adult↗
PubMed1980

Quantitative analysis of hydralazine pyruvic acid hydrazone, the major plasma metabolite of hydralazine.

A specific, high-performance liquid chromatographic technique for the measurement of hydralazine pyruvic acid hydrazone is described. This method utilized reversed-phase chromatography for the separation of this hydrophilic metabolite of hydralazine from other fluid constituents present in serum, plasma, or urine of human volunteers and rabbits receiving hydralazine. Detection of the compound of interest is accomplished spectrophotometrically at 250 nm.

Animals↗
PubMedDate not supplied

Hypotensive effect of the hydralazine--acetone hydrazone in conscious rabbits: evidence for its back-conversion to hydralazine in vivo.

The hydralazine--acetone hydrazone (HAH) has previously been identified as a metabolite of hydralazine (H) in humans. We compared the hypotensive effects of HAH and H in groups of hypertensive rabbits. Both compounds caused a dose-dependent depressor response, with a potency ratio of HAH to H of approximately 0.2. Upon their intravenous administration to anephric rabbits, both H and HAH produced sustained concentrations in plasma of the H-pyruvic acid hydrazone, demonstrating that back-conversion of HAH to H occurred in vivo. We conclude that HAH is hydrolyzed in vivo to yield parent H. The levels of the H-metabolite, the pyruvic acid hydrazone, suggest that the hypotensive effect of HAH could be explained entirely by generation of H in vivo. This combined pharmacokinetic and pharmacodynamic approach can be applied to other H-hydrazones to evaluate their backconversion to H in vivo.

Animals↗
PubMed1982

Endogenous generation of hydralazine from labile hydralazine hydrazones.

The hypothesis that the pharmacologically active hydralazine hydrazones (HH) are endogenously hydrolyzed to parent hydralazine (H) was tested in a series of in vitro and in vivo systems. The stable hydrazones H alpha-ketoglutaric acid hydrazone and H pyruvic acid hydrazone did not hydrolyze to H in vitro (buffer or plasma), were inactive in vivo and did not generate urinary metabolites of parent H. By contrast, the labile HH, H acetaldehyde hydrazone and acetone hydrazone (HAH) generated H in vitro. H acetaldehyde hydrazone produced in vitro effects that were equipotent to the H concentration measured in the dose solutions. When administered to conscious rats and rabbits, the labile hydrazones reduced blood pressure. This effect was more gradual in onset than that of H. The hypotensive effects of HH were significantly greater than predicted by the amount of H contained in the dose solutions. Metabolic studies were conducted with the labile HH, HAH. After administration of HAH to rabbits, the proportional excretion of the urinary H metabolite, H pyruric acid hydrazone, was equal to that observed after the administration of H. We conclude that HH are inactive, except when hydrolyzed to H. The hydrolysis of certain HH, including HAH and H acetaldehyde hydrazone, in vivo may be nearly complete. Differences in the pharmacodynamic properties between labile HH and H may be related to the time course of generation of H, sequestration of hydrolysis in physiologically inactive sites or other unrecognized mechanisms.

Animals↗