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PubMed2006

Rat liver-mediated metabolism of hydroxyurea to nitric oxide.

Hydroxyurea is an approved treatment for sickle cell disease. Oxidation of hydroxyurea results in the formation of nitric oxide (NO), which also has drawn considerable interest as a sickle cell disease therapy. Although patients on hydroxyurea demonstrate elevated levels of nitric oxide-derived metabolites, little information regarding the site or mechanism of the in vivo conversion of hydroxyurea to nitric oxide exists. Chemiluminescence detection experiments show the ability of crude rat liver homogenate to convert hydroxyurea to nitrite/nitrate, evidence for NO production. Nitrite/nitrate form at therapeutic concentrations of hydroxyurea in a clinically relevant time frame. Electron paramagnetic resonance (EPR) studies show the formation of iron nitrosyl complexes during this incubation and experiments with labeled hydroxyurea show the NO derives from the drug. Gas chromatography-mass spectrometry measurements indicate the hydrolysis of hydroxyurea to hydroxylamine in this system. Incubation of hydroxylamine with crude rat liver homogenate also generates nitrite/nitrate and iron nitrosyl complexes. A line of evidence including inhibitor studies, EPR spectroscopy, and nitrite/nitrate detection identifies catalase as a possible oxidant for the conversion of hydroxyurea to NO. These results reveal the ability of liver tissue to convert hydroxyurea to nitric oxide and provide insight into the metabolism of this drug.

Animals↗

PubMed1996

Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia.

PURPOSE: This open-label pilot study was designed (1) to determine the effect of hydroxyurea on the hemoglobin level in children with sickle cell anemia, (2) to evaluate the toxicity of hydroxyurea, and (3) to assess any impact of hydroxyurea on the frequency of vaso-occlusive crises (VOCs). PATIENTS AND METHODS: Ten children (group 1) with three or more VOCs of the extremities or two or more VOCs of the lungs (acute chest syndrome) in the preceding 12 months, and five children (group 2) with hemoglobin levels less than 70 gm/L were treated with hydroxyurea in doses of 20 to 35 mg/kg per day. The frequency of VOCs before hydroxyurea therapy was compared with the frequency during therapy, and the peak hemoglobin levels during hydroxyurea therapy were compared with the pretreatment values. RESULTS: One patient in group 1 was removed from the study within 1 month because of nausea. Seven of the remaining nine patients in group 1 had a decrease in the frequency of VOCs. The number of VOCs per patient-year for all 14 patients decreased from 2.5 before hydroxyurea therapy to 0.87 during hydroxyurea therapy, a decrease of 65% (p < 0.00001). Two of five patients in group 2 had an increase in hemoglobin of 27 gm/L and 34 gm/L over the baseline. The median rise in hemoglobin was 19 gm/L (range, 7 to 37) for all 14 patients. Nine patients are still receiving hydroxyurea for a median period of 23 months (range, 18 to 59). CONCLUSIONS: Hydroxyurea decreases the severity of anemia in some patients, and it may decrease the frequency of VOC. Its short-term hematologic toxicity is minimal.

Adolescent↗

PubMed1997

Effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia.

1. As an ancillary study carried out during the recently completed Multicenter Study of Hydroxyurea, we examined the effect of hydroxyurea on the body weight, body composition and exercise capacity of adult patients with sickle-cell anaemia. 2. The subjects received either hydroxyurea (six males and four females) or placebo (eight males and six females). Data for each subject were generated during four separate 24 h admissions to the General Clinical Research Center. These admissions occurred at baseline and then at 6, 12 and 18 months after the start of study drug (hydroxyurea or placebo) administration. During each admission, body composition was measured by using a dual X-ray absorptiometer, and exercise testing was performed by cycle ergometry. Anaerobic performance was assessed according to a 'Wingate' protocol (20 s at maximal intensity against a cycling resistance of 7.5% body weight). Aerobic performance was examined using a steady state submaximal exercise protocol (10 min cycling time). 3. At baseline, no significant difference in any parameter was found between the hydroxyurea- and placebo-treated groups. At 18 months, the hydroxyurea-treated subjects exhibited an average weight gain of 3.16 kg. The mean weight gain in the placebo-treated subjects was 1.82 kg. Body composition analysis showed that the additional weight in both groups involved both lean and fat body mass components. In anaerobic performance, the subjects given hydroxyurea showed an increase in peak muscle power of 104.9 W. The placebo group also showed an increase, but theirs was a more modest gain of 57.7 W. The most marked improvement in anaerobic performance was observed in the hydroxyurea-treated men (P < 0.05). In aerobic performance, the hydroxyurea-treated subjects exhibited a decrease in peak heart rate response to a standardized workload of 15.2 beats/min, as compared with a decrease of only 4.3 beats/min in the placebo-treated patients. 4. Taken together, the overall weight gain, combined with increases in both anaerobic muscular performance and aerobic cardiovascular efficiency, provides objective data to support the subjective impression that hydroxyurea administration produces an improvement in the physical capacity of patients with sickle-cell anaemia.

Adult↗

PubMed1990

Treatment of sickle cell anemia with hydroxyurea and erythropoietin.

BACKGROUND: Hydroxyurea increases the production of fetal hemoglobin (hemoglobin F) in patients with sickle cell anemia and therefore has the potential for alleviating both the hemolytic and vaso-occlusive manifestations of the disease. There is preliminary evidence that recombinant human erythropoietin may also increase hemoglobin F production. METHODS AND RESULTS: We treated five patients with sickle cell disease with escalating doses of intravenous erythropoietin for eight weeks. Three of these patients were subsequently treated with daily doses of oral hydroxyurea. After the optimal dose was determined, erythropoietin was then given along with hydroxyurea for four weeks. Treatment with erythropoietin, either alone or in combination with hydroxyurea, had no significant effect on the percentage of hemoglobin F-containing reticulocytes (F reticulocytes) or red cells (F cells). In contrast, hydroxyurea treatment was associated with a 3-to-25-fold increase in F reticulocytes, a 1.6-to-7-fold increase in F cells, and a 2.3-to-16-fold increase in the percentage of hemoglobin F. In all three patients given hydroxyurea, treatment with this drug was associated with reduced hemolysis, shown by decreases in serum bilirubin and lactic dehydrogenase and prolongation of red-cell survival. Hydroxyurea treatment also resulted in a decrease in the percentage of irreversibly sickled cells and sickling at partial oxygen saturation, an increase in oxygen affinity and total red-cell cation content, and a reduction in potassium-chloride cotransport. All three patients had a decrease in the number of pain crises. CONCLUSIONS: This study confirms that hydroxyurea therapy increases hemoglobin F production and provides objective evidence that hydroxyurea reduces the rate of hemolysis and intracellular polymerization of hemoglobin S. In contrast, recombinant human erythropoietin, whether alone or in combination with hydroxyurea, offers no measurable benefit.

Administration, Oral↗

PubMed2004

Chemical and functional analysis of hydroxyurea oral solutions.

The primary hypothesis of the upcoming NIH-sponsored phase III infant hydroxyurea (BABY HUG) trial is that hydroxyurea can prevent chronic organ damage in infants with sickle cell anemia. Since hydroxyurea is currently commercially available only in capsules, a liquid formulation of hydroxyurea is needed for young patients. Hydroxyurea oral solutions were prepared by dissolving the contents of the capsules in water (room temperature or mildly heated) with vigorous stirring, filtering excipients, and adding flavored syrup to a final concentration of 100 mg/mL. Chemical stability was determined by measuring the hydroxyurea concentration using a standardized analytical colorimetric analysis, while functional stability was determined by measuring the inhibition of phytohemagglutinin-induced T lymphocyte proliferation. Hydroxyurea oral solutions prepared using room-temperature water had statistically equivalent spectrophotometric concentration and inhibition of T-lymphocyte proliferation for 3 to 6 months. Mild heating of the water to facilitate dissolution of the hydroxyurea capsule contents resulted in a reduced concentration and inhibitory activity of the preparations. Hydroxyurea oral solutions (100 mg/mL) prepared and maintained at room temperature have chemical and functional stability for several months. Hydroxyurea oral solutions prepared and dispensed monthly are suitable for use in the upcoming infant BABY HUG trial.

Administration, Oral↗

PubMed1999

Hydroxyurea potentiates the antiherpesvirus activities of purine and pyrimidine nucleoside and nucleoside phosphonate analogs.

Hydroxyurea has been shown to potentiate the anti-human immunodeficiency virus activities of 2',3'-dideoxynucleoside analogs such as didanosine. We have now evaluated in vitro the effect of hydroxyurea on the antiherpesvirus activities of several nucleoside analogs (acyclovir [ACV], ganciclovir [GCV], penciclovir [PCV], lobucavir [LBV], (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine [H2G], and brivudin and nucleoside phosphonate analogs (cidofovir [CDV] and adefovir [ADV]). When evaluated in cytopathic effect (CPE) reduction assays, hydroxyurea by itself had little effect on CPE progression and potentiated in a subsynergistic (herpes simplex virus type 1 [HSV-1]) to synergistic (HSV-2) fashion the antiviral activities of ACV, GCV, PCV, LBV, H2G, ADV, and CDV. Hydroxyurea also caused marked increases in the activities of ACV, GCV, PCV, LBV, and H2G (compounds that depend for their activation on a virus-encoded thymidine kinase [TK]) against TK-deficient (TK(-)) HSV-1. In fact, in combination with hydroxyurea the 50% effective concentrations of these compounds for inhibition of TK(-) HSV-1-induced CPE decreased from values of 20 to > or = 100 microg/ml (in the absence of hydroxyurea) to values of 1 to 5 microg/ml (in the presence of hydroxyurea at 25 to 100 microg/ml). When evaluated in a single-cycle virus yield reduction assay, hydroxyurea at a concentration of 100 microg/ml inhibited progeny virus production by 60 to 90% but had little effect on virus yield at a concentration of 25 microg/ml. Under these assay conditions hydroxyurea still elicited a marked potentiating effect on the antiherpesvirus activities of GCV and CDV, but this effect was less pronounced than that in the CPE reduction assay. It is conceivable that the potentiating effect of hydroxyurea stems from a depletion of the intracellular deoxynucleoside triphosphate pools, thus favoring the triphosphates of the nucleoside analogues (or the diphosphates of the nucleoside phosphonate analogues) in their competition with the natural nucleotides at the viral DNA polymerase level. The possible clinical implications of these findings are discussed.

Animals↗

PubMed2003

The nitric oxide producing reactions of hydroxyurea.

Hydroxyurea is used to treat a variety of cancers and sickle cell disease. Despite this widespread use, a complete mechanistic understanding of the beneficial actions of this compound remains to be understood. Hydroxyurea inhibits ribonucleotide reductase and increases the levels of fetal hemoglobin, which explains a portion of the effects of this drug. Administration of hydroxyurea to patients results in a significant increase in levels of iron nitrosyl hemoglobin, nitrite and nitrate suggesting the in vivo metabolism of hydroxyurea to nitric oxide. Formation of nitric oxide from hydroxyurea may explain a portion of the observed effects of hydroxyurea treatment. At the present, the mechanism or mechanisms of nitric oxide release, the identity of the in vivo oxidant and the site of metabolism remain to be identified. Chemical oxidation of hydroxyurea produces nitric oxide and nitroxyl, the one-electron reduced form of nitric oxide. These oxidative pathways generally proceed through the nitroxide radical (2) or C-nitrosoformamide (3). Biological oxidants, including both iron and copper containing enzymes and proteins, also convert hydroxyurea to nitric oxide or its decomposition products in vitro and these reactions also occur through these intermediates. A number of other reactions of hydroxyurea including the reaction with ribonucleotide reductase and irradiation demonstrate the potential to release nitric oxide and should be further investigated. Gaining an understanding of the metabolism of hydroxyurea to nitric oxide will provide valuable information towards the treatment of these disorders and may lead to the development of better therapeutic agents.

Free Radicals↗

PubMed2003

Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.

CONTEXT: Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality. OBJECTIVE: To determine whether hydroxyurea attenuates mortality in patients with SCA. DESIGN: Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period. SETTING: Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada. PATIENTS: Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients. INTERVENTION: In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147). MAIN OUTCOME MEASURE: Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality. RESULTS: Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal. CONCLUSIONS: Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.

Adult↗

PubMed1978

Ribonucleotide reductase from wild type and hydroxyurea-resistant chinese hamster ovary cells.

The kinetic properties of partially purified ribonucleotide reductase from Chinese hamster ovary cells have been investigated. Double reciprocal plots of velocity against substrate concentration were found to be linear for three the substrates tested, and yielded apparent Km values of 0.12 mM for CDP, 0.14 mM for ADP and 0.026 mM for GDP. Hydroxyurea, a potent inhibitor of ribonucleotide reduction, was tested against varying concentrations of ribonucleotide substrates and inhibited the enzyme activity in an uncompetitive fashion. Intercept replots were linear and exhibited Ki values for hydroxyurea of 0.08 mM for CDP reduction, 0.13 mM for ADP reduction and 0.07 mM for GDP reduction. Guanazole, another inhibitor of ribonucleotide reductase, interacted with the enzyme in a similar manner to hydroxyurea showing an uncompetitive pattern of inhibition with CDP reduction and yielding a Ki value of 0.57 mM. Partially purified ribonucleotide reductase from hydroxyurea-resistant cells was compared to enzyme activity from wild type cells. Significant differences were observed in the hydroxyurea Ki values with the three ribonucleotide substrates that were tested. Also, CDP reductase activity from the drug-resistant cells yielded a significantly higher Ki value for guanazole inhibition than the wild type activity. The properties of partially purified ribonucleotide reductase from a somatic cell hybrid constructed from wild type and hydroxyurea-resistant cells was also examined. The Ki value for hydroxyurea inhibition of CDP reductase was intermediate between the Ki values of the parental lines and indicated a codominant expression of hydroxyurea-resistance at the enzyme level. The most logical explanation for these results is that the mutant cells contain a structurally altered ribonucleotide reductase whose activity is less sensitive to inhibition by hydroxyurea or guanazole.

Animals↗

PubMed1988

A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix. A preliminary report of a Gynecologic Oncology Group study.

Between June 1981 and December 1985, 296 evaluable patients with carcinoma of the cervix (stages IIB, III, or IVA) were randomized to radiation therapy and either hydroxyurea (139 patients) or misonidazole (157 patients). All patients had undergone clinical, radiographic, and surgical staging. Patients with metastasis to periaortic nodes were ineligible for study. Patients received external radiation therapy to the pelvis and either one or two intracavitary applications. Hydroxyurea was given in a dose of 80 mg/kg each Monday and Thursday during external radiation therapy. Misonidazole was given in a dose of 1 gm/m2 in the same schedule, not to exceed 12 gm/m2. Of the evaluable patients, 60.8% had stage IIB disease and 33.8% had stage IIIB disease. Negative pelvic lymph nodes were found in 79.2% of the patients. Median age was 49 years (first and third quartiles 40 and 60, respectively). There were 51 patients who had severe and 15 patients who had life-threatening adverse effects (including two treatment-related deaths). As of February 1987 half the patients have either failed or been followed-up for at least 43 months. The group treated with hydroxyurea had a longer progression-free interval, bordering on statistical significance, than those treated with misonidazole (p = 0.08). The median progression-free interval for all patients randomized to hydroxyurea is 42.9 months and for misonidazole it is 40.4 months. The median progression-free interval for patients with stage III and IV disease who received hydroxyurea has not been reached and for the misonidazole group it was 10.1 months. There have been 120 recurrences, 51 (36.7%) in the hydroxyurea group and 69 (43.9%) in the misonidazole group; 51.7% of the recurrences have been limited to the pelvis or vagina. Failure limited to the pelvis occurred in 18.0% of patients receiving hydroxyurea and 23.6% of patients receiving misonidazole. There were 108 deaths, 47 (33.8%) in the hydroxyurea group and 61 (38.9%) in the misonidazole group; survival does not differ statistically between the two regimens at this point in follow-up (p = 0.25). Hydroxyurea has more short-term gastrointestinal and marrow toxicity, but is free of long-term neurotoxicity. Preliminary analyses indicate that there is no role for radiation therapy with misonidazole in cervical carcinoma.

Adenocarcinoma↗

PubMed1990

DNA repair induced by various mutagens in rat hepatocyte primary cultures measured in the presence of hydroxyurea, guanazole or aphidicolin.

Guanazole and aphidicolin were chosen as candidates in the search for a selective, non-genotoxic inhibitor of DNA replication which could be used instead of hydroxyurea to measure DNA repair synthesis in rat hepatocyte primary cultures by liquid scintillation counting. The genotoxicity of these 3 chemicals was studied using the Salmonella/liver homogenate assay and the autoradiographic UDS test in hepatocytes. Hydroxyurea was positive in both of these assays. Guanazole and aphidicolin did not induce DNA repair in hepatocytes. Aphidicolin was not mutagenic for Salmonella typhimurium, whereas guanazole increased the revertant numbers of strain TA102 slightly. The incorporation of [3H]thymidine was measured by liquid scintillation to determine DNA repair induced by 2-acetylaminofluorene (2-AAF), aflatoxin B1, benzo[a]pyrene, cyclophosphamide, H2O2, 6-hydroxydopamine, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methylnitrosourea (MNU), 4-nitroquinoline-N-oxide and UV irradiation in the presence of either 10 mM hydroxyurea, 15 mM guanazole or 0.015 mM aphidicolin. Aphidicolin had an inhibitory effect on DNA repair. Except for the 3 chemicals mentioned below, the sensitivity of the DNA repair measurement was the same, no matter whether hydroxyurea or guanazole was used to inhibit replicative DNA synthesis. In the presence of hydroxyurea, DNA repair synthesis was found at lower concentrations in the case of aflatoxin B1, due to differences in the solvent control values, and in the case of H2O2, possibly due to a synergistic effect between hydroxyurea and H2O2. Guanazole allowed the detection of DNA repair induced by MNNG at lower concentrations, probably because of an antagonistic effect between hydroxyurea and MNNG. Based on these results, it was concluded that guanazole, but not aphidicolin, could be used instead of hydroxyurea to measure DNA repair synthesis by liquid scintillation in rat hepatocyte primary cultures. Although guanazole does not completely fulfill the criteria for an ideal DNA replication inhibitor, it has the advantage of being less genotoxic than hydroxyurea, and also appears to have a smaller potential to falsify the results by interacting with the test compounds.

Animals↗

PubMed1986

Changes in H1 content, nucleosome repeat lengths and DNA elongation under conditions of hydroxyurea treatment that reportedly facilitate gene amplification.

Depletion of histone H1, changes in nucleosome repeat lengths, and extents of DNA elongation were investigated in synchronized Chinese hamster (line CHO) cells using the general conditions of hydroxyurea treatment that appear to increase the frequency of gene amplification, i.e., synchronized cultures of G1 cells were allowed to begin to enter S phase before treatment with hydroxyurea was effected to retard DNA synthesis (Mariani, B.D. and Schimke, R.T. (1984) J. Biol. Chem. 259, 1901-1910). During the time that synchronized G1 cells begin to enter S phase, there occur considerable synchrony decay and accumulation of new DNA that increase with time before treatment with hydroxyurea is initiated. During exposure to hydroxyurea, there occur depletion of histone H1 and shortened repeat lengths for the DNA synthesized in the presence of hydroxyurea. In contrast, DNA synthesized in S phase before exposure to hydroxyurea has essentially the same repeat lengths as bulk chromatin at both the time that hydroxyurea treatment is effected and after 6 h in its presence. Sedimentation measurements indicate that the early replicating DNA undergoes considerable elongation both before and during 6 h of exposure to 0.3 mM hydroxyurea. Thus, nearly all of the early replicating DNA is elongated to greater than average replicon size under those conditions of hydroxyurea treatment that appear to favor gene amplification. Because the extents of DNA synthesis and cell cycle progression vary as functions of drug concentration, treatment times, and unknown factors (from experiment to experiment), it would appear that the parameters must be carefully monitored in each experiment if biochemical results are to be related to the position of cells in the growth cycle.

Animals↗

PubMed2002

Iron nitrosyl hemoglobin formation from the reactions of hemoglobin and hydroxyurea.

Hydroxyurea represents an approved treatment for sickle cell anemia and acts as a nitric oxide donor under oxidative conditions in vitro. Electron paramagnetic resonance spectroscopy shows that hydroxyurea reacts with oxy-, deoxy-, and methemoglobin to produce 2-6% of iron nitrosyl hemoglobin. No S-nitrosohemoglobin forms during these reactions. Cyanide and carbon monoxide trapping studies reveal that hydroxyurea oxidizes deoxyhemoglobin to methemoglobin and reduces methemoglobin to deoxyhemoglobin. Similar experiments reveal that iron nitrosyl hemoglobin formation specifically occurs during the reaction of hydroxyurea and methemoglobin. Experiments with hydroxyurea analogues indicate that nitric oxide transfer requires an unsubstituted acylhydroxylamine group and that the reactions of hydroxyurea and deoxy- and methemoglobin likely proceed by inner-sphere mechanisms. The formation of nitrate during the reaction of hydroxyurea and oxyhemoglobin and the lack of nitrous oxide production in these reactions suggest the intermediacy of nitric oxide as opposed to its redox form nitroxyl. A mechanistic model that includes a redox cycle between deoxyhemoglobin and methemoglobin has been forwarded to explain these results that define the reactivity of hydroxyurea and hemoglobin. These direct nitric oxide producing reactions of hydroxyurea and hemoglobin may contribute to the overall pathophysiological properties of this drug.

Electron Spin Resonance Spectroscopy↗

PubMed2002

Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease.

Hydroxyurea therapy reduces the rates of vaso-occlusive crisis in patients with sickle cell anaemia and recent data suggest that hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of hydroxyurea, as well as 10 patients not taking hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated- haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I3- reductants respectively). Consistent with NO release from hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored.

Adolescent↗

PubMed2005

Activator protein-1 (AP-1) DNA binding activity is induced by hydroxyurea in organogenesis stage mouse embryos.

Hydroxyurea is a potent teratogen; free radical scavengers or antioxidants reduce its teratogenicity. Activator Protein-1 (AP-1) and NF-kappaB are redox-sensitive transcription factors with important roles in normal development and the stress response. This study was designed to determine if exposure to teratogenic doses of hydroxyurea induces oxidative stress and alters gene expression by activating these transcription factors. Pregnant mice were treated with saline or hydroxyurea (400, 500, or 600 mg/kg) on gestation day 9 (GD 9) and killed either on GD 9, 0.5, 3, or 6 h after treatment, to assess oxidative stress and transcription factor activities, or on GD 18, to assess fetal development. Exposure to 400 mg/kg hydroxyurea did not affect the progeny, whereas exposure to 500 or 600 mg/kg resulted in dose-dependent increases in fetal resorptions and malformations, including curly tails, abnormal limbs (oligodactyly, hemimelia, and amelia), and short ribs. Hydroxyurea did not induce oxidative stress, as assessed by the ratio of oxidized to reduced glutathione, nor did it alter NF-kappaB DNA binding activity in the GD 9 conceptus. In contrast, exposure to hydroxyurea at any dose increased AP-1 DNA binding activity in embryos and yolk sacs 0.5 or 3 h after treatment. Hydroxyurea-induced c-Fos heterodimer activity in the embryo peaked 3-4-fold above control at 3 h and remained elevated by 6 h; in contrast, the activity of c-Jun dimers was not altered by drug exposure. A dramatic and region-specific increase in c-Fos immunoreactivity was found in hydroxyurea-treated embryos. The induction of AP-1 DNA binding activity by hydroxyurea represents an early, sensitive marker of the embryonic response to insult.

Animals↗

PubMed1997

Evaluation of continuous-infusion gallium nitrate and hydroxyurea in combination for the treatment of refractory non-Hodgkin's lymphoma.

Based on preclinical studies demonstrating synergy between gallium and hydroxyurea, we evaluated the efficacy and toxicity of continuous intravenous gallium nitrate in combination with oral hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients, median age 64 years (range 53-89), with stage III or IV low- or intermediate-grade lymphoma were treated with gallium nitrate and hydroxyurea in combination for 7 days at four different dose levels: (a) gallium nitrate, 200 mg/m2/day; hydroxyurea, 500 mg/day; (b) gallium nitrate, 250 mg/m2/day; hydroxyurea, 1,000 mg/day; (c) gallium nitrate, 300 mg/m2/day; hydroxyurea, 1,000 mg/day; and (d) gallium nitrate, 350 mg/m2/day, hydroxyurea, 1,000 mg/day. All patients had progressive disease and had been heavily pretreated. Six of 14 patients had objective tumor regression following treatment (one complete response, one near-complete response, and four partial responses) with a median duration of response of 7 weeks (range 3-38 weeks). An additional four patients had minor responses. Responses occurred at all dose levels and in both low- and intermediate-grade histologic subtypes. The predominant toxicities encountered were anemia and reversible nephrotoxicity. Combination gallium nitrate and hydroxyurea has significant activity in lymphoma and is well tolerated even by elderly patients. Because of the lack of cross-resistance to other drugs and the potential synergistic antineoplastic activity, gallium nitrate and hydroxyurea should be further evaluated in combination with other chemotherapeutic agents.

Aged↗

PubMed2000

Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea.

BACKGROUND: Sensory neuropathy is a common adverse effect of the nucleoside analogue anti-retroviral drugs didanosine (ddl) and stauvudine (d4T). These drugs are increasingly being used in combination, and it is not currently known whether the incidence of neuropathy is higher with combination compared to individual drug use. It is also not known if hydroxyurea, used to potentiate the antiviral efficacy of these drugs, may also increase the risk of neuropathy. The purpose of this analysis is to investigate if the combination of ddl and d4T, with or without hydroxyurea, has a higher incidence of neuropathy than a single drug regimen. METHODS: Data were obtained from patients followed longitudinally by the Johns Hopkins AIDS Services. Incidence rates of development of neuropathy were calculated for each of five regimens: ddl (+/- hydroxyurea), ddl + d4T (+/- hydroxyurea), and d4T. Cox proportional hazard regression was used to compare the relative risk of neuropathy for each regimen adjusting for CD4 cell count, other drugs received, and time on therapy. RESULTS: A total of 1116 patients received at least one of the five regimens. There were 117 cases of neuropathy. The crude incidence rate of neuropathy ranged from 6.8 cases per 100 person-years for ddl to 28.6 cases per 100 person-years for ddl + d4T + hydroxyurea. Compared with ddl alone, and adjusting for CD4 cell counts and other variables, the relative risk of neuropathy was 1.39 [95% confidence interval (CI): 0.84-2.32] for d4T alone, 2.35 (95% CI: 0.69-8.07) for ddl + hydroxyurea, 3.50 (95% CI: 1.81-6.77) for ddl + d4T, and 7.80 (95% CI: 3.92-15.5) for ddl + d4T + hydroxyurea. CONCLUSIONS: Based on the data, the risk of neuropathy is additive or even synergistic for ddl + d4T + hydroxyurea compared with ddl or d4T alone. The combination of ddl + d4T also increases the risk of neuropathy but less than when hydroxyurea is included.

Adult↗

PubMed2005

Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms.

BACKGROUND: The hydroxyurea-didanosine combination has been shown to limit immune activation (a major pathogenic component of HIV/AIDS) and suppress viral load by both antiviral and cytostatic ('virostatic') activities. Virostatics action represent a novel approach to attack HIV/AIDS from multiple directions; however, the use of these drugs is limited by the lack of understanding of their dose-dependent mechanism of action and by fear of pancreatic toxicity, even though a large review of ACTG studies has shown that hydroxyurea does not increase the incidence of pancreatitis. METHODS: In vitro cytostatic and cytotoxic activity, inhibition of viral replication and immune activation by pharmacologically attainable plasma concentrations of hydroxyurea (10-100 micromol/l) and didanosine (1-5 micromol/l) were analyzed by cell proliferation, viability, apoptosis and infection assays using peripheral blood mononuclear cells. In vivo, 600, 900 and 1200 mg daily doses of hydroxyurea in combination with standard doses of didanosine and stavudine were studied in 115 randomized chronically infected patients. RESULTS: A cytostatic low (10 micromol/l) concentration of hydroxyurea inhibited cell proliferation and HIV replication in vitro. A gradual switch from cytostatic to cytotoxic effects was observed by increasing hydroxyurea concentration to 50-100 micromol/l, predicting that lower doses of hydroxyurea would be less toxic and more potent in vivo. The clinical results confirmed that 600 mg hydroxyurea was better tolerated, had fewer side effects and was more potent in suppressing HIV replication than the higher doses. CONCLUSIONS: A bimodal, dose-dependent, cytostatic-cytotoxic switch is an immune-based mechanism explaining the apparent paradox that lowering the dose of hydroxyurea to 600 mg daily induces maximal antiviral suppression in HIV-infected patients.

Anti-HIV Agents↗