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PubMedDate not supplied

Toxicity and side effects of hydroxyurea used for primary thrombocythemia.

Over the last 20 years a vast array of data has been accumulated on the efficacy of hydroxyurea (HU) in patients with Philadelphia-negative myeloproliferative disorders (MPD). However, several side effects have been described as well. Besides many anecdotal reports, no evaluation of their prevalence and type exists in large series of treated patients. We report here the side effects of HU in a retrospective, single institution, cohort study of 152 patients suffering from MPD with thrombocytosis (median follow-up 8.13 years). In 6.5% of patients drug failure was registered. Unwanted side-effects (five symptomatic macrocytic anemia, two fever reactions, two allergic reactions, four cases each of leg painful ulcers, three acute leukemia or myelodysplasia) induced to withdraw therapy in 16 patients. Three cases of nail pigmentation were observed. In our experience, HU showed to be an effective and safe drug in most patients with MPD. Prompt recognition of side effects, which have been mostly minor and rapidly subsiding on drug withdrawal, is in any case crucial to avoid more severe complications.

Adult↗

PubMed2006

Secondary cutaneous effects of hydroxyurea: possible pathogenetic mechanisms.

We report the case of a 73-year-old man who had been on hydroxyurea for essential thrombocythemia since 1988. After 12 years of treatment he developed a symmetrical dermatomyositis-like eruption together with a leg ulceration and five squamous cell carcinomas of the face. The possible pathogenetic mechanisms of these known side effects are discussed.

Aged↗

PubMed1977

The effect of 60Co gamma-radiation and hydroxyurea on the in vivo chain growth of DNA in crypt cells of the small intestine of the mouse.

DNA chain growth has been studied in small intestinal crypt cells of the mouse in vivo using a sensitive method. The method is designed primarily to study radiation-induced DNA-breaks and their repair; but since there are breaks in DNA at the replicating fork, it is also possible to study DNA chain growth after a 3H-thymidine pulse. We found that DNA chain growth is not depressed by 200 rad of 60Co gamma radiation. This finding supports the hypothesis that irradiation interfers mainly with the initiation of new replicons in mammalian cells affecting DNA chain growth only at higher doses. Hydroxyurea at sufficient dosage, however, depresses or even stops DNA chain growth in mouse crypt cells in vivo.

Animals↗

PubMed1992

The yield of fission neutron-induced chromatid aberrations in G2-stage human lymphocytes: effect of caffeine, hydroxyurea and cytosine arabinoside post-irradiation.

To evaluate the influence of inhibitors of DNA synthesis/repair on the yield of chromosomal aberrations in the G2 phase of the cell cycle, whole-blood cultures of human lymphocytes were exposed to various doses of fission neutrons or X-rays and treated post-irradiation during the last 2.45 h before harvesting, with 5 mM caffeine, 5 mM hydroxyurea (HU) and 0.05 mM cytosine arabinoside (ara-C). The presence of caffeine and HU strongly potentiated the yield of chromatid-type aberrations induced by both neutrons and X-rays. No potentiating effect, except at the highest dose of neutrons, was observed when irradiated cells were subsequently treated with ara-C. Since ara-C strongly potentiated the frequency of chromatid aberrations induced in G2 lymphocytes by X-rays, the results presented here indicate that fission neutrons produce a smaller proportion of lesions, the repair of which can be inhibited by ara-C, compared with the number produced by X-rays. In addition, neutron-induced mitotic delay was shortened by treatment with caffeine, mainly within the first 2 h after irradiation.

Caffeine↗

PubMed2004

Plasma levels of TNF-alpha in sickle cell patients receiving hydroxyurea.

Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-alpha) from human macrophages in vitro and the concentration of TNF-alpha is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF-alpha and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count. Therefore, we examined the relationship between plasma levels of TNF-alpha and HbF in SCD patients during steady-state (StSt) conditions (in the absence of VOC) and during VOC conditions after the acute administration of HU. Venous blood was collected in SCD patients over 6 h after administering a single dose of HU. Plasma TNF-alpha was found to be greater in SCD subjects than in reported normal adult controls (p<0.05). TNF-alpha in the StSt group was not significantly different than in the VOC group; however, the plasma TNF-alpha tended to greater in the VOC group (p>0.1). An increase in the HbF concentration after acute administration of HU (p<0.01) was not associated with a significant change in plasma TNF-alpha (p>0.1). Contrary to the results of in vitro studies, HU did not increase the plasma concentration of TNF-alpha. These findings suggest that a HU-induced increase in TNF-alpha does not contribute to VOC and sickle cell patients can be counseled that the HU-induced increase in TNF-alpha does not counteract the beneficial effects of HU in SCD.

Adolescent↗

PubMed2005

Do alpha deletions influence hydroxyurea response in thalassemia intermedia?

Thalassemia intermedia patients show variable phenotypes. Hydroxyurea (HU) may benefit some of the thalassemia intermedia cases (1), however, the parameters influencing the response to HU have not been reported. In this study, the molecular parameters, alpha-globin and beta-globin genotype and the Xmn I polymorphism, were correlated with the HU response. Twenty patients with thalassemia intermedia were given HU (10-20 mg/kg) and responses were evaluated over a one year period. Twelve patients (60%) showed a good response to therapy with a significant increase in Hb and HbF levels and with elimination of the transfusion requirement in four patients. Four out of the twelve (33%) patients were positive for -alpha(3.7) deletions whereas none of the 8 non-responders were positive for alpha deletions. One each of the responders and non-responders were positive for alpha alpha alpha(anti-3.7) triplication. Three (25%) responsive and one non-responsive patients were homozygous for the IVS1-1 (G-->T) mutation. Three of the responsive patients with alpha deletions were also homozygous positive for Xmn I polymorphism. Thus, in addition to acting in synergy with the XmnI polymorphism, alpha deletions may be an independent factor predicting good response to HU in thalassemia intermedia, although this needs to be confirmation in larger studies.

Adolescent↗

PubMed2006

Effects of hydroxyurea and L-arginine on the production of nitric oxide metabolites in cultures of normal and sickle erythrocytes.

Previous in vitro studies suggest that erythrocytes may be a source of nitric oxide (NO) produced by nitric oxide synthase (NOS) or by oxyhemoglobin-mediated oxidation of hydroxyurea (HU). This study was performed to determine the roles of HU and NOS in the production of NO by normal and sickle erythrocytes. Red blood cells (RBCs) from normal adult hemoglobin (HbAA) and homozygous sickle cell subjects (HbSS) were incubated with PBS containing 0.2 mM hydrogen peroxide (control) for 2 h at 37 degrees C in the presence and absence of l-arginine, the substrate for NOS, and with l-arginine plus HU in the presence and absence of l-NMMA, a specific inhibitor of NOS. The nitrate and nitrite metabolites of NO, expressed as [NOx], were measured. [NOx] in the HbAA and HbSS RBC cultures was not significantly different in the presence and absence of 1.0 mM l-arginine (p>0.1). [NOx] in the HbAA and HbSS cultures treated with a clinically relevant dose of HU (1.0 mM) plus 1.0 mM l-arginine was significantly greater than that in controls incubated with PBS and with l-arginine p < 0.01. However, [NOx] in the HbAA and HbSS cultures treated with 50 microg/ml l-NMMA was not significantly different than that in the cultures treated with HU plus l-arginine in the absence of l-NMMA. These findings suggest that NOx production by erythrocytes may be increased by treatment with HU and may not be decreased by inhibiting NOS. Therefore, we conclude that a therapeutic dose of HU may increase the plasma concentration of NO by a mechanism that does not require erythrocytes NOS activity.

Adolescent↗

PubMed2003

Prognostic factor analysis in advanced gastric cancer patients treated with hydroxyurea, leucovorin, 5-fluorouracil, and cisplatin (HLFP regimen).

This study was performed to determine the prognostic factors of 102 nonresectable locally advanced or metastatic gastric cancer patients prospectively treated with a multimodulation of 5-fluorouracil (5FU), hydroxyurea, leucovorin, and cisplatin. Response rate in 85 patients with measurable disease was 62.4% (95% confidence interval 51.9% to 72.9%). A weight increase (5% or more) was observed in 47% of patients, performance status improved in 70.6%, and symptoms disappeared in 69%. Median times for progression-free survival and overall survival were eight and 11 months, respectively. Liver metastases, more than two involved sites, and increased carcinoembryonic antigen (CEA) were found to be univariate adverse prognostic factors for survival. In a multivariate analysis, only the presence of liver metastasis was found to be an independent prognostic factor. Response rate and survival in patients with gastric linitis or diffuse forms were in the same range as in patients with intestinal forms of gastric adenocarcinoma.

Adenocarcinoma↗

PubMed2003

Flow cytometric analysis of hydroxyurea effects on fetal hemoglobin production in cultures of beta-thalassemia erythroid precursors.

An increase in fetal hemoglobin (Hb F) ameliorates the clinical symptoms of the underlying disease in the beta hemoglobinopathies-sickle cell anemia and beta-thalassemia (thal). Hydroxyurea (HU) can elevate Hb F production in erythroid cells and is the agent currently in clinical use for patients with sickle cell anemia; it is presently being tested in clinical trials for thalassemia. We have developed a two-phase liquid culture system that mimics the in vivo hematological changes that are observed in patients treated with HU. Adding HU during the second phase of the culture increases the proportion of Hb F, increases the levels of total hemoglobin (Hb) content per cell and increases cell size, but it decreases the numbers of cells and the total amount of Hb produced. In the present study we developed and utilized a double labeling procedure for flow cytometric analysis of the cellular distribution of Hb F. Cells exposed to various concentrations of HU on day 6 of the second phase of the culture were harvested on day 12, and stained simultaneously with fluorochrome-conjugated monoclonal antibodies specific for human glycophorin A, an erythroid specific marker, and human Hb F. Both the percentage of the Hb F-containing cells and their intensity of fluorescence were recorded. The latter value gives a semi-quantitative estimation of the mean cellular Hb F content. The results indicated that cultures derived from different beta-thalassemic patients differ in their response to HU. In most patients, low doses of HU decreased the percentage of Hb F-cells as well as their Hb F content. At high doses, some patients showed an increase in both parameters, while others showed an increase in the percentage of Hb F-cells with minimal increase in their mean Hb F content, while still other patients showed little effect at all. In all patients, high doses of HU caused a decrease in cell numbers. These results suggest that HU has mixed effects on erythroid precursors. Both the two-phase liquid culture and the flow cytometric analysis procedures described herein provide the experimental tools for screening of Hb F-inducing drugs and for evaluating patients' cell response prior to treatment.

Adult↗

PubMed1999

Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir.

Current treatments for human immunodeficiency virus (HIV) require uninterrupted drug administration because they are unable to reconstitute the immune response and do not affect the viral reservoir. Ten patients were treated during acute HIV infection before complete Western blot (WB) seroconversion with the combination of hydroxyurea, didanosine, and indinavir. This treatment was associated with the normalization of some immune parameters and functions. No loss of naive CD4 T lymphocytes was observed, and recovery of up to 35% of naive CD8 T lymphocytes occurred in several weeks. A vigorous HIV-specific T helper response (stimulation index >8) was observed in 7 of 8 patients treated before complete WB seroconversion but in only 1 of 5 controls treated after seroconversion. In addition, a limited latent viral reservoir (<0.02-0.5 infectious units/106 cells) was documented in quiescent peripheral blood lymphocytes after treatment initiated before complete WB seroconversion.

Anti-HIV Agents↗

PubMed1997

Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy.

The pattern of mutations in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) strains that confer resistance to didanosine (ddI) was analyzed in 2 groups of patients receiving either ddI monotherapy or ddI plus hydroxyurea (HU) combination therapy. Twelve patients receiving combination therapy and 8 receiving monotherapy were tested. Combinations of ddI plus HU did not prevent the onset of mutations, which emerged in 50% of the patients in this group compared with 25% of the ddI monotherapy group. In addition, in 1 patient from the combination therapy arm, who had a limited response to the therapy, an unusual pattern of mutations was found: the insertion of 2 amino acids between residues 69 and 70, a region critical for resistance to nucleoside analogs. The higher efficacy of the combination of HU and ddI compared with that of ddI monotherapy cannot be attributed to a delayed or decreased onset of resistance to ddI.

Anti-HIV Agents↗

PubMed2004

Effect of adjunct hydroxyurea on helper T cell immunity in HIV type 1-infected patients with virological suppression.

Hydroxyurea (HU) has preferential activity in virus reservoirs not effectively targeted by current antiretroviral drug regimens, but concern for potential toxicity has precluded its routine use. The effect of adjunct HU on T cell proliferative responses and phenotypic markers was examined in a randomized study of 39 chronically HIV-1-infected patients with virological suppression on potent antiretroviral therapy. While patients in the HU arm showed modest declines in the median CD4(+) T cell counts (total, -151 cells/mm(3); naive, -91 cells/mm(3)), no significant differences were noted in the Candida, HIV-1 p24, and HIV-1 gp160 responses between the treatment arms following 24 weeks of therapy. In conclusion, although adjunct HU was associated with modest declines in the CD4(+) T cell counts, there was no significant adverse effect on helper T cell function. Further trials to address the role of HU in HIV-1 treatment may be appropriate after careful selection of HU dose and the adjunct drugs to avoid nonhematological toxicity.

Adult↗

PubMed1999

Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.

Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

Anti-HIV Agents↗

PubMed1999

Chloroquine exerts an additive in vitro anti-HIV type 1 effect when associated with didanosine and hydroxyurea.

Several groups, including ours, have reported that chloroquine (CQ) or its analog hydroxychloroquine has anti-HIV-1 activity both in vitro and in vivo. We studied in vitro whether the addition of CQ to the combination of hydroxyurea (HU) plus didanosine (ddI) had an additive effect in inhibiting the replication of HIV-1. Therefore both the H-9 T lymphocytic cell line and the U-937 promonocytic cell line as well as primary T cells and monocytes were infected with HIV-1 and then treated with HU at 0.2 mM and ddI at 1 microM and varying concentrations of CQ. Addition of CQ resulted in an additional inhibition of HIV-1 replication, as assessed by reverse transcriptase (RT) activity, with a CQ EC50 of 0.4-0.9 microM for the cell lines and of 0.2-0.9 microM for the primary cells. Similarly, addition of CQ further inhibited HIV-1 replication in U-1 cells stimulated either with LPS or H2O2 and in ACH-2 cells stimulated either with PMA or H2O2, with CQ EC50 values of 0.1 and 1 microM, respectively. Under the experimental conditions used, CQ induced neither toxicity nor apoptosis in the H-9 and U-937 cells. This in vitro additive anti-HIV-1 activity of CQ, in combination with HU + ddI, supports the idea that this triple regimen should be studied in clinical trials. It may become of particular interest to HIV-1-infected individuals from the developing world, in view of the low cost of both CQ and HU.

Anti-HIV Agents↗

PubMed1999

Immune restoration by combination of a cytostatic drug (hydroxyurea) and anti-HIV drugs (didanosine and indinavir).

Cell activation is essential for HIV infection. CD4+ T lymphocyte activation allows virus replication and CD8+ T lymphocyte activation may contribute to pathogenesis. We combined hydroxyurea, a cytostatic drug that inhibits cell activation and proliferation, with two drugs that inhibit HIV (didanosine and indinavir), to block the "cell activation-virus production-pathogenesis" cycle. HIV was strongly suppressed in treated patients, and the average CD4 count increased to 224/mm3. Compared with a matched group of patients who had declined antiretroviral treatment, treated patients had a significantly lower proportion of activated CD8+ T lymphocytes and a significantly higher number of naive CD8+ and CD4+ T lymphocytes. The proliferative responses to allogeneic and influenza virus antigens were increased in treated patients, and a defect in CD3-zeta expression, the signaling chain of the T cell receptor complex, was reversed. The use of a cytostatic drug was not detrimental to the immune system; on the contrary, the combination of antiviral and cytostatic treatment improved all of the immune parameters tested.

Anti-HIV Agents↗

PubMed2002

High-dose hydroxyurea plus G-CSF mobilize BCR-ABL-negative progenitor cells (CFC, LTC-IC) into the blood of newly diagnosed CML patients at any time of hematopoietic regeneration.

The objective of this study was to analyze the mobilization kinetics of normal (BCR-ABL(neg)) and malignant (BCR-ABL(pos)) progenitor cells using a new, low toxic, out-patient-based mobilization regimen for Philadelphia chromosome-positive (Ph(pos)) chronic myelogenous leukemia (CML) patients. High doses of hydroxyurea (HD-HU, 3.5 g/m(2) per day, orally for 7 days) followed by granulocyte colony-stimulating factor (G-CSF) (10 microg/kg subcutaneously) were administered to 11 newly diagnosed CML patients. Each apheresis product (n = 30) was individually analyzed for the number and genotype of mature colony-forming cells (CFC) and primitive long-term culture initiating cells (LTC-IC), respectively, by reverse transcription polymerase chain reaction (RT-PCR) of individual colonies. Sufficient numbers of CD34(+) cells/kg bodyweight (BW) could easily be obtained in all patients (median, 15 x 10(6)/kg BW per patient) with a median number of three aphereses performed per patient (range 2-4). Almost each apheresis itself (25/30) contained > or =2 x 10(6) CD34(+) cells/kg BW. All patients with low and intermediate Sokal risk indices (9/11) mobilized primarily BCR-ABL(neg) LTC-IC (median 92%, range 47-100) and CFC (median 89%, range 57-100). Moreover, the mean percentage of BCR-ABL(neg) CFC and LTC-IC in the various apheresis products in these patients did not change throughout the entire time of hematopoietic regeneration. The toxicity of the mobilization procedure was low. Side effects were mild erythema in 8/11 and oral mucositis in 3/11 patients. Overall, the low toxicity of this regimen, together with the fact that sufficient BCR-ABL(neg) progenitors can be collected throughout the entire period of hematopoietic regeneration, renders this mobilization regimen particularly attractive for the collection of BCR-ABL(neg) progenitors in early chronic phase of Ph(pos) CML.

Adult↗

PubMed1997

Didanosine but not high doses of hydroxyurea rescue pigtail macaque from a lethal dose of SIV(smmpbj14).

It has been previously reported that hydroxyurea (HU) displays anti-HIV-1 activity and potentiates the antiviral effects of didanosine (ddI) in vitro. To assess the antiviral efficacy of HU in an animal model, the effects of HU and ddI, either individually or as combination therapy, were tested in a model using infection of pigtail macaque with the acutely fatal variant SIV(smpbj14). At the high dosage used (100 mg/kg/day), HU monotherapy failed to protect the exposed animals from viral infection and death, which occurred within 10 days postinoculation. However, both of the ddI-treated animals (5 mg/kg/day) survived the SIV(smmpbj14) lethal dose and displayed a reduction in viral load (undetectable SIV RNA or p27gag) in the primary phase of infection. Of the animals treated with the combination of drugs, one died at day 18 after infection and failed to seroconvert to viral antigens. These data suggest that a high dose of HU monotherapy does not protect against death induced by SIV(mmpbj14). However, lower doses of HU as monotherapy or combination therapy deserve further evaluation for their therapeutic effects.

Animals↗

PubMed2004

Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307.

We performed a 24-week, placebo-controlled, comparative trial of hydroxyurea (HU) monotherapy, didanosine(ddI) monotherapy, and the combination of ddI plus HU administered as 1000 mg qd or 1500 mg qd in antiretroviral-naive and experienced subjects with CD4+ lymphocyte counts of 200-700 cells/mm3. Enrollment included 134 subjects. HU enhanced the antiviral activity of ddI by 1.0 log10 copies/ml after 8 weeks of therapy, with sustained responses over 24 weeks. HU alone over 4 weeks had no effect. Lamivudine resistance had little impact on antiretroviral activity when examined across treatment arms. Increases in absolute CD4+ T cell counts, but not CD4+ T cell percentages, were less in subjects who received HU compared to ddI monotherapy, and lymphoproliferative responses to antigenic and mitogenic stimuli were not altered. Subjects who received HU 1500 mg were more likely to experience dose-limiting hematological toxicities compared to those who received 1000 mg, without any additional antiviral benefit. HU may continue to have a role as a component of HIV therapy.

Anti-HIV Agents↗