HIV-1

Hydroxyurea treatment consistently lowers WBC and ANC without anemia improvement during a 17-week period. At 50 mg/kg, hydroxyurea creates a decreased white blood cell count, zero neutrophil count, and no improvement in anemia when compared to sickle cell mice receiving a vehicle treatment.

The same patients' erythroid cells from their peripheral blood are treated with hydroxyurea in vitro one year after they stopped taking it orally for two years, starting at a dose of 5 mg/kg/day for five days a week and increasing to a maximum of 10 mg/kg/day. Thirteen β-Thal/HbE patients receive this treatment.Cells are treated in primary culture for 96 hours with 30 μM hydroxyurea.

Absorption, Distribution and Excretion
After oral administration hydroxyurea is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients. After oral administration of 20 mg/kg of hydroxyurea, a rapid absorption is observed with peak plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with sickle cell syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg.h/L in children and adolescents and 135 mg.h/L in adult patients. The oral bioavailability of hydroxyurea is almost complete as assessed in indications other than sickle cell syndrome. In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxyurea oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxyurea oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p = 0.0467), indicating a faster rate of absorption.[L47137 In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p = 0.14).
A significant fraction of hydroxycarbamide is eliminated by nonrenal (mainly hepatic) mechanisms. In adults, the urinary recovery of unchanged drug is reported to be approximately 37% of the oral dose when renal function is normal. In children, the fraction of hydroxyurea excreted unchanged into the urine comprised about 50%.
Hydroxyurea distributes rapidly throughout the human body, enters the cerebrospinal fluid, appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of hydroxycarbamide approximates total body water. The volume of distribution following oral dosing of hydroxycarbamide is approximately equal to total body water: adult values of 0.48 – 0.90 L/kg have been reported, whilst in children a population estimate of 0.7 L/kg has been reported.
The total body clearance of hydroxyurea in adult patients with Sickle Cell Disease is 0.17 L/h/kg. The respective value in children was similar, 0.22 L/h/kg.
Hydroxyurea is readily absorbed from the GI tract. Peak serum concentrations are attained within 1-4 hours following oral administration. Blood concentrations decline rapidly and there is no cumulative effect with repeated administration. For this reason, higher blood concentrations are attained if the regular dosage is given in a large, single oral dose than if it is administered in divided doses. Disproportionate increases in peak plasma concentrations and areas under the concentration-time curve (AUCs) result when drug dosage is increased. The effect of food on the absorption of hydroxyurea has not been determined.
Hydroxyurea distributes rapidly throughout the body and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of the drug approximates total body water. Hydroxyurea crosses the blood-brain barrier; peak hydroxyurea CSF concentrations are attained within 3 hours following oral administration. The drug distributes into ascites fluid, resulting in drug concentrations in ascites fluid of 2-7.5 times less than plasma drug concentrations.
Studies using(14)C-labeled hydroxyurea indicate that about one-half an orally administered dose is degraded in the liver and is excreted as respiratory carbon dioxide and in urine as urea. The remaining portion of the drug is excreted intact in urine.
About 30-60% of an orally administered dose of hydroxyurea is excreted unchanged by the kidneys, although about 35% is generally excreted.
For more Absorption, Distribution and Excretion (Complete) data for HYDROXYUREA (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation to acetohydroxamic acid by urease found in intestinal bacteria.
Studies indicate that up to 50% of an orally administered dose of hydroxyurea is metabolized in the liver; however, the precise metabolic pathways have not been determined. A minor metabolic pathway may involve degradation of the drug by urease, an enzyme produced by intestinal bacteria. Acetohydroxamic acid, possibly resulting from the breakdown of hydroxyurea by urease, was detected in the serum of 3 patients with leukemia treated with hydroxyurea.
Hepatic.
Route of Elimination: Renal excretion is a pathway of elimination.
Half Life: 3-4 hours

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Biological Half-Life
In adult cancer patients, hydroxyurea was eliminated with a half-life of approximately 2-3 hours. In a single-dose study in children with Sickle Cell Disease, the mean half-life was reported to be 1.7 hours.
The half-time of hydroxyurea is short, with an initial half-time of 0.63 hr after intravenous administration and 1.78 hr after oral administration and a terminal half-time of 3.32 hr after oral administration and 3.39 hr after intravenous administration /to humans/.
The half-time of hydroxyurea in rats given 137 mg/kg bw per day intraperitoneally on days 9-12 of gestation was 15 min in the dams and 85 min in the embryos. In rhesus monkeys given 100 mg/kg bw per day intravenously on days 23-32 of gestation, the half-time was 120 min after the last injection in the mothers and 265 min in their fetuses.

Toxicity Summary
IDENTIFICATION AND USE: Hydroxyurea is a white, crystalline powder. It is a drug indicated for the following uses: the treatment of resistant chronic myeloid leukemia; treatment of locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation; the palliative treatment of sickle cell anemia generally in patients with recurrent moderate to severe painful crises occurring on at least 3 occasions during the preceding 12 months (designated an orphan drug by the US Food and Drug Administration for this use). HUMAN EXPOSURE AND TOXICITY: During a 2-year period, 26 patients taking hydroxyurea for more than 6 months who had consultations at the dermatology department were systematically examined regarding cutaneous side effects. All but one had cutaneous side-effects, including dryness, moderate alopecia, increased skin pigmentation, melanonychia, cutaneous atrophy, leg ulcers, plantar keratoderma, pseudodermatomyositis, lichen planus-like eruption on the dorsum of the hands actinic keratosis, squamous cell carcinomas, and mouth ulcerations. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic failure were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine (note: hydroxyurea is not indicated for the treatment of HIV infection). In one case of an 85-year-old man taking hydroxyurea for chronic myelomonocytic leukemia, severe interstitial pneumonitis was induced by the drug. Gangrene of the toes and digits is a rare but very severe complication of long-term hydroxyurea therapy. A retrospective review of four adult men who had semen analysis during hydroxyurea therapy and in three cases after its cessation, suggests that the drug generally reduces sperm counts and motility and results in abnormal morphology. Hydroxyurea induced DNA hypermethylation in normal human embryonic lung fibroblasts and their simian virus 40-transformed counterparts. While cancer has been observed in some patients receiving long-term treatment with hydroxyurea, the drug is not yet classifiable as to its carcinogenicity to humans. ANIMAL STUDIES: Symptoms of exposure in dogs have included vomiting, ataxia, methemoglobinemia, tachycardia, lethargy, and hypothermia. Groups of 50 mice of each sex were treated intraperitoneally with hydroxyurea starting at two days of age and then at weekly intervals for one year. The incidences of pulmonary tumors were 30/50 (60%) in control and 16/35 (46%) in treated mice. Hydroxyurea is a swiftly acting developmental toxicant that inhibits DNA synthesis and is teratogenic in all mammals studied. Data from a study on mice suggest that hydroxyurea compromises folliculogenesis and the ability of generated embryos to develop. A group of 27 pregnant golden hamsters received an intravenous injection of 50 mg/kg bw hydroxyurea on day 8 of pregnancy. A high rate of fetal death and malformations, especially of the central nervous system, was observed. Hydroxyurea caused cell transformation in mass cultures of embryonic cells from mice, but not in cultures derived from two other strains of mice, nor in BALB/c 3T3 cells. Hydroxyurea treatment led to hypermethylation of DNA in hamster fibrosarcoma cells. Hydroxyurea was inactive as either a frameshift or base-pair substitution mutagen in Salmonella typhimurium strains TA1537, TA1535, TA98 and TA100, and addition of an exogenous metabolic activation system did not affect these results. Hydroxyurea induced SOS repair in Escherichia coli K12 cells. In various Saccharomyces cerevisiae strains, hydroxyurea induced mitotic crossing over, mitotic gene conversion, intrachromosomal recombination and aneuploidy, but not petite mutations. It also increased the frequency of ultraviolet-induced mitotic gene conversion and induced recombination in dividing but not G1 or G2 arrested cells of the RS112 strain of yeast. In meiotic yeast cells, hydroxyurea increased the frequency of meiotic recombination. Hydroxyurea induced micronuclei in the bone marrow of non-tumor-bearing male NMRI mice but did not induce micronucleated cells in female C57BL/6 C3H/He hybrid mice, although it produced sperm abnormalities in male mice of this strain.
Hydroxyurea is converted to a free radical nitroxide (NO) in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replicase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea also increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia. Levels of fetal hemoglobin increase in response to activation of soluble guanylyl cyclase (sGC) by hydroxyurea-derived NO.

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Toxicity Data
Oral, mouse: LD₅₀ = 7330 mg/kg; Oral, rat: LD₅₀ = 5760 mg/kg

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Interactions
The purpose of this analysis is to investigate if the combination of didanosine and stauvudine, with or without hydroxyurea, has a higher incidence of neuropathy than a single drug regimen. 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: didanosine (+/- hydroxyurea), didanosine + stauvudine (+/- hydroxyurea), and stauvudine. 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. 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 didanosine to 28.6 cases per 100 person-years for didanosine + stauvudine + hydroxyurea. Compared with didanosine 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 stauvudine alone, 2.35 (95% CI: 0.69-8.07) for didanosine + hydroxyurea, 3.50 (95% CI: 1.81-6.77) for didanosine + stauvudine, and 7.80 (95% CI: 3.92-15.5) for didanosine + stauvudine + hydroxyurea. Based on the data, the risk of neuropathy is additive or even synergistic for didanosine + stauvudine + hydroxyurea compared with didanosine or stauvudine alone. The combination of didanosine + stauvudine also increases the risk of neuropathy but less than when hydroxyurea is included.
Concomitant therapy with hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse effects, and dosage adjustment may be required.
Because hydroxyurea therapy may cause increased serum uric acid concentrations, dosage adjustment of uricosuric medication may be required.
The antitumor activity of hydroxyurea can be potentiated by the addition of iron-chelating agents and prevented by the addition of Fe2+ to the medium.
For more Interactions (Complete) data for HYDROXYUREA (7 total), please visit the HSDB record page.

[1]. Clin Infect Dis . 2000 Jun:30 Suppl 2:S193-7.

[2]. Clin Infect Dis . 2000 Jun:30 Suppl 2:S143-50.

[3]. Exp Hematol . 2005 Dec;33(12):1486-92.

[4]. Gene Ther . 2002 Aug;9(15):1023-30.

Therapeutic Uses
Antineoplastic Agents; Antisickling Agents; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Hydroxyurea is included in the database.
Hydroxyurea Capsules USP are indicated for the treatment of: Resistant chronic myeloid leukemia. Locally advanced squamous cell carcinomas of the head and neck (excluding the lip) in combination with chemoradiation. /Included in US product label/
Hydroxyurea has been used in the treatment of psoriasis and is reportedly beneficial in the treatment of hypereosinophilic syndrome that does not respond to corticosteroid therapy. /NOT included in US product label/
For more Therapeutic Uses (Complete) data for HYDROXYUREA (12 total), please visit the HSDB record page.

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Drug Warnings
Hydroxyurea is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. Hydroxyurea therapy may be complicated by severe, sometimes life-threatening or fatal, adverse effects. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents or the use of this agent for sickle cell anemia.
Hydroxyurea should be admin with caution to patients who have recently received other cytotoxic drugs or irradiation therapy, since bone marrow depression is likely in these patients. In addition, an exacerbation of post-irradiation erythema may occur.
Hepatotoxicity, in some cases resulting in fatal hepatic failure, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral agents. Fatal hepatotoxicity occurred most frequently in patients receiving combination therapy with hydroxyurea, didanosine, and stavudine. Elevation of serum concentrations of hepatic enzymes has been reported in patients receiving hydroxyurea.
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients receiving hydroxyurea for myeloproliferative disorders, particularly in patients who have received or who are receiving interferon therapy.
For more Drug Warnings (Complete) data for HYDROXYUREA (37 total), please visit the HSDB record page.

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Pharmacodynamics
The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known.

CH4N2O2

76.05

76.027

C, 15.79; H, 5.30; N, 36.83; O, 42.07

127-07-1

3657

White to off-white solid powder

1.5±0.1 g/cm3

222.1±23.0 °C at 760 mmHg

135-140 °C

88.1±22.6 °C

0.0±1.0 mmHg at 25°C

1.501

-1.8

3

2

0

5

42.9

0

O([H])N([H])C(N([H])[H])=O

VSNHCAURESNICA-UHFFFAOYSA-N

InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4)

hydroxyurea

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (32.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (32.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (32.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (1314.92 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)