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PubMed1995

[Modification of pyrimidine nucleosides using nicotinic acid derivatives].

Interaction of nicotinoyl chloride in situ with 2'-deoxyuridine, its 3'-O-acetyl-, or 5'-O-trityl derivatives led to 3'-O-nicotinoyl-, 5'-O-nicotinoyl-, 3',5'-di-O-nicotinoyl-, and N3,3'-di-O-nicotinoyl-2'-deoxyuridine. Similarly, 5'-O-nicotinoyl-6-azauridine resulted from the reaction of 2',3'-O-ethoxymethylidene-6-azauridine followed by the deprotection. Reaction of 5'-amino-5'-deoxy-2',3'-O-ethoxymethylidene-6-azauridine with nicotinic acid in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline followed by the cleavage of the 2',3'-O-protecting group gave 5'-deoxy-5'-nicotinamido-6-azauridine. The same compound was obtained from 5'-amino-5'-deoxy-6-azauridine and N-succinimidyl nicotinate. Structures of the compounds obtained were corroborated by 1H NMR spectra. It is shown that 3',5'-di-O-nicotinoyl-2'- deoxyuridine and 5'-deoxy-5'-O-nicotinamido-6-azauridine are cytotoxic toward CaOv cells in vitro (CE50 10(-5) M).

Antineoplastic Agents↗
PubMed1995

[Interaction of derivatives of 3-(indol-3-yl)propionic, nicotinic, and 1-nitroanthraquinone-2-carboxylic acid with pyrimidine nucleosides and their 5'-amino-5'-deoxy analogs].

The reaction of 5'-amino-2',5'-dideoxyuridine and 5'-amino-5'-deoxy-2',3'-O-ethoxymethyliden-6- azauridine with 3-(3-indolyl)propionic or 1-nitroanthraquinon-2-carboxylic acids in THF in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) resulted in the corresponding amide derivatives. The reaction conditions of the standard procedure for the removal of the O-alkylidene protecting group turned out to be too severe for the 5'-N-acylamide derivatives of 6-azauridine. 5'-Deoxy-5'-[3-(3-indolyl)propionyl-amino]-6-azauridine was synthesized from 5'-amino-5'-deoxy-6-azauridine and 3-(3-indolyl)propionic acid in THF in the presence of EEDQ. A reaction between 5'-O-tosyl-2',3'-O-ethoxymethyliden-6-azauridine and 3-aminopropanol gave 3-(3-hydroxypropylamino)-2-(2',3'-O-ethoxymethylidene-beta- D-ribofuranosyl)-as-triazine-5(2H)-one, the structure of which was confirmed also by synthesis from O2,5'-anhydronucleoside and 3-aminopropanol followed by further chemical transformations. A reaction of 3-(3-hydroxypropylamino) derivative obtained with nicotinoyl chloride prepared in situ, or with 1-nirtoanthraquinon-2-carboxylic acid in the presence of DCC with subsequent deprotection, afforded 3-[(3-pyridin-3-ylcarboxy)propylamino]- or 3-[3-(1-nitroanthraquinon-2-carboxy)propylamino]-2-beta-D-ribof ura nosyl-as- triazine-5(2H)-one, respectively. Structures of the nucleosides prepared were examined by 1H NMR spectroscopy. 2',5'-Dideoxy-5'-[(1-nitroanthraquinon-2-carbonyl)amino]uridine at a 10(-4) M concentration was shown to inhibit thymidine incorporation into cell DNA (CE50 10(-5) M) by 72%.

Amines↗
PubMed1978

Molecular orbital studies on nucleoside analogs. II. Conformation of 6-azapyrimidine nucleosides.

PCILO (Perturbative Configuration Interaction using Localised Orbitals) computations have been carried out for three 6-azapyrimidine nucleosides, 6-azauridine, 6-azacytidine and 6-azathymidine, for both C(2')-endo and C(3')-endo pucker of the sugar ring. The results indicate a syn (chiCN=180 degrees) conformation followed by chiCN=90 degrees and gg conformation for C(3')-endo 6-aza analogs as compareed to the anti (chiCN=0 degrees) and gg conformation preferred by the corresponding pyrimidine nucleosides. For C(2')-endo sugar geometry, 6-azauridine and 6-azacytidine prefer, respectively, chiCN=0 degrees (anti) and phi C(4')-C(5')=60 degrees C (gg) and chiCN-240 degrees (syn) and phi C(4')-C(5')=120 degrees. The corresponding nucleosides, uridine and cytidine, show a preference for syn (chiCN=240 degrees) and gg and anti(chiCN=0 degrees) and gg , respectively. The X-ray crystallographic conformations of 6-azauridine and 6-azacytidine have been attributed to intermolecular hydrogen bonding and crystal packing forces. The results of PMR, CD and ORD studies on 6-azauridine and 6-azacytidine in aqueous solutions are in agreement with the PCILO predictions.

Azacitidine↗
PubMed2002

Identification of active antiviral compounds against a New York isolate of West Nile virus.

The recent West Nile virus (WNV) outbreak in the United States has increased the need to identify effective therapies for this disease. A chemotherapeutic approach may be a reasonable strategy because the virus infection is typically not chronic and antiviral drugs have been identified to be effective in vitro against other flaviviruses. A panel of 34 substances was tested against infection of a recent New York isolate of WNV in Vero cells and active compounds were also evaluated in MA-104 cells. Some of these compounds were also evaluated in Vero cells against the 1937 Uganda isolate of the WNV. Six compounds were identified to be effective against virus-induced CPE with 50% effective concentrations (EC50) less than 10 microg/ml and with a selectivity index (SI) of greater than 10. Known inhibitors of orotidine monophosphate decarboxylase and inosine monophosphate dehydrogenase involved in the synthesis of GTP, UTP, and TTP were most effective. The compounds 6-azauridine, 6-azauridine triacetate, cyclopententylcytosine (CPE-C), mycophenolic acid and pyrazofurin appeared to have the greatest activities against the New York isolate, followed by 2-thio-6-azauridine. Anti-WNV activity of 6-azauridine was confirmed by virus yield reduction assay when the assay was performed 2 days after initial infection in Vero cells. The neutral red assay mean EC50 of ribavirin was only 106 microg/ml with a mean SI of 9.4 against the New York isolate and only slightly more effective against the Uganda isolate. There were some differences in the drug sensitivities of the New York and Uganda isolates, but when comparisons were made by categorizing drugs according to their modes of action, similarities of activities between the two isolates were identified.

Amides↗
PubMed1989

Inhibitory effect of selected antiviral compounds on measles (SSPE) virus replication in vitro.

A variety of antiviral compounds were examined for their inhibitory effect on measles (SSPE) virus plaque formation in VERO cells. The following compounds inhibited SSPE virus (strain Niigata-1) replication at concentrations that were significantly lower than their minimum cytotoxic concentrations: neplanocin A, neplanocin C, carbocyclic 3-deazaadenosine, 9-(trans-2', trans-3'-dihydroxycyclopent-4'-enyl)adenine, 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine, (RS)-3-adenin-9-yl-2-hydroxypropanoic acid isobutyl ester, carbodine, cyclopentenyl cytosine, 3-deazaguanine, pyrazofurin, ribavirin and 6-azauridine. As the most selective inhibitors of SSPE virus replication emerged pyrazofurin, 3-deazaguanine, 6-azauridine and ribavirin. These compounds were further examined for their relative potency against a number of measles (SSPE) virus strains. Their order of (decreasing) potency was pyrazofurin greater than 6-azauridine approximately 3-deazaguanine greater than ribavirin. Amantadine, inosiplex and glycyrrhizin, that were also included in these assays, did not show appreciable activity against any of the measles (SSPE) virus strains.

3-Deazauridine↗
PubMed1979

The thrombogenicity of 6-azouridine.

The antimetabolite 6-azauridine blocks the de novo synthesis of pyrimidines and causes increased serum levels of several amino acids including homocystine. 6-Azauridine was was withdrawn from clinical use for the treatment of psoriasis because of the occurence of arterial and venous thromboembolic episodes in some psoriatic patients. Utilizing a standard animal model for the recognition of venous and arterial thrombosis, 6-azauridine was demonstrated in this study to cause thrombosis without producing homocystinemia when administered orally or intravenously.

Administration, Oral↗
PubMed1977

Uridine triphosphate deficiency, growth inhibition, and death in ascites hepatoma cells induced by a combination of pyrimidine biosynthesis inhibition with uridylate trapping.

A selective deficiency of uridine triphosphate (UTP) was induced in AS-30D rat ascites hepatoma cells by the synergistic action of D-galactosamine and 6-azauridine. The resistance of these hepatoma cells to low concentrations of D-galactosamine (less than 2 mM) was due to their active de novo pyrimidine synthesis which compensated the trapping of uridylate in the form of uridine diphosphate-amino sugars derived from D-galactosamine. The additional blockage of de novo pyrimidine synthesis led to noncompensated uridylate trapping with a UTP content of less than 0.05 mmole/kg of cell wet weight as compared to the control level of 0.66 mmole/kg. The induction of UTP deficiency by incubating the cells with low concentrations of D-galactosamine and 6-azauridine (0.5 mM each) was not accompanied by significant changes in the content of adenine and guanine nucleotides, uridine diphosphate glucose, and uridine diphosphate galactose. The depletion of UTP pools could be reversed within 10 min by the addition of uridine; orotate or uracil were completely ineffective in these hepatoma cells. A UTP content in the range of 0.1 to 0.4 mmole/kg, induced by either 6-azauridine or D-galactosamine, was associated with a reversible depression of cell growth in suspension culture. A UTP content below 0.05 mmole/kg led to irreversible growth inhibition and to necrocytosis in culture, as well as to a loss of transplantability in vivo. Uridine reversal studies indicated that the percentage of cells able to resume growth in culture decreased with an increasing time period of UTP deficiency. The deficiency period required for irreparable or lethal damage in these hepatoma cells ranged from 3 to 20 hr. The principle of noncompensated uridylate trapping can be extended to other inhibitors of nucleotide synthesis combined with various nucleotide-trapping sugar analogs. Noncompensated nucleotide trapping may be useful for an induction of selective nucleotide deficiencies in tumor cells.

Animals↗
PubMed1989

Orotic aciduria fibroblasts express a labile form of UMP synthase.

Orotic aciduria (type 1) results from a mutation in the gene for UMP synthase, a bifunctional protein containing the two enzyme activities which convert orotic acid and 5-phosphoribosyl-1-pyrophosphate to UMP and CO2. In fibroblasts from individuals with orotic aciduria, these two enzymatic activities are about 1% of normal but increase dramatically when deficient cells are grown in the presence of 6-azauridine. Using a polyclonal antiserum to sodium dodecyl sulfate-denatured, pure human UMP synthase, we show that fibroblasts from a patient with orotic aciduria have a low level of immunoreactive UMP synthase protein. Pulse-chase analysis reveals that the UMP synthase is degraded rapidly in the deficient cells. Growth of deficient cells in 6-azauridine leads to an increase in UMP synthase protein and its two enzymatic activities via a decreased rate of proteolytic degradation of UMP synthase. UMP synthase in extracts from deficient cells is more readily denatured by heat and is stabilized after growth of cells in 6-azauridine. These data suggest that the detrimental deficiency of this one patient results from a structurally altered UMP synthase that is probably present in low steady-state amounts due to proteolysis and that this labile protein can be stabilized against heat denaturation and proteolytic degradation by 6-aza-UMP.

Azauridine↗
PubMed1989

Cytogenetic analysis of amplification and deamplification of UMP synthase genes in Chinese hamster cells.

Chinese hamster lung cells selected for resistance to pyrazofurin and 6-azauridine contain amplified UMP synthase genes. With selection in 5-fluorouracil, cells that have lost the amplified gene copies can be isolated. Reselection of deamplified cells in pyrazofurin and 6-azauridine results in reamplification of the UMP synthase genes. We have used chromosomal banding and in situ hybridization techniques to characterize this cyclic process of amplification and deamplification. Homogeneously staining regions (HSRs) were observed in cells containing amplified copies of the UMP synthase gene but not in cells in which the amplified UMP synthase genes had been lost. After reselection in pyrazofurin and 6-azauridine, abnormally banded regions (ABRs) were observed. Both HSRs and ABRs were located at a single site on the distal regions of a small acrocentric autosome, and both were shown to contain the amplified genes. The majority of 5-fluorouracil-selected cells showed residual marker acrocentric chromosomes of various sizes, suggesting excision of portions of the HSR or ABR as the mechanism of deamplification. The acrocentrics carrying the amplified genes resulted from rearrangements involving chromosome 4, site of the endogenous gene. This reversible selection system provides a unique model for investigating gene amplification and deamplification in association with chromosomal rearrangements and the relationship of G-banding to underlying DNA structure.

Animals↗
PubMed1976

Photochemical studies and ultraviolet sensitization of Escherichia coli thymidylate kinase by various halogenated substrate analogs.

The effect of 5-iodo-2'-deoxyuridine monophosphate (IdUMP), various 5-halogenated-5'-azido-2', 5' -dideoxyuridine derivatives, 2'-deoxy-6-azauridine (AzdUrd), and its halogenated analogs on the ultraviolet sensitization of Escherichia coli thymidylate kinase has been investigated. Only those compounds iodinated in position 5 enhance the rate of ultraviolet inactivation of this enzyme. However, 5'-azido nucleosides with iodo, bromo, chloro, or fluoro substituents in position 5 neither protect nor sensitize thymidylate kinase to ultraviolet inactivation. Thymidine 5'-monophosphate partially protects the enzyme against ultraviolet inactivation either in the presence or absence of ultraviolet-sensitizing iodinated analogs. Magnesium ion does not enhance the ultraviolet inactivation of thymidylate kinase by 5-iodinated nucleoside analogs. The kinatic data support an active site-directed enhancement of the enzyme to ultraviolet inactivation by 5-iodo-2'-deoxyuridine monophosphate, since the concentration of IdUMP required to attain 50% maximal enhancement is 0.24 mM which is in good agreement with its Ki of 0.18 mM. When either [125I]IdUMP or [2-14C]IdUMP was irradiated with the enzyme, both radioactivities were associated with the enzyme, however only with the 14C analog was the amount bound at half-saturation essentially equal to the amount required to inactivate the enzyme by 50%. These data support the hypothesis that the active entity in the enhancement by IdUMP of thymidylate kinase inactivation during ultraviolet irradiation is the uridylate free radical which is formed photochemically from IdUMP. Photochemical studies of 6-azauracil (AzUra), 2'-deoxy-6-azauridine, and 5-iodo-2'-deoxy-6-azauridine (IAzdUrd) were performed. Photolysis of IAzdUrd in the presence of a hydrogen donor yields AzdUrd which upon further photolysis yields the photohydrate. The photohydrate of AzdUrd when incubated in the dark at pH 5.2 is 90% converted back to AzdUrd, whereas the photohydrate of AzUra is only partially (20%) converted to AzUra. The rate of deiodination of IAzdUrd is 2.1-fold greater than that of IdUMP. Although the Ki of IdUMP and IAzdUrd is similar, the increased photosensitivity of the aza analog accounts for the much greater enhancement of ultraviolet inactivation of thymidylate kinase. The ability of a compound to enhance the ultraviolet inactivation of deoxythymidylate kinase is correlated with the potential of the compound to produce a free radical rather than a photohydrate when the enzyme-substrate analog complex is irradiated.

Escherichia coli↗
PubMed1989

A reversible selection system for UMP synthase gene amplification and deamplification.

The bifunctional enzyme UMP synthase provides a unique reversible selection system whereby cells that have amplified the UMP synthase gene can be isolated from a wild-type population and cells that have deleted the extra genes can be selected from a population with amplified copies of the gene. UMP synthase catalyzes the conversion of orotic acid to orotidine 5'-monophosphate (OMP) and then OMP to UMP. In the amplification step, Chinese hamster lung cells are selected for resistance to pyrazofurin and 6-azauridine, two inhibitors of the orotidine 5'-decarboxylase activity that converts OMP to UMP. The resistant cells have increased levels of both activities of UMP synthase as a result of a stable amplification of the UMP synthase gene. The deamplification step depends on 5-fluorouracil (5FU), which is converted to its monophosphate form by the orotate phosphoribosyltransferase activity of UMP synthase. Thus cells with increases in this activity are more sensitive to 5FU cytotoxicity, permitting single-step selection of revertants that have lost their amplified UMP synthase genes. These 5FU-selected cells are similar to the parental cell line in their level of UMP synthase activity and number of UMP synthase gene copies. Reselection in increasing concentrations of pyrazofurin and 6-azauridine allows one to isolate cells that have reamplified the UMP synthase gene. The ability to cycle cells of a single lineage through states of amplification and deamplification will facilitate study of the gene amplification process and the factors that influence the composition and stability of amplified regions.

Amides↗
PubMed1985

Azapyrimidine nucleosides: metabolism and inhibitory mechanisms.

Triazine nucleosides represent highly active compounds affecting different cellular processes. While 6-azauridine displays a rather selective inhibitory effect, biological action of 5-azacytidine reflects the polyvalent inhibitory mechanism of the drug (interaction with pyrimidine synthesis de novo, incorporation into RNA and DNA, depressed maturation of ribosomal RNA, inhibition of RNA and DNA methylation, etc.) and the analog displays pronounced cytostatic and immunosuppressive activity. 5-Aza-2'-deoxycytidine action is directed against DNA synthesis similar to that of 5-azacytosine arabinoside. N4-Substituted derivatives of 5-azacytidine affect gastric secretion and together with 5-azacytosine and 5-azacytidine represent a new type of drugs with antiulcer activity. 6-Amino-5-azacytosine nucleosides interfere with the metabolism of purines rather than pyrimidines as evidenced by the character of their inhibitory mechanism and measurement of conformation. 6-Azauridine (as 2',3',5'-triacetate) and 5-azacytidine were used with certain success in human chemotherapy, the first one as a drug affecting recalcitrant psoriasis, the second one for the treatment of different forms of leukemia. The inhibitory mechanisms of individual azapyrimidine nucleosides are discussed in relation to their known biological effects.

Animals↗
PubMed2004

In vitro inhibition of Chikungunya and Semliki Forest viruses replication by antiviral compounds: synergistic effect of interferon-alpha and ribavirin combination.

Chikungunya virus (CHIKV) and Semliki Forest virus (SFV) were used in our laboratory to screen active antiviral compounds against viruses of the Alphavirus genus. Antiviral activity was estimated by the reduction of the cytopathic effect of each alphavirus on infected Vero cells and by virus titer reduction. Cytotoxicity was evaluated by determining the inhibition of Trypan blue exclusion in confluent cell cultures and by the evaluation of the inhibitory effect on cell growth. With CHIKV and SFV, the selectivity indices of human recombinant interferon-alpha and iota-carrageenan were much higher than that of ribavirin, which has been previously investigated for its inhibitory effect on alphavirus infections. Compared to ribavirin, 6-azauridine was more effective against CHIKV and showed a similar antiviral activity against SFV. IFN-alpha2b, glycyrrhizin, 6-azauridine, and ribavirin caused a concentration-dependent reduction in the virus yield with CHIKV and SFV. Moreover, the combination of IFN-alpha2b and ribavirin had a subsynergistic antiviral effect on these two alphaviruses and should be evaluated for the treatment of these infections.

Animals↗
PubMed2004

A simple assay for determining antiviral activity against Crimean-Congo hemorrhagic fever virus.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that is emerging as a significant human pathogen in many regions of the world, including Africa, Asia, and Europe. In this report, we describe a simple screening method for discovering new antiviral compounds directed against CCHFV. Antiviral activity was determined by assaying infected SW-13 cells (human adrenal gland carcinoma) for protection from cytopathic effect (CPE). By using an in vitro neutral red uptake assay, we were able to quantitatively measure CPE induced by CCHFV. As a proof of concept, we used this method to evaluate the antiviral activity of ribavirin and a series of structural analogs (ribamidine, 6-azauridine, selenazofurin, and tiazofurin) against four geographically diverse strains of CCHFV. Ribavirin inhibited the replication of CCHFV as reported previously using plaque reduction assays. One drug, ribamidine, showed antiviral activity that was 4.5- to 8-fold less than that of ribavirin, and the other three drugs (6-azauridine, selenazofurin, and tiazofurin) did not show significant antiviral activity. There were no significant differences in drug sensitivities among the CCHFV strains. Development of this simple and reliable assay will potentially allow high-throughput screening for discovering additional antiviral drugs to combat this important public health threat.

Animals↗
PubMed1985

Rationally designed combination chemotherapy for the treatment of patients with recalcitrant psoriasis.

In an effort to improve clinical response and reduce systemic toxicity, nine patients with recalcitrant psoriasis were treated with rational combinations of chemotherapeutic agents. Five patients received methotrexate by injection, 7.5 or 10 mg, followed 1 hour later by intravenous 5-fluorouracil, 170 to 562 mg/m2, on a weekly schedule. Four patients received oral triacetyl-azauridine, 2 to 4 gm daily, in combination with intravenous 5-fluorouracil, 225 to 600 mg/m2, administered every week. Three patients experienced greater than 75% clearing of disease, five patients experienced greater than 50% clearing, and only one patient failed to respond. Response rates did not differ between the two treatment groups. Adverse effects of these therapies were mild and infrequent. We conclude that 5-fluorouracil in combination with either methotrexate or triacetyl-azauridine is a relatively safe and effective alternative for the therapy of patients with severe psoriasis.

Adult↗
PubMed1975

Effect of aza-substituted nucleotides on the starve-refeed response of rats.

Rat liver glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME) activities were increased by starvation-refeeding to levels above those found in rats fed ad libitum. The increases in enzyme activities above ad libitum-fed levels were prevented by 8-azaguanine and 6-azauridine, but not by 2-azauridine. Blood insulin levels were not affected at the time studied. Two aza analogs, 8-azaadenine and 5-azacytidine, proved to be too toxic in this type of studies. Since 8-azahypoxanthine, 8-azaxanthine and 5-azauracil were neither effective in preventing the enzyme overshoot, nor toxic to the animals, it was concluded that the toxiciyty to the animals of 8-azaadenine and 5-azacytidine is due to the compounds themselves rather than to the breakdown products.

Adenine↗
PubMed1978

Effects of natural pyrimidines and of certain related compounds on the spontaneous activity of the mouse.

Uracil and perhaps other natural pyrimidines may effect the level of arousal of the mammalian brain since: 1) heterocyclic 6-membered rings, which resemble uracil, form part of the structure of many hypnotics; and 2) 6-azauracil (and its riboside) have shown to be hypnotic for several mammalian species, including man. The parenteral administration of uridine, 6-azauridine, cytidine or thymidine depressed the spontaneous activity of adult male C-57 mice. 6-Azauridine was much less potent than the other ribosides tested. Cytosine, barbituric acid, 2-thiobarbituric acid, 2,4-dihydroxypyridine and a variety of pyrimidine catabolites had no effect on activity. Thymine, uracil, 6-azauracil, barbital and phenobarbital increased activity at lower doses and decreased activity at higher ones. 6-Azauracil and uracil were about equally potent as stimulants of activity, but 6-azauracil had about twice the potency of uracil as a depressant of activity. Thymine, which was more active than uracil, had about 10% the potency of barbital, both as a stimulant and as a depressant of activity. For thymine and the two barbiturates the ED50 (for depression of activity) was of the same magnitude as the LD50, while the dose which caused 50% stimulation of activity was about an order of magnitude less than the LD50. These results suggest that the barbiturates might affect arousal by simulating the structure of thymine or uracil at some receptor.

Animals↗
PubMed1985

Tetrahydrouridine, cytidine analogues, and hemoglobin F.

5-Azacytidine (azaC) has previously been shown to raise Hb F levels in the repeatedly phlebotomized baboon (PCV: around 20%). The administration of tetrahydrouridine (THU), an inhibitor of the enzymatic conversion of azaC to 5-azauridine, made it possible to reduce the amount of azaC and also of 2-deoxy-5-azacytidine (d-azaC) by more than 90% and still achieve maximal Hb F elevations. However, the granulocytopenia, usually occurring after 5-azaC, was not altered by the lowering of the dosages in the presence of THU. Thus, the granulocytopenia is not due to 5-azauridine or other catabolic products resulting from deamination. It is also unlikely that it is caused by a direct influence of azaC on RNA since d-azaC also causes granulocytopenia. The persistence of reticulocytosis throughout the treatment with azaC or d-azaC makes it appear likely that the observed increase in Hb F levels to more than 60% of total hemoglobin is not due to a cytotoxic effect on erythropoiesis resulting in a shift of cell populations toward greater immaturity, but to a direct influence of the drug on the regulation of gamma globin chain production.

Agranulocytosis↗