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The New England Journal of Medicine Jan 1993Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are... (Clinical Trial)
Clinical Trial
BACKGROUND
Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in gamma-globin--gene expression in the developing fetus, cultured cells, and animal models.
METHODS
To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of gamma-globin messenger RNA (mRNA) were determined before and during treatment.
RESULTS
In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P < 0.01). The proportion of F reticulocytes increased about twofold, and the level of gamma-globin mRNA increased twofold to sixfold. The increase in gamma-globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations.
CONCLUSIONS
In patients with beta-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate beta-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or beta-thalassemia.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Arginine; Butyrates; Child; Child, Preschool; Female; Fetal Hemoglobin; Globins; Humans; Infusions, Intravenous; Male; RNA, Messenger; beta-Thalassemia
PubMed: 7677966
DOI: 10.1056/NEJM199301143280202 -
British Journal of Haematology Dec 2010Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose-ranging trials... (Randomized Controlled Trial)
Randomized Controlled Trial
Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose-ranging trials of Arginine Butyrate in beta haemoglobinopathies. Here, a controlled Phase II trial was performed in sickle cell patients who had lower extremity ulcers refractory to standard care for at least 6 months. Patients were randomized to receive standard local care alone (Control Arm) or standard care with Arginine Butyrate administered 5 d/week (Treatment Arm), for 12 weeks. Ulcers were photographed weekly, traced, and ulcer areas were calculated by computerized planimetry and compared between the two study arms. Twenty-seven study courses were evaluated. Control Arm subjects had 25 ulcers with a mean area of 25·7 cm(2) initially and 23·2 cm(2) after 12 weeks; 2/25 (8%) healed completely. Treatment Arm subjects had 37 ulcers with a mean area of 50·6 cm(2) initially and 28·3 cm(2) at 12 weeks; 11/37 of these (30%) healed completely. After 3 months, proportions of ulcers which healed were 6/25 (24%) and 29/37 (78%), in the Control and Treatment Arms respectively (P < 0·001). These findings strongly suggest that Arginine Butyrate merits further evaluation for the treatment of refractory sickle cell leg ulcers in larger trials.
Topics: Adult; Anemia, Sickle Cell; Arginine; Butyrates; Chronic Disease; Female; Humans; Leg Ulcer; Male; Middle Aged; Prospective Studies; Treatment Outcome; Wound Healing; Young Adult
PubMed: 20955402
DOI: 10.1111/j.1365-2141.2010.08395.x -
Blood Feb 2005Fetal hemoglobin (Hb F) levels increase in most patients with sickle cell disease following intermittent butyrate therapy. Although the full effects of butyrate on Hb F... (Clinical Trial)
Clinical Trial
Fetal hemoglobin (Hb F) levels increase in most patients with sickle cell disease following intermittent butyrate therapy. Although the full effects of butyrate on Hb F levels usually require multiple treatment cycles, in some patients a peak level is achieved after a few days of butyrate therapy. Our investigation of the mechanism(s) responsible for this rapid induction of Hb F by butyrate showed that reticulocyte gamma-globin chain synthesis markedly increased within 24 hours of butyrate exposure, without concomitant changes in reticulocyte gamma-globin mRNA levels. This suggests that butyrate might induce Hb F by increasing the efficiency of translation of gamma-globin mRNA. This hypothesis was confirmed by ribosome loading studies that demonstrated enrichment of the polysomal fraction of reticulocytes with gamma-globin mRNA following butyrate exposure. Thus, the induction of Hb F by butyrate may be mediated by translational effects in addition to its well-known effects on transcription of the gamma-globin genes.
Topics: Adult; Anemia, Sickle Cell; Arginine; Butyrates; Fetal Hemoglobin; Globins; Humans; Peptide Chain Initiation, Translational; Protein Biosynthesis; RNA, Messenger; Reticulocytes
PubMed: 15479724
DOI: 10.1182/blood-2004-02-0454 -
The Journal of Laboratory and Clinical... Dec 1998The exposure of endothelial cells to hypoxic environments regulates the expression of a number of genes with products that are vasoactive or mitogenic for vascular...
The exposure of endothelial cells to hypoxic environments regulates the expression of a number of genes with products that are vasoactive or mitogenic for vascular tissue, including platelet-derived growth factor, endothelin-1, and endothelial nitric oxide synthase. Hypoxia is also known to alter the adhesive properties of endothelium toward a variety of blood cell types. Thrombospondin-1 (TSP-1) is a glycoprotein with major roles in cellular adhesion and vascular smooth muscle proliferation and migration. We report here that hypoxia induces TSP-1 gene and protein expression. Oxygen tensions of < or =30 torr resulted in TSP-1 transcript induction initially apparent at 1 to 6 hours, with maximal induction (6.5-fold+/-1.2-fold) within 24 to 48 hours in both human and bovine endothelial cells. TSP-1 protein levels remain elevated after 72 hours of continuous hypoxic exposure. The induction of TSP-1 steady-state transcript levels is caused in large part, if not entirely, by post-transcriptional stabilization of the TSP-1 mRNA. The TSP-1 induction by hypoxia is a graded and reversible physiologic response and can be mimicked by the use of cobalt chloride or the inhibition of nitric oxide production, suggesting both the involvement of a heme-containing oxygen sensor and a role for the endogenous production of nitric oxide in TSP-1 regulation. The effects of hypoxia both on the stabilization of the TSP-1 transcript and the stimulation of TSP-1 protein production are completely inhibited by arginine butyrate.
Topics: Animals; Arginine; Butyrates; Cattle; Cells, Cultured; Cobalt; Cycloheximide; Dactinomycin; Endothelium, Vascular; Gene Expression Regulation; Humans; Hydroxamic Acids; Hypoxia; NG-Nitroarginine Methyl Ester; Oxygen; RNA, Messenger; Thrombospondin 1
PubMed: 9851743
DOI: 10.1016/s0022-2143(98)90131-7 -
Blood Jan 2012Induction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated... (Comparative Study)
Comparative Study
Induction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated lymphomas. Short-chain fatty acids or certain chemotherapeutics have been used to induce EBV lytic-phase gene expression in cultured cells and mouse models, but these studies generally have not translated into clinical application. The recent success of a clinical trial with the pan-histone deacetylase (pan-HDAC) inhibitor arginine butyrate and the antiherpes viral drug ganciclovir in the treatment of EBV lymphomas prompted us to investigate the potential of several HDAC inhibitors, including some new, highly potent compounds, to sensitize EBV(+) human lymphoma cells to antiviral agents in vitro. Our study included short-chain fatty acids (sodium butyrate and valproic acid); hydroxamic acids (oxamflatin, Scriptaid, suberoyl anilide hydroxamic acid, panobinostat [LBH589], and belinostat [PXD101]); the benzamide MS275; the cyclic tetrapeptide apicidin; and the recently discovered HDAC inhibitor largazole. With the exception of suberoyl anilide hydroxamic acid and PXD101, all of the other HDAC inhibitors effectively sensitized EBV(+) lymphoma cells to ganciclovir. LBH589, MS275, and largazole were effective at nanomolar concentrations and were 10(4) to 10(5) times more potent than butyrate. The effectiveness and potency of these HDAC inhibitors make them potentially applicable as sensitizers to antivirals for the treatment of EBV-associated lymphomas.
Topics: Antineoplastic Agents; Antiviral Agents; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Ganciclovir; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Herpesvirus 4, Human; Histone Deacetylase Inhibitors; Humans; Lymphoma; Molecular Targeted Therapy; Osmolar Concentration; RNA, Messenger; Time Factors; Viral Proteins; Virus Activation
PubMed: 22160379
DOI: 10.1182/blood-2011-06-362434 -
Blood Oct 1994
Topics: Adult; Anemia, Sickle Cell; Arginine; Butyrates; Female; Hemoglobins, Abnormal; Humans; Leg Ulcer; Thalassemia
PubMed: 7919358
DOI: No ID Found -
Biochemical Pharmacology Mar 1996The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has been shown previously to form adducts preferentially within internucleosomal or linker DNA rather...
The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has been shown previously to form adducts preferentially within internucleosomal or linker DNA rather than to DNA within the nucleosome. To determine whether other "open" regions of chromatin have an increased affinity for cisplatin, adduct formation within specific chromatin domains was analyzed. There was a significant increase in cisplatin-DNA adduct formation for DNA associated with the nuclear matrix (NM) compared with other chromatin domains and total unfractionated DNA. In contrast, treatment of the same cells with trans-diamminedichloroplatinum(II) (transplatin) did not result in preferential adduct formation. These findings led to the hypothesis that it might be possible to alter DNA to make it a more favorable target for cisplatin. The effect of arginine butyrate on cisplatin-DNA adduct formation was analyzed in human cancer cells. The combination of arginine butyrate and cisplatin resulted in a concentration-responsive increase in cisplatin-DNA adduct formation in PC-3 cells and an overall increase in cisplatin-DNA adduct formation in three other human cancer cell lines. The same combination also resulted in a significant increase in drug-induced cytotoxicity at a low concentration of cisplatin. These results suggest that chromatin configuration can affect cisplatin adduct formation.
Topics: Antineoplastic Agents; Arginine; Butyrates; Chromatin; Cisplatin; DNA; DNA Adducts; Humans; Nucleic Acid Conformation; Tumor Cells, Cultured
PubMed: 8615910
DOI: 10.1016/s0006-2952(95)02256-2 -
Journal of Clinical Pharmacology Aug 2011Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small... (Randomized Controlled Trial)
Randomized Controlled Trial
Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers.
Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease (SCD) and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate (AB), and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous (IV) infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel short chain fatty acids (SCFA) derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with 1 of 4 single dose levels (2, 5, 10, and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9 to 15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable pharmacokinetics (PK) profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies.
Topics: Administration, Oral; Adolescent; Adult; Biological Availability; Blood Cell Count; Butyrates; Dose-Response Relationship, Drug; Double-Blind Method; Drugs, Investigational; Female; Fetal Hemoglobin; Food-Drug Interactions; Half-Life; Hematinics; Humans; Male; Metabolic Clearance Rate; Plasma; Reticulocytes; Urine; Young Adult
PubMed: 21422239
DOI: 10.1177/0091270010379810 -
Blood Cells, Molecules & Diseases Jun 1998Lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infections can occur in the setting of immunosuppression. In some patients, the...
Lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infections can occur in the setting of immunosuppression. In some patients, the lymphoproliferative disorder can resemble an aggressive monoclonal non-Hodgkins lymphoma (NHL). These NHL are poorly responsive to conventional therapy. Similarly, antiviral therapy with synthetic nucleosides such as ganciclovir are ineffective because the genes that render the virus susceptible to therapy are not expressed in EBV+ lymphomas. Using a cell line derived from a lung transplant recipient with an EBV+ immunoblastic NHL, we studied the ability of arginine butyrate to induce the expression of EBV thymidine kinase. Arginine butyrate was not only effective in inducing EBV thymidine kinase transcription, but also acted synergistically with the antiviral agent ganciclovir to inhibit cell proliferation and decrease cell viability. Based on these findings, the patient from whom the cell line was derived was treated with arginine butyrate/ganciclovir as well as conventional cytotoxic chemotherapy. No additional toxicity was observed with the arginine butyrate/ganciclovir therapy. Histologic examination of the tumor showed substantial necrosis. These observations suggest the feasibility of arginine butyrate induction of ganciclovir susceptibility in patients with EBV-associated lymphomas.
Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Apoptosis; Arginine; Aspergillosis; Butyrates; Cyclophosphamide; Doxorubicin; Drug Synergism; Enzyme Induction; Epstein-Barr Virus Infections; Fatal Outcome; Ganciclovir; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Herpesvirus 4, Human; Humans; Lung Neoplasms; Lung Transplantation; Necrosis; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Thymidine Kinase; Tumor Cells, Cultured; Vincristine; Viral Nonstructural Proteins
PubMed: 9628848
DOI: 10.1006/bcmd.1998.0178 -
American Journal of Hematology Jul 2014This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain... (Randomized Controlled Trial)
Randomized Controlled Trial
This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β(0) thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1-1.6%) with HQK-1001 and 0.2% (95% CI: -0.7-1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK-1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation.
Topics: Administration, Oral; Adolescent; Adult; Anemia, Sickle Cell; Antisickling Agents; Butyrates; Child; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fetal Hemoglobin; Humans; Male; Middle Aged; Placebos; Young Adult
PubMed: 24677033
DOI: 10.1002/ajh.23725