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Clinical Pharmacology and Therapeutics May 1980Vidarabine (Vira-A) was given intravenously for 5 days to 5 immunosuppressed patients with herpes zoster. The daily dose, 10 mg/kg, was given by slow infusion over 12...
Vidarabine (Vira-A) was given intravenously for 5 days to 5 immunosuppressed patients with herpes zoster. The daily dose, 10 mg/kg, was given by slow infusion over 12 hr. Blood samples were taken at 0, 1, 2, 4, 8, and 12 hr on days 1, 3, and 5. Twenty-four-hour urine specimens were collected before treatment and on days 1, 3, and 5. Blood and urine specimens were assayed for vidarabine and its principal metabolite, hypoxanthine arabinoside (ara-Hx), by high pressure liquid chromatography. The results showed that vidarabine is quickly deaminated; virtually all of the drug present in the plasma and urine was in the form of ara-Hx. The highest plasma level, approximately 3 microgram/ml, was at the end of the infusion period. The urinary excretion of ara-Hx accounted for between 40% and 50% of the dose. The renal clearance values varied, but were close to the expected glomerular filtration rate of 125 ml/min. The plasma levels and the excretion levels were much the same on days 1, 3, and 5, indicating that drug did not cumulate. The results of the study were consistent with those observed in single-dose studies. The results indicated that the infusion of vidarabine is clinically appropriate, since therapeutic plasma levels are reached promptly, drug is rapidly excreted, and there is no cumulation.
Topics: Biotransformation; Deamination; Herpes Zoster; Humans; Kinetics; Time Factors; Vidarabine
PubMed: 7371366
DOI: 10.1038/clpt.1980.98 -
Pharmaceutical Research Jul 1990The chemical reaction of vidarabine (VIDA) with isohexyl cyanoacrylate nanoparticles in a pH-dependent fashion occurs only in the presence of dioctylsulfosuccinate...
The chemical reaction of vidarabine (VIDA) with isohexyl cyanoacrylate nanoparticles in a pH-dependent fashion occurs only in the presence of dioctylsulfosuccinate (DOSS). The formation of an ion pair with DOSS allows a better contact of VIDA with the monomer during the polymerization process taking place in micelles. On the basis of molecular weight profiles of the polymer, determined by gel permeation chromatography (GPC), it is proposed that VIDA induces the polymerization of cyanoacrylic monomers through a zwitterionic pathway. This mechanism allows the covalent linkage of the drug with the polymer, which is consistent with NMR experiments. The present study illustrates the need for physicochemical studies in the design of new colloidal drug delivery formulations.
Topics: Chemical Phenomena; Chemistry, Physical; Chromatography, Gel; Chromatography, Thin Layer; Magnetic Resonance Spectroscopy; Molecular Weight; Particle Size; Polymers; Vidarabine
PubMed: 2395802
DOI: 10.1023/a:1015819706491 -
Seminars in Oncology Apr 2003Waldenstrom's macroglobulinemia (WM), a rare B-cell malignancy, is incurable. Conventional treatment consists of alkylating agents (especially chlorambucil), with or... (Review)
Review
Waldenstrom's macroglobulinemia (WM), a rare B-cell malignancy, is incurable. Conventional treatment consists of alkylating agents (especially chlorambucil), with or without corticosteroids. Purine analogues such as fludarabine are also active. Response rates to first-line therapy range from 38% to 85%. Discrepancies in response rates between different studies could be due to the small patient populations in two studies and to differences in patient characteristics and response criteria. Since 1990, several phase 2 trials of purine analogues have been done with previously treated patients; fludarabine induced responses in about one third of patients who were resistant to previous treatments. Response rates to fludarabine in previously treated patients range from 30% to 50% and are highest among patients who are still sensitive to their primary therapy. The responses last from 32 to 41 months. The principal toxicity of fludarabine is myelosuppression. Trials of fludarabine combination therapy with drugs such as rituximab are ongoing.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Vidarabine; Waldenstrom Macroglobulinemia
PubMed: 12720144
DOI: 10.1053/sonc.2003.50040 -
Annals of the New York Academy of... Mar 1977A new potent inhibitor of adenosine deaminase (co-vidarabine) was used in combination studies with adenine arabinoside (vidarabine, Vira-ATM) to protect this purine...
A new potent inhibitor of adenosine deaminase (co-vidarabine) was used in combination studies with adenine arabinoside (vidarabine, Vira-ATM) to protect this purine nucleoside from enzymatic deamination to the more weakly active metabolite, hypoxanthine arabinoside. Comparing the combination to vidarabine alone, a significant increase (10-fold) of the antiviral activity of the combined drugs was observed against herpes and vaccinia viruses in tissue culture and subcutaneously, against cranial herpesvirus infections in mice. Several other investigators have also recently reported several-fold enhancement of vidarabine activity by newly described deaminase inhibitors. They observed that plaque formation by several large DNA-containing viruses (herpes, vaccinia, varicella zoster) and an RNA-containing oncogenic virus was markedly prevented by the combination compared to vidarabine alone. In animals, enhanced protection (increased survivors) and/or highly significant increase in the life span of dying mice treated with the 2-drug combination, was also observed compared to vidarabine administered singly. These observations in animals clearly indicate that combination studies with vidarabine (Vira-ATM) and co-vidarabine (deaminase inhibitor) deserve serious consideration as future therapy for systemic virus infections in man including herpesvirus encephalitis.
Topics: Adenosine Deaminase Inhibitors; Animals; DNA Viruses; Drug Interactions; Female; Herpesviridae; Herpesviridae Infections; Mice; Nucleoside Deaminases; Vaccinia virus; Vidarabine; Virus Cultivation; Virus Replication
PubMed: 212990
DOI: 10.1111/j.1749-6632.1977.tb21937.x -
Journal of Medicinal Chemistry Jan 1982
Topics: Adenosylhomocysteinase; Antiviral Agents; Hydrolases; Simplexvirus; Vidarabine
PubMed: 6283083
DOI: 10.1021/jm00343a021 -
Antimicrobial Agents and Chemotherapy Oct 1983The relative therapeutic effects of vidarabine (9-beta-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and... (Comparative Study)
Comparative Study
Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice.
The relative therapeutic effects of vidarabine (9-beta-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%. Among control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100% mortality was observed, with a mean survival time of 4.6 days. Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P less than 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebrally with 10 50% lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of greater than or equal to 3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.
Topics: Animals; Antiviral Agents; Drug Evaluation, Preclinical; Encephalitis; Female; Herpes Simplex; Mice; Vidarabine
PubMed: 6651280
DOI: 10.1128/AAC.24.4.538 -
Expert Review of Anticancer Therapy Sep 2006Fludarabine is a prodrug that is converted to the free nucleoside 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A), which enters cells and accumulates mainly as the... (Review)
Review
Fludarabine is a prodrug that is converted to the free nucleoside 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A), which enters cells and accumulates mainly as the 5'-triphosphate, F-ara-ATP. F-ara-ATP has multiple mechanisms of action, which are mostly directed toward DNA. Collectively, these actions affect DNA synthesis, which is the major mechanism of F-ara-A-induced cytotoxicity. Secondarily, incorporation into RNA and inhibition of transcription has been shown in cell lines. As a single agent, fludarabine has been effective for indolent leukemia. Biochemical modulation strategies resulted in enhanced accumulation of cytarabine triphosphate and led to the use of fludarabine for the treatment of acute leukemia. The combination of fludarabine with DNA-damaging agents to inhibit DNA repair processes has been highly effective for indolent leukemia and lymphomas. Other strategies have incorporated fludarabine into preparative regimens for nonmyeloablative stem-cell transplantation.
Topics: Animals; Antineoplastic Agents; Hematologic Neoplasms; Humans; Prodrugs; Vidarabine
PubMed: 17020450
DOI: 10.1586/14737140.6.9.1141 -
The Medical Letter on Drugs and... Feb 1979
Clinical Trial
Topics: Clinical Trials as Topic; Encephalitis; Herpes Simplex; Humans; Vidarabine
PubMed: 368553
DOI: No ID Found -
Marine Drugs Oct 2010Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often... (Review)
Review
Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine) isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hoped to be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed.
Topics: Animals; Antiviral Agents; Aquatic Organisms; Biotechnology; Drug Discovery; HIV Infections; Herpes Simplex; Humans; Metagenomics; Porifera; Simplexvirus; Symbiosis; Vidarabine
PubMed: 21116410
DOI: 10.3390/md8102619 -
Blood Reviews 2010Drug-induced immune hemolytic anemia (DIIHA) is rare; it can be mild or associated with acute severe hemolytic anemia (HA) and death. About 125 drugs have been... (Review)
Review
Drug-induced immune hemolytic anemia (DIIHA) is rare; it can be mild or associated with acute severe hemolytic anemia (HA) and death. About 125 drugs have been implicated as the cause. The HA can be caused by drug-independent antibodies that are indistinguishable, in vitro and in vivo, from autoantibodies causing idiopathic warm type autoimmune hemolytic anemia (AIHA). More commonly, the antibodies are drug-dependent (i.e., will only react in vitro in the presence of the drug). The most common drugs to cause DIIHA are anti-microbials (e.g., cefotetan, ceftriaxone and piperacillin), which are associated with drug-dependent antibodies. The most common drug to cause AIHA is fludarabine. Finding out which drug is causing the problem and stopping that drug is the first approach to therapy. It is not easy to identify the drug interactions accurately in vitro; laboratories specializing in this area can be of great help.
Topics: Anemia, Hemolytic, Autoimmune; Anti-Infective Agents; Humans; Vidarabine
PubMed: 20650555
DOI: 10.1016/j.blre.2010.06.004