Pharmacokinetics of Vidarabine in the Treatment of Infants and Children with Infections Due to Herpesviruses

Shope, Thomas C.; Kauffman, Ralph E.; Bowman, David; Marcus, E. L.

doi:10.1093/infdis/148.4.721

Cited by 9 publications

(6 citation statements)

References 7 publications

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“…The Ara-H clearance values are compatible with filtration and reabsorption of Ara-H. A-relationship between renal Ara-H clearance and glomerular filtration rate has been reported (18), which compares infants and older children, and the Ara-H renal clearances reported in the older children are of the same order of magnitude as those presented in this report. Qur data, however, are considered only to represent approximate values of these clearances, particularly in patient 2 who was ill and probably dehydrated on the study day and may have had incomplete bladder emptying on voiding.…”

supporting

confidence: 85%

High-pressure liquid chromatographic methods for determining arabinosyladenine-5'-monophosphate, arabinosyladenine, and arabinosylhypoxanthine in plasma and urine

McCann¹,

Hall²,

Siler³

et al. 1985

Antimicrob Agents Chemother

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New high-pressure liquid chromatographic methods for determining concentrations of arabinosyladenine (Ara-A), its 5'-monophosphate (Ara-AMP), and arabinosylhypoxanthine (Ara-H) in plasma and urine are presented. A fluorescence detector is used for Ara-A and Ara-AMP, which are first converted to highly fluorescent derivatives with chloroacetaldehyde. This increases sensitivity greatly over previous methods. The sensitivities of the methods (in micrograms per milliliter) are as follows: in plasma, Ara-AMP, 0.002; Ara-A, 0.0015; and Ara-H, 0.35; and in urine, 9 times these values, respectively. Drug concentration data are also presented, which were obtained after doses of Ara-AMP were given intramuscularly to two patients treated with this drug for severe herpes zoster. One patient was given 13 mg of Ara-AMP per kg of body weight once daily, and the other was given 6.5 mg/kg twice daily. Peak Ara-AMP and Ara-A levels in plasma occurred within 1 h after the doses, and neither exceeded 2 micrograms/ml. Ara-AMP and Ara-A concentrations in plasma fell to less than 0.01 micrograms/ml in both patients by 4 to 6 h after the doses. Peak Ara-H concentrations in plasma occurred within 1 to 2 h after doses and were 21 micrograms/ml in patient 1 and 2. The highest concentration of Ara-AMP in urine was 0.09 micrograms/ml. The highest Ara-A concentration in urine was 62 micrograms/ml, and the highest Ara-H concentration in urine was 1,080 micrograms/ml. An interfering substance of unknown nature, cochromatographing with Ara-H, was encountered sporadically in urine samples. An algorithm based on differential spectrophotometry to identify and correct for this problem is described. Estimates of the renal clearances of Ara-AMP, Ara-A, and Ara-H are also given.

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supporting

confidence: 85%

High-pressure liquid chromatographic methods for determining arabinosyladenine-5'-monophosphate, arabinosyladenine, and arabinosylhypoxanthine in plasma and urine

McCann¹,

Hall²,

Siler³

et al. 1985

Antimicrob Agents Chemother

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“…The investigators estimate that ",50% of systemic araHx may be removed by typical dialysis sessions and doses should be reduced by 25% and given after dialysis in patients with renal failure. Urinary recovery and urinary clearance of ara-Hx were reduced in full-term and preterm infants (Shope et al 1983).…”

Section: Vidarabinementioning

confidence: 92%

“…In fact while many studies were unable to detect vidarabine after a 12h infusion, ara-Hx concentrations ranged from 3 to 6 mg/L after a 12h infusion of vidarabine 5 to 15 mg/kg/day (Whitley et al 1980a). Urinary recovery of ara-Hx after continuous infusion of vidarabine range from 40 to 50% of the administered dose (Buchanan et al 1980;LePage et al 1973;Preiksaitis et al 1981;Shope et al 1983). Therefore, renal excretion is the predominant elimination pathway for ara-Hx.…”

Section: Vidarabinementioning

confidence: 99%

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Comparative Pharmacokinetics of Antiviral Nucleoside Analogues

Morse

Shelton

O’Donnell

1993

Clinical Pharmacokinetics

119

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The recent development of nucleoside analogues with antiviral activity has expanded the small but useful armamentarium for the treatment of certain viral diseases such as the human immunodeficiency virus, cytomegalovirus and others. Their intracellular site of action and need for sequential phosphorylation require that traditional pharmacokinetic parameters be used in conjunction with an understanding of intracellular metabolism when designing dosage regimens. This review summarises the available pharmacokinetic literature for zidovudine, didanosine, zalcitabine, aciclovir, ganciclovir, vidarabine and ribavirin. After oral administration, didanosine, aciclovir and ribavirin are < 50% bioavailable and ganciclovir is < 6% absorbed. In contrast, zidovudine and zalcitabine are > 60% bioavailable, although zidovudine undergoes considerable and variable first-pass hepatic glucuronidation while zalcitabine has no first-pass effect. Zidovudine, zalcitabine and didanosine are absorbed rapidly in the fasted state, with peak plasma concentrations exceeding their respective in vitro antiretroviral inhibitory concentrations. All reviewed agents except ribavirin have a relatively short plasma half-life (approximately 0.5 to 4h), with each agent demonstrating a different intracellular enzymatic activation scheme. For example, the rate-limiting step for formation of zidovudine triphosphate is the conversion of the monophosphate to the diphosphate, while didanosine is ultimately converted to dideoxyadenosine triphosphate which has the longest intracellular half-life (approximately 12 to 24h) among these agents. These drugs are not highly protein bound and they distribute into tissues with an apparent volume of distribution at steady-state ranging from 0.3 to 1.2 L/kg. They vary in the extent to which they enter cerebrospinal fluid, ranging from a low of < 25% for didanosine to a high of > 70% of a concurrent plasma concentration for ribavirin and vidarabine. These agents also vary with regard to degree of renal excretion of the parent drug, with the lowest noted for vidarabine (1 to 3%) and the highest for zalcitabine (approximately 75%) and ganciclovir (> 90%). With the increasing number of clinically useful nucleoside analogues, it is essential for the clinician to appreciate the subtle differences among these agents to ensure that optimal therapeutic outcomes may be attained with minimal toxicity.

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“…Despite its proven ability as a therapeutic agent which is active against a variety of viruses, vidarabine has some significant limitations. It is readily metabolized by adenosine deaminase (ADA) to arabinofuranosyl hypoxanthine (ara-H), which is 10-fold less potent [13,14] and has low lipophilicity and thus low intestinal membrane permeability. It is also poorly soluble in aqueous solutions and has low intramuscular absorption, requires large fluid volumes for intravenous administration, and must be given over prolonged periods (8 to 12 h) [15] to obtain therapeutic effects.…”

Section: Vidarabine or Ara-amentioning

confidence: 99%

Antiviral Lead Compounds from Marine Sponges

2010

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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 hopedto 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.

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Pharmacokinetics of Vidarabine in the Treatment of Infants and Children with Infections Due to Herpesviruses

Cited by 9 publications

References 7 publications

High-pressure liquid chromatographic methods for determining arabinosyladenine-5'-monophosphate, arabinosyladenine, and arabinosylhypoxanthine in plasma and urine

High-pressure liquid chromatographic methods for determining arabinosyladenine-5'-monophosphate, arabinosyladenine, and arabinosylhypoxanthine in plasma and urine

Comparative Pharmacokinetics of Antiviral Nucleoside Analogues

Antiviral Lead Compounds from Marine Sponges

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