Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis

Whitley, Richard J.; Soong, Seng‐Jaw; Dolin, Raphael; Galasso, George J.; Ch’ien, Lawrence T.; Alford, Charles A.

doi:10.1056/nejm197708112970601

Cited by 663 publications

(120 citation statements)

References 26 publications

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“…In recent years several compounds have been described which are all endowed with selective anti-herpes properties. These compounds include phosphonoacetic acid (3,4), phosphonoformic acid (5, 6), 9-f3-D-arabinofuranosyladenine (araA) (7,8), 5-iodo-5'-amino-2',5'-dideoxyuridine (AIDDU) (9, 10), 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) (11,12), 1-f3-D-arabinofuranosylthymine (araT) (13,14), 5-iodo-and 5-bromo-2'-deoxycytidine (15, 16), 5,6-dihydro-5-azathymidine (17,18), and erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA) (19). Among the 5-substituted 2'-deoxyuridines, various compounds-namely, 5-methylamino-dUrd (20), 5-methoxymethyl-dUrd (21), 5-propyl-dUrd (22), and 5-propynyloxy-dUrd (23)-proved more inhibitory to herpes than to any other DNA (or RNA) virus.…”

mentioning

confidence: 99%

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

Clercq¹,

Descamps²,

Somer³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

440

198

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Of a series of five newly synthesized 2'-deoxyuridine derivatives, including 5(1-chlorovinyl)-dUrd, (E--(2-bromovinyl)-dUrd, and (E)5-(2-iodovinyl).dUrd, the last two compounds were found to exert a marked inhibitory effect on the replication of herpes simplex virus type 1 [ID50 (mean inhibitory dose), 0.004-0.02 ;tg/mll.Both (E)5(2-bromovinyl).dUrd and (E>5S(2-iodovinyl).dUrd were highly selective in their anti-herpes activity in that they did not affect the growth or metabolism of the host (primary rabbit kidney) cells unless drug concentrations were used that were 5,000-to 10,000-fold greater than those required to inhibit virus multiplication. In this sense (E-5-2-bromovinyl Idoxuridine (5-iodo-2'-deoxyuridine) and trifluorothymidine (5-trifluoromethyl-2'-deoxyuridine) are among the best known antiviral agents currently used in the chemotherapy of-herpesvirus infections (1). Their clinical usefulness is restricted to the topical treatment of local herpes simplex virus (HSV) infections such as herpetic keratitis and "cold sores" (herpes labialis). The unfavorable therapeutic index of Idoxuridine when administered parenterally-as most dramatically exemplified by its inefficacy in patients with herpes simplex encephalitis (2)-has prompted the search for more effective and less toxic anti-herpes agents. In recent years several compounds have been described which are all endowed with selective anti-herpes properties. These compounds include phosphonoacetic acid (3, 4), phosphonoformic acid (5, 6), 9-f3-D-arabinofuranosyladenine (araA) (7, 8), 5-iodo-5'-amino-2',5'-dideoxyuridine (AIDDU) (9, 10), 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine) (11, 12), 1-f3-D-arabinofuranosylthymine (araT) (13, 14), 5-iodo-and 5-bromo-2'-deoxycytidine (15, 16), 5,6-dihydro-5-azathymidine (17, 18), and erythro-9-[3-(2-hydroxy- vinyl)-dUrd. These compounds surpassed all previously described anti-herpes agents, including acycloguanosine, in both potency and selectivity, at least in primary rabbit kidney (PRK) cells infected with herpes simplex virus type 1 (HSV-1). Compounds 5-Vinyl-dUrd, 5-ethynyl-dUrd, (E)-5-(2-bromovinyl)-dUrd, and (E)-5-(2-iodovinyl)-dUrd were obtained by condensing the trimethylsilyl derivatives of the appropriate 5-substituted uracils with 2'-deoxy-3,5-di-0-p-toluoyl-a-D-erythropentofuranosyl chloride to give a mixture of the a-and f3-anomers of the protected nucleosides. T anomers were separated by chromatography on silica gel and the p-toluoyl protecting groups were removed by treatment with sodium methoxide in methanol. The results indicated for the biological experiments were all obtained by using the f3-anomers (Fig. 1). The a-anomers were also tested for biological activity, but they were inactive. The synthesis of 25). The synthesis of (E)-5-(2-bromovinyl)-dUrd, (E)-5-(2-iodovinyl)-dUrd, and 5-(1-chlorovinyl)-dUrd has been published elsewhere (ref. 26 and unpublished data). The structures assigned to these compounds were established by elemental analysis and UV and NMR spectroscopy.The sour...

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mentioning

confidence: 99%

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

Clercq¹,

Descamps²,

Somer³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

440

198

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“…In neonates, however, herpesvirus encephalitis usually results from dissemination of virus acquired from maternal genital infections, and these are usually caused by HSV-2 (14). If left untreated, the mortality rate associated with this disease is approximately 70 to 80% (33,34,36,38 a 12-h period for 10 days, was found to significantly reduce the mortality due to HSV-1 encephalitis from 70 to ca. 28% among those patients (36).…”

Section: Discussionmentioning

confidence: 99%

“…If left untreated, the mortality rate associated with this disease is approximately 70 to 80% (33,34,36,38 a 12-h period for 10 days, was found to significantly reduce the mortality due to HSV-1 encephalitis from 70 to ca. 28% among those patients (36). Another collaborative study was recently completed in which ara-A was also evaluated in newborn infants with localized central nervous system infection or disseminated disease.…”

Section: Discussionmentioning

confidence: 99%

“…The antiviral drug vidarabine (9-p-D-arabinofuranosyladenine; ara-A) is highly effective in the systemic treatment of herpes simplex virus (HSV) encephalitis both in laboratory animals (11,12,17,25,29,30) and in humans (33,34,36,37). This clinically effective purine nucleoside analog is rapidly deaminated in biological systems by the enzyme adenosine deaminase (2,4,6,9,40).…”

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confidence: 99%

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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

Shannon¹,

Westbrook²,

Arnett³

et al. 1983

Antimicrob Agents Chemother

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The relative therapeutic effects of vidarabine (9-,-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%, Amnong control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100%to 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 < 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebraily with 10 50o 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 -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.

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“…Os métodos de detecção de anticorpos no LCR apresentam pequena sensibilidade na fase aguda da doença e baixa reprodutibilidade [17][18][19][20][21][22] . O isolamento viral a partir de tecido cerebral obtido por biópsia é método sensível, específico e reprodutível, mas altamente agressivo [23][24][25][26] .…”

Section: Discussão Discussão Discussão Discussão Discussãounclassified

Diagnósticos alternativos em pacientes com suspeita de encefalite por Herpes simplex e negativos à reação em cadeia por polimerase (PCR)

Domingues

Pannuti

Fink

et al. 2000

Arq. Neuro-Psiquiatr.

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RESUMO -O objetivo do presente estudo é analisar os diagnósticos encontrados em uma série de pacientes cuja suspeita clínica inicial era de encefalite herpética (HSE), mas que tiveram este diagnóstico afastado através de resultado negativo à reação em cadeia por polimerase (PCR) para detecção do Herpes simples (HSV) em líquido cefalorraqueano (LCR). Em 43 dos 61 pacientes com suspeita de HSE estudados (70,5%) o resultado à PCR foi negativo. O diagnóstico diferencial foi elucidado em 41,9% dos 43 casos em que a PCR para HSV resultou negativa. Nestes, as patologias diagnosticadas foram infecções virais (2 casos-11,1%) e não virais (5 casos-27,2%), doenças vasculares (4 casos-22,2%), desmielinizantes (3 casos-16,7%), distúrbios tóxico-metabólicos (3 casos-16,7%) e tumor do sistema nervoso central (1 caso-5,6%). A pouca especificidade do quadro clínico e a disponibilidade de tratamento eficaz e seguro para a HSE justificam a grande quantidade de casos tratados com aciclovir, mas cujo diagnóstico de encefalite pelo HSV não foi confirmado. A utilização da PCR no LCR contribuiu para melhor avaliação etiológica dos quadros de encefalite aguda aqui estudados. PALAVRAS-CHAVE: encefalite herpética, reação em cadeia por polimerase (PCR), diagnóstico diferencial. Alternative diagnoses among suspected Herpes simplex encephalitis patients with negative polymerase chain reaction (PCR)ABSTRACT -The aim of this study was to analyze the diagnosis found in a series of patients in which the diagnosis of Herpes simplex encephalitis (HSE) was ruled out by a negative polymerase chain reaction (PCR) result for HSV DNA in cerebrospinal fluid (CSF) samples. Forty three out of 61 HSE suspected patients had negative PCR. An alternative diagnosis was established in 41.9% of these patients. These patients were diagnosed as having viral (2 cases-11.1%) and non viral (5 cases-27.2%) CNS infections, vascular (4 cases-22.2%) and demyelinating diseases (3 cases-16.7%), metabolic disturbances (3 cases-16.7%), and CNS tumor (1 case-5.6%). The non specific clinical presentation of this disease and the availability of an efficient treatment for HSE explain why several patients with other diseases were initially treated with acyclovir. The early use of PCR in CSF was considered essential for the evaluation of the acute encephalitis cases in this study.KEY WORDS: Herpes simplex encephalitis, polymerase chain reaction (PCR), differential diagnosis.A encefalite pelo vírus Herpes simples (HSV) é doença grave, com altos índices de morbidade e letalidade 1 . O tratamento antiviral com o aciclovir melhora significativamente o prognóstico desta doença, particularmente quando ele é administrado precocemente 2 . Assim, o diagnóstico precoce desta patologia é fundamental. Entretanto, diversas patologias podem ser confundidas com a encefalite

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Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis

Cited by 663 publications

References 26 publications

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent.

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

Diagnósticos alternativos em pacientes com suspeita de encefalite por Herpes simplex e negativos à reação em cadeia por polimerase (PCR)

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