Antiviral Therapy of Shingles in Dermatology

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H. Martina Lilie, Sawko W. Wassilew

Dermatology Department, Klinikum Krefeld, Krefeld, Germany

The major goals of therapy in patients with herpes zoster are:

(1) shortening of virus replication,

(2) prevention of dissemination of skin lesions,

(3) reduction of acute zoster-associated pain (ZAP),

(4) prevention of chronic ZAP and postherpetic neuralgia (PHN),

(5) prevention of other complications, e.g. ophthalmic involvement. Recent research has shown that antiviral therapy with acyclovir, valacy-

clovir, famciclovir, and brivudin, started as early as possible, can significantly shorten viral replication, prevent lesion dissemination and reduce intensity and duration of ZAP particularly in elderly patients, provided that treatment is started early in the course of disease. This suggests that antiviral therapy (table 1) should be offered to all patients as soon as herpes zoster is diagnosed, preferably within 72 h after onset of rash. In patients of any age with ophthalmic herpes zoster and in all immunocompromised patients antiviral therapy should be started even later as long as viral replication can be considered in skin and nerves, e.g. as long as new blisters appear in the skin.

Dermatologists are trained to diagnose early skin lesions as herpes zoster and should be consulted in time.

In the immunocompetent patient antiviral therapy should normally be given for 7 days, whereas in the immunocompromised host antiviral therapy should be given intravenously and for at least 10 days.

Immunocompetent Patients

Acyclovir

Acyclovir (9-{2-hydroxyethoxymethyl}guanine) is a nucleoside analog. After penetrating into the infected cells acyclovir is converted to its monophosphate

Table 1. Antiviral therapy in immunocompetent patients with herpes zoster: management with antivirals, therapy for 7 days [30, 31]

Acyclovir, i.v.

Acyclovir, or.

Famciclovir or.

Valacyclovir, or. Brivudin, or.

250 mg 500 mg 750 mg1 1,000 mg 125 mg

5-10mg/kg body-weight 3X/day world

800 mg

5X/day world

3X /day Europe 3X /day USA 1 X/day UK

3X /day world 1 X/day Europe

1Data only on acute pain.

derivative by the viral thymidine kinase and to acyclovir triphosphate by cellular kinases. The resulting acyclovir triphosphate inhibits viral DNA polymerase as a competitive inhibitor of guanosine triphosphate [1].

Acyclovir is available in intravenous and oral preparations for the management of herpes zoster. The efficacy and safety of acyclovir has been demonstrated in several placebo-controlled trials. When given intravenously, acyclovir was found to reduce acute pain and to shorten cutaneous healing [2]. Acyclovir 800 mg

5 times daily for 7 days speeds skin healing and reduces the severity of acute neuritis. The benefit of acyclovir therapy was most evident when therapy started within 72 h of disease onset [3-9]. A meta-analysis of the acyclovir data showed that acyclovir has a significant benefit in the reduction of ZAP since it shortened the time to complete cessation of pain in all patients by nearly 80% compared with placebo [10]. Other studies have shown no benefit of acyclovir in reducing the duration of PHN [11, 12]. Typical side effects are transient rises in serum creati-nine or urea, nausea, vomiting, diarrhoea, stomach pain, rash and headache.

If given orally, the mean steady-state plasma level of acyclovir is very low, whereas much higher plasma levels can be reached by intravenous application of acyclovir. Because of its poor bioavailability of about 20% and its short intracellular half-life, ester derivatives of antiviral agents, the so-called prodrugs, were developed, which have much better pharmacocinetic properties. These substances are valacyclovir (prodrug of acyclovir) and famciclovir (prodrug of penciclovir).

Valacyclovir

Valacyclovir, the l-valyl ester of acyclovir, is rapidly converted to acyclovir. This results in a significantly (3-5-fold) increased oral acyclovir bioavailability of about 65%. It is FDA approved since 1995. The benefit of orally administered valacyclovir 1,000 mg three times daily has been shown in several large placebo-controlled trials [13, 14]. Skin healing occurred at a similar time with valacyclovir and acyclovir, but cessation of ZAP occurred 34% faster in the valacyclovir group (HR = 1.34, 95% CI: 1.12, 1.60). Patients treated with valacyclovir had only a 19% incidence of pain at 6 months in comparison to those treated with acyclovir with an incidence of 26%, p = 0.02 [13]. In another randomized study [15] on 110 patients, valacyclovir reduced the incidence of the ocular complications of herpes zoster ophthalmicus to a similar degree as acyclovir 800 mg five times daily. Overall, valacyclovir therapy has a positive effect on the reduction of ZAP and the prevention or the reduction of ocular complications [3, 15, 16]. Moreover, valacyclovir was well-tolerated, its safety profile being similar to that of acyclovir. Therefore, valacyclovir appears to be more suitable than oral acyclovir, especially because of its simple three-times-daily dose regimen.

Famciclovir

Famciclovir is the prodrug of penciclovir, a guanine nucleoside analog, and was approved by the FDA in 1994. The substance is rapidly absorbed and converted to penciclovir during transit through the intestinal wall and liver. Afterwards penciclovir is converted to its monophosphate by the VZV thymidine kinase within the VZV-infected cells. The monophosphate is subsequently converted by cellular kinases to the diphosphate and triphosphate forms. Penciclovir triphosphate has a significantly longer intracellular half-life than acyclovir triphosphate. The advantage of famciclovir is its good oral bioavailability of about 77% while being administered less frequently than acyclovir [3, 16].

Data from clinical studies did not advocate one particular, universally accepted dose regimen of famciclovir. Therefore, the approved doses vary in different countries: 500 mg t.i.d. especially in the USA, 250 mg t.i.d. in some European countries, and 750 mg q.d. e.g. in the United Kingdom (data only on acute pain). In several large placebo-controlled trials, the benefit of famciclovir could be demonstrated in the resolution of skin lesions and in accelerating the resolution of acute neuritis [3, 14, 16, 17]. Famciclovir is equally effective as valacyclovir. No differences could be shown between famciclovir and valacyclovir concerning rash healing, resolution of acute pain and PHN [14]. Famciclovir is as effective as oral acyclovir 5 X 800 mg daily for herpes zoster ophthalmicus concerning prevention of ocular complications [18].

Brivudin

Brivudin, [(e)-5-(2-bromovinyl)-2'deoxyuridine], is a potent virostatic agent with an exceptionally high and selective activity against VZV and herpes simplex virus type 1. De Clercq and co-workers demonstrated that brivudin has a greater antiviral in vitro activity against varicella-zoster virus than acyclovir and penciclovir [19-22].

Pharmacocinetic data showed that brivudin has a bioavailability of approximately 30%, presumably due to first-pass metabolism. The substance has a long plasma half-life of approximately 16h (>95% bound to plasma proteins). The antiviral activity of brivudin depends on its phosphorylation by viral, followed by cellular enzymes and the ensuing interaction with the viral enzymes, but not cellular DNA polymerase. Brivudin undergoes hydrolysis to bromovinyl uracil by pyrimidine nucleoside phosphorylase, mainly in the liver. The second phos-phorylation step, however, is catalyzed by the viral thymidine kinase.

The efficacy of brivudin has been shown in two large randomized, double blind multicenter studies, one on a total of 1,227 patients comparing brivudin 125 mg once daily with standard acyclovir 800 mg five times daily for 7 days [23-25], and the other on a total of 2,025 patients comparing brivudin 125 mg once daily with famciclovir 250 mg t.i.d. for 7 days [26].

Compared with acyclovir in the standard dose of 800 mg five times daily, brivudin 125 mg once daily for 7 days showed a significantly better antiviral activity (faster stop of viral replication), and it was as effective as acyclovir with respect to the resolution of acute zoster pain. With its once daily dosing schedule, brivudin offers a considerable advantage over current antiviral therapies. It is as yet available in Germany and had been licensed in many other European countries like Italy, Greece, Spain, Austria, Portugal and Luxemburg. It could be demonstrated that brivudin is well-tolerated and has a similar safety profile as acyclovir and famciclovir. The most frequently reported side effects were headache and gastrointestinal complaints, similar to the known side effects of acyclovir and famciclovir [16, 23, 24, 26, 27].

In conclusion, brivudin 125 mg once daily is as effective as famciclovir 250 mg t.i.d. in reducing the prevalence and the duration of ZAP and PHN 3 months after start of therapy. Although the duration of PHN was shorter in the brivudin group than in the famciclovir group, this difference was not statistically significant [26].

In animal trials, the toxicity of brivudin was low. In long-term (2-year) animal carcinogenicity assays, no tumors were observed in mice, whereas tumors in testes and the liver were observed in rats after a 2-year therapy with an extremely high brivudin dose of 30mg/kg body-weight/day. In lower doses of up to 12mg/kg body-weight/day, no tumors were observed. As the established dose in man (125 mg once daily) equals to 1.8 mg/kg body-weight/day and as it is given for only 7 days, carcinogenicity observed in the animal after long-term use does not appear predictive of human risk. Brivudin has no mutagenic potency and did not induce cell-transformation [28, 29].

Table 2. Antiviral therapy in immunocompromised patients with herpes zoster: management with antivirals, therapy for 7-10 days

Acyclovir, i.v. 10 mg/kg body-weight

Acyclovir, or. 800 mg Valacyclovir, or. 1,000 mg

Famciclovir, or. 500 mg

As the metabolite bromovinyl uracil interferes with the metabolism of 5-fluorouracil through the inhibition of the enzyme dihydropyrimidine dehydrogenase, brivudin and 5-FU are not allowed to be administered together [27].

Studies using treatment with famciclovir or brivudin for herpes zoster oti-cus and for herpes zoster ophthalmicus have not yet been published.

Immunocompromised Host

Immunocompromised patients such as transplant recipients, patients with malignancies, HIV-infection and others, receiving immunosuppressant therapy, corticosteroids and chemotherapy are at greater risk of herpes zoster and its complications.

Normally intravenous acyclovir therapy is recommended for the immunocompromised patient [27, 32], but oral antivirals can also be considered in some cases, table 2 [33]. In immunocompromised patients with suspected acyclovir-resistent VZV foscarnet can be administered [1, 3, 34]. Foscarnet is a pyrophosphate analog of phosphonoacetic acid. The substance inhibits the DNA polymerase by directly blocking the pyrophosphate binding site [1]. Due to the less oral bioavailability the substance has to be given intravenously with infusion of 120-200 mg/kg/day in 2-3 doses unless first symptoms of renal failure appear [1]. In cases, where foscarnet may also be ineffective due to gene mutations intravenous cidofovir is the only alternative treatment [35].

Brivudin is not admitted for the treatment in immunocompromised patients.

In summary, the effects of all virostatics given orally or intravenously are comparable concerning the resolution of virus replication, cessation of dissemination of skin lesions and reduction of acute herpes zoster pain. Concerning the incidence and/or prevalence of chronic pain, ZAP and PHN valacyclovir, famci-clovir and brivudin in different dosages are comparably effective. Normally all antivirals are well-tolerated, but transient side effects such as headache, gastrointestinal and neurological complaints are possible in all antiviral drugs [31].

Adjunctive Therapies

During the acute phase of herpes zoster, cool compresses or drying solutions, creams, and ointments can help to alleviate local symptoms and dry the skin lesions. They have no proven effect on shortening the disease or preventing complications and PHN.

All virostatics have comparable but not sufficient influence on pain. Therefore, concomitant analgesic therapy is recommended and consists of a variety of modalities including analgesics, narcotics [36], early use of tricyclic antidepressants (amitriptyline) in elderly patients [37-39], opioids [40-42], gabapentin [43-45], capsaicin [5, 46], local 5%-lidocaine-patch [46], cutaneous stimulation, sympathectomy/nerve blocks [47, 48] and corticosteroids therapy. Corticosteroids should be combined with an antiviral therapy in patients >50 years of age only with significant acute pain at presentation, if they have no contraindications for high dose corticosteroids administration, i.e. high blood pressure, diabetes, etc. Benefits of this adjunctive therapy are improvement in quality of life, total cessation of analgesic use and undisturbed sleep at night. The dosage of prednisone is recommended at least 1 mg/kg body-weight and day respectively 60 mg daily for first week, 30 mg daily the second week and 15 mg daily the third week. Nevertheless, the adjunctive corticosteroid therapy has been considered controversial, especially due to the fact that no benefit could be proven upon preventing ZAP, PHN or ocular complications [1, 36, 49-51].

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Dr. H. Martina Lilie

Dermatology Department, Klinikum Krefeld Lutherplatz 40

DE-47805 Krefeld (Germany)

Tel. +49 2151 32 2880, Fax +49 2151 32 2005, E-Mail [email protected]

Gross G, Doerr HW (eds): Herpes Zoster.

Monogr Virol. Basel, Karger, 2006, vol 26, pp 131-142

Highly Potent and Selective Inhibition of Varicella-Zoster Virus Replication by Bicyclic Furo[2,3-d ]pyrimidine Nucleoside Analogues (BCNAs)

Erik De Clercq

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

Varicella-zoster virus (VZV) causes two distinct syndromes [1]: primary infection presents as varicella (or chickenpox), a usually benign illness during childhood, and subsequent reactivation of latent VZV in dorsal-root ganglia results in a localized cutaneous eruption termed 'herpes zoster' (or 'shingles'). The annual incidence of herpes zoster is 0.2%, although in the elderly (persons older than 75 years) and in immunocompromised patients it can exceed 1 and 2%, respectively [1]. Therapy for herpes zoster is warranted to accelerate healing, limit the severity and duration of acute and chronic pain, and reduce complications (among which postherpetic neuralgia, defined as pain that persists for more than 30 days after the onset of rash, is the most feared complication in immunocompetent patients); in immunocompromised patients, an additional therapeutic objective is to reduce the risk of dissemination of VZV [1].

In the United States three drugs - acyclovir (ACV), valacyclovir and famciclovir - are approved for the treatment of herpes zoster: ACV at a dosage of 800 mg every 4h (5 times daily) for 7-10 days, valacyclovir at a dosage of 1,000 mg every 8h (3 times daily) for 7 days, and famciclovir at a dosage of 500 mg every 8 h (3 times daily) for 7 days: because of the simpler dosing regimens, valacyclovir and famciclovir (which are therapeutically equipotent) are preferred to ACV for the treatment of herpes zoster [1]. In addition to ACV, valacyclovir and famciclovir, also brivudin (BVDU) has been licensed for the therapy of herpes zoster in Germany and several other European Countries (Austria, Belgium, Greece, Italy, Luxemburg, Portugal, Spain): BVDU has the

Fig. 1. Structures of BVDU and prototype furo[2,3-rfjpyrimidine nucleoside analogues: Cf 1368, Cf 1369, Cf 1742 and Cf 1743.

simplest dosing regimen of all, as it must be administered (orally) only once daily (125 mg) for 7 days, to achieve equivalent efficacy to valacyclovir and famciclovir [2].

Here, I report on a totally new class of compounds, that of the bicyclic furo[2,3-d]pyrimidine nucleoside analogues (BCNAs), which can be viewed as somewhat related to BVDU (fig. 1), but which differ from BVDU in several biological and biochemical aspects that make these furopyrimidine derivatives ideally suited as selective (candidate) anti-VZV drugs.

Structure-Activity Relationships of Furo[2,3-d ]Pyrimidine Nucleoside Analogues (BCNAs)

The target structures were originally obtained as by-products in Pd-catalysed coupling of terminal alkynes with 5-iodo-nucleoside analogues such as 5-iodo-2'-deoxyuridine [3]. Among a first series of 6-substituted furopyrimidine derivatives, the 6-octyl-substituted derivative Cf 1368 (fig. 1) was found to inhibit the replication of VZV (strains OKA and YS) in human embryonic lung cells at a 50% effective concentration (EC50, concentration required to inhibit virus-induced plaque formation by 50%) of 0.008 |xm, while not being toxic at a concentration (CC50, cytotoxic concentration required to inhibit human embryonic lung cell growth by 50%) of 50 |xm (CC50 > 50 |xm) [3],thus achieving a selectivity index (SI, ratio CC50 to EC50) of >5,000. Also 6-nonyl- and 6-decyl-substi-tuted derivatives showed comparable antiviral activity. Shorter (i.e. heptyl, hexyl)

or longer (i.e. undecyl, dodecyl) side chains resulted in decreased anti-VZV activity (table 1).

Further lead optimization resulted in the synthesis of 6-(p-alkylphenyl)-substituted furopyrimidine nucleoside analogues. Among these derivatives, the 6-(p-pentylphenyl)- and 6-(p-hexylphenyl)-substituted derivatives (Cf 1743 and Cf 1742, respectively) (fig. 1) [EC50: ~0.0001-0.0005 ^m and selectivity index (>100,000)] emerged as the most potent and selective anti-VZV compounds ever reported (table 2) [4]. Shortening or lengthening the alkyl chain length of the 6-pentyl- or 6-hexylphenyl chain with one or more carbons again resulted in decreased anti-VZV activity. For both the alkyl and p-alkylphenyl-substituted compounds an optimal length of the side chain could be defined; thus, for the alkyl derivatives, this appeared to be 8-10 carbons, and for the p-alkylphenyl derivatives 5 or 6 carbons, the phenyl group being equivalent to 3-4 carbons.

Anti-VZV Properties of Bicyclic Furo[2,3-d ]Pyrimidine

Nucleoside Analogues (BCNAs)

From the 6-alkyl-substituted furopyrimidine nucleoside series, the octyl derivative Cf 1368, and from the 6-p-alkylphenyl-substituted furopyrimidine nucleoside series, the pentylphenyl derivative Cf 1743 and hexylphenyl derivative Cf 1742 (fig. 1) were selected for further exploration of their anti-VZV properties. As compared to (£)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), Cf 1743 and Cf 1742 were about 10-20-fold more potent against VZV, and, as compared to ACV and penciclovir (PCV), they were even 10,000-fold more potent in their activity against VZV [5-8].

When Cf 1368, Cf 1742 and Cf 1743 were evaluated against a variety of clinical VZV isolates, EC50 values were obtained that were quite comparable to those obtained for the laboratory OKA and YS VZV strains [9]. Cf 1368, Cf 1742 and Cf 1743 inhibited the replication of wild-type clinical VZV isolates at a mean EC50 value of 0.032, 0.00082 and 0.00044 |M, respectively, whereas for BVDU the mean EC50 value was 0.0098 |M. The corresponding EC50 values for ACV, PCV and foscarnet (phosphonoformic acid [PFA]) were 3.51, 3.31 and 83.62 |xm, respectively (fig. 2).

Thus, in terms of activity against both laboratory and clinical VZV strains, the order of (decreasing) potency was Cf 1743 ~ Cf 1742 > Cf 1368 ~ BVDU > PCV ~ ACV > PFA (fig. 2). Cf 1743 and Cf 1742 are much more potent in their anti-VZV activity than the drugs that are formally approved for the treatment of VZV infections [PCV (penciclovir, oral prodrug form: famciclovir) and ACV (acyclovir, oral prodrug form: valacyclovir)] and than foscar-

Table 1. Anti-VZV activity of BCNAs containing an alkyl side chain on the furanyl ring [3]

/(CHJCH3

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Headache Happiness

Headache Happiness

Headache Happiness! Stop Your Headache BEFORE IT STARTS. How To Get Rid Of Your Headache BEFORE It Starts! The pain can be AGONIZING Headaches can stop you from doing all the things you love. Seeing friends, playing with the kids... even trying to watch your favorite television shows. And just think of how unwelcome headaches are while you're trying to work.

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