A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis

doi:10.1016/S1079-2104(99)70164-2

Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology

Volume 87, Issue 6, June 1999, Pages 700-705

https://doi.org/10.1016/S1079-2104(99)70164-2 Get rights and content

Abstract

In a 2-armed, double-blind, randomized clinical study, the efficacy in the treatment of recurrent herpes labialis of 5% acyclovir in a novel liposomal carrier (ethosome) was evaluated in comparison with that of a commercial 5% acyclovir cream (Zovirax cream) and that of a drug-free vehicle. Data were based on 61 herpetic episodes in 40 subjects. In a crossover arm in which the 2 active preparations were compared, the time to crusting of lesions was significantly shorter (P < .025) with the ethosomal acyclovir (1.8 days) than with the cream (3.5 days). Time to loss of crust was also significantly shorter (4.2 vs 5.9 days; P < .05). In a parallel arm in which all 3 preparations were compared, the time to crusting with the ethosomal acyclovir (1.6 days) was significantly shorter than the time with the acyclovir cream (4.3 days; P < .02) and the time with the drug-free vehicle (4.8 days; P < .005); in this arm, the shorter time to loss of crust for the ethosome (3.5 days), in comparison with the times for the cream (6.4 days) and the drug-free vehicle (6.1 days), did not reach statistical significance. Approximately 30% of all episodes treated with the ethosome were clinically abortive; this compared with 10% of those treated with the cream or the drug-free vehicle. No adverse effects were reported, other than minor burning sensations at the application site that lasted a few seconds after application and were evenly distributed between the investigated preparations. This pilot study suggests the improved clinical efficacy of the new liposomal preparation in comparison with Zovirax cream in the treatment of recurrent herpes labialis. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:700-5)

Section snippets

Subject population

Subjects with histories of RHL (as diagnosed at our clinic by an oral medicine specialist) who had no major underlying disease, experienced 3 or more recurrences per year, and were at least 18 years of age were considered eligible to participate in the study. Subjects were excluded if they were pregnant, lactating, immunocompromised, or receiving immunosuppressive or antiviral medications. All participants gave written informed consent.

Materials

The new ethosomal 5%-acyclovir preparation (EA) and a

Characterization of subject population

Fifty-eight participants were enrolled, having met the inclusion criteria and signed informed consent forms. Thirteen participants were inactive throughout the trial period, experiencing no assessable episodes. Five participants were dropped: 1 because of pregnancy, 1 because of overseas travel, 1 because of discontent with the treatment randomly assigned for the first episode (V), and 2 (of whom one had been assigned to receive EA and the other to receive V) because of noncompliance with the

DISCUSSION

Inadequate skin absorption was proposed as a major contributor to the modest clinical efficacy of previously studied topical ACV formulations in the treatment of RHL. The ethosome, designed as a novel carrier for enhanced topical and transdermal delivery of drugs, appears to improve the clinical efficacy of ACV in treating RHL.

The results of the present clinical study suggest the improved clinical efficacy of liposomal ACV, as compared to ZC. The major clinical parameter measured in the study,

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Cited by (127)

COMPARATIVE EFFICACY OF ANTIVIRAL AGENTS FOR PREVENTION AND MANAGEMENT OF HERPES LABIALIS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
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Citation Excerpt :
Additionally, some other antivirals, antibacterial agents or chemical compounds included in the analysis were inosine pranobex, monocaprin, doxycycline, 1,5-pentanediol, tetracaine, Betadine paint, Stoxil ointment (idoxuridine), foscarnet, undecylenic acid, vidarabine monophosphate, thymopentin, butylated hydroxytoluene, ether, levamisole and chloroform21,28,53,39,40,42,44,45,46,57,62,67,68,69 Most of these 52 studies had 2 treatment arms, except 9 studies with 3 treatment arms 3,25,31,34,45,48,54,62,70 and 2 studies with 4 treatment arms.50,64 Another 10 studies did not have placebos as control groups.3,22,31,65,32,33,36,43,47,55
To compare the relative efficacy and safety of antiviral agents used in the prevention and management of herpes labialis through a network meta-analysis of clinical trials.
A systematic search was performed in Ovid Medline PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus and Clinicaltrials.gov for randomized controlled trials (RCTs) reporting a comparison of antiviral agents in the management and prevention of herpes labialis in healthy/immunocompetent adults. The data extracted from the selected RCTs were assessed and a network meta-analysis (NMA) was performed. The interventions were ranked according to the surface under the cumulative ranking (SUCRA).
A total of 52 articles were included for qualitative synthesis and for the quantitative part, 26 articles were analyzed for the primary treatment outcome and 7 studies were analyzed for the primary prevention outcome. The combination therapy of oral valacyclovir and topical clobetasol was the best ranked with a mean reduction in healing time of -3.50 (95% CI -5.22 to -1.78) followed by vidarabine monophosphate of -3.22 (95% CI -4.59 to -1.85). No significant inconsistencies, heterogeneity, and publication bias were reported for TTH outcome analysis. For primary prevention outcomes, only 7 RCTs fulfilled the inclusion criteria, and none of the interventions was shown to be superior to each other. The absence of adverse events was reported by 16 studies, whereas other studies reported mild side effects only.
NMA highlighted that several agents were effective in the management of herpes labialis among which the combination of oral valacyclovir with topical clobetasol therapy was the most effective in reducing the time to heal. However, further studies are required to determine which intervention is the most effective in preventing the recurrence of herpes labialis.
Ethosomes: a potential vesicular carrier for drug delivery
2022, Systems of Nanovesicular Drug Delivery
Ethosomes are noninvasive drug delivery vehicles that allow entrapped drug(s) to penetrate deep layers of the skin and/or the systemic circulation. Ethosomes are commonly utilized to encourage the permeation of hydrophilic and lipophilic drugs through the skin. Ethosomes have the unique ability to transport drugs across membranes, maintain drug release, and protect encapsulated actives from the surrounding environment. The inclusion of ethanol in the bilayers is responsible for the increased bioavailability and skin penetration of ethosomes. This chapter referred to a number of reviews and research publications in order to produce a thorough and simple-to-comprehend chapter. In this chapter, the data were gathered after a grid search of scientific publications and information was presented in terms of the principle of ethosomes, composition, and mechanism of actions, Various commonly employed procedures for the preparation of ethosomes have been explored that includes thin-film hydration, cold injection, the hot procedure, and ethanol injection–sonication. Further vesicles evaluation procedures and ethosomes applications in drug delivery have been thoroughly covered. This chapter includes several aspects that will aid academician and research investigators in comprehending the design and benefits of the ethosomes system. Further, the information provided in this chapter will aid in the development of an improved ethosomes drug delivery system. Based on the literature survey, it is concluded that the use of ethosomes holds considerable promise in addressing the drug delivery challenges in the future as well. However, a well-thought-out procedure is needed to optimize many process factors in the production of large-scale manufacturing of more stable, safe, and cost-effective ethosomes systems for dermal/transdermal delivery.
Nanovesicles for transdermal drug delivery
2022, Applications of Nanovesicular Drug Delivery
The skin as an effective barrier makes drug penetration and permeation difficult, which limits the efficiency of drug delivery through the skin. There are several strategies including “chemical” and “physical” methods to improve the permeation of active substances through the skin for local or systemic drug delivery. Among the penetration enhancement methods, nanovesicles have been one of the popular and well-studied approaches for delivering drug to deeper layers of the skin or even systemic circulation. To overcome the poor permeability of drugs, innovative vesicular systems were developed including deformable liposomal systems such as invasomes, Transfersomes, ethosomes, etc., and nonlipid building blocks vesicular nanostructures such as niosomes. Polysomes have demonstrated encouraging results in delivering small molecules and large proteins to the skin. In the current review, we provide an overview of different vesicular nanostructures for transdermal drug delivery and their skin penetration mechanisms. Also, it is necessary to recognize the concepts of numerous vesicular systems and analyze their drawbacks and advantages. A deep analysis of these factors is expected to provide new insights and new avenues of exploration for research in this field, which may help vesicular formulations to enter the market in the near future.
In vitro, ex vivo, and in vivo studies of binary ethosomes for transdermal delivery of acyclovir: A comparative assessment
2021, Journal of Drug Delivery Science and Technology
The study investigated a comparative assessment of binary ethosomes (ETHOs) and elastic liposomes (ELPs) for transdermal delivery of acyclovir sodium (ACV-Na). Optimized binary ETHO (ETHO2) and ELPs (ELP3) were evaluated for vesicle size, entrapment efficiency, elasticity, extruded volume, in vitro drug release, morphology, ex vivo skin permeation, and drug deposition (albino rat skin). In vivo studies were performed to evaluate transepidermal water loss (TEWL) and skin irritation. The components of ELP3 and ETHO2 (ethanol, propylene glycol, Tween 80, lipids) had a significant impact on in vitro and in vivo parameters. ETHO2 showed convincing findings as compared to ELP3. The permeation steady-state flux (J_ss) and enhancement ratio (E_R) were significantly (p˂0.05) enhanced in ETHO2 (J_ss = 87.6 ± 4.8 μg/cm²/h and E_R = 7.3) as compared to drug solution (DS) (J_ss = 12 ± 2.6 μg/cm²/h) and marketed cream (J_ss = 52 ± 7.0 μg/cm²/h and E_R = 4.3). The findings of TEWL and scanning electron microscopy confirmed better permeation of ETHO2. Hemolysis and Draize studies confirmed the hemocompatibility and non-irritant behavior of formulations, respectively. Conclusively, ETHO2 can be a suitable alternative to classical vesicular systems for transdermal application against infections caused by the herpes simplex virus.
What's new in the field of phospholipid vesicular nanocarriers for skin drug delivery
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Citation Excerpt :
The outcome was that with ethosomal acyclovir both the time to crusting of lesions and that to loss of crust were significantly shorter than with the cream. Moreover, approximately 30% of herpetic episodes treated with ethosomes were clinically abortive, while, as for those treated with Zovirax, only 10% (Horwitz et al., 1999). Finally, it is interesting to point out that a topical acyclovir-loaded ethosomes formulation, namely SupraVir cream (Trima, Israel), reached the market.
Over the last three decades, research in the field of phospholipid nanocarriers as tools to improve dermal and transdermal drug delivery has grown substantially. In particular, liposomes have been the target of studies aimed at reformulating vesicles with a greater ability to deliver drugs trans-dermally. A number of additives with varied physicochemical properties have been combined with traditional components of liposomes. These novel modification processes have produced new classes of vesicles with the potential to enhance the treatment of both dermatological disorders and systemic pathologies. Development of the first deformable and elastic phospholipid vesicles has highlighted the key role of vesicle composition in promoting release of vesicle content into and through the skin. This paper discusses the key vesicle properties and mechanisms of delivery by which newly developed phospholipid vesicles can improve percutaneous drug delivery.
Lipid vesicles for (trans)dermal administration
2020, Nanomaterials for Clinical Applications: Case Studies in Nanomedicines
Transdermal administration can solve the biopharmaceutical issues of several drugs, thereby improving patient compliance. Nevertheless, overcoming the skin barrier is not an easy task. In the past years, high expectations for nanotechnologies have been raised. In particular liposomes have been the most investigated carriers because of the composition that resembles that of the extracellular environment of the stratum corneum. This chapter provides a brief description of the skin architecture and the main limits of transdermal drug delivery. Then the use and the potentialities of all classes of lipid vesicles developed as carriers for cutaneous application are discussed. Finally the main clinical outcomes of the studies on these nanocarriers are reviewed focusing on the products that really reached the pharmaceutical market.

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^☆: Reprint requests: Elka Touitou, PhD, Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel

^☆☆: 1079-2104/99/$8.00 + 0 7/13/97861

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A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis☆,☆☆

Abstract

Section snippets

Subject population

Materials

Characterization of subject population

DISCUSSION

Am J Med

Oral Surg Oral Med Oral Pathol

J Am Acad Dermatol

Am J Med

The natural history of recurrent oro-facial herpes simplex virus infection

Seminars in Dermatology

Management of non-genital herpes simplex virus infections in immunocompetent patients

Am J Med

The natural history of recurrent herpes labialis

N Engl J Med

9-(2-hydoxyethoxymethyl)-guanine activity against viruses of the herpes group

Nature

Acyclovir: pharmacology and clinical experience

Arch Intern Med

Herpes labialis treatment with acyclovir 5% ointment

J Can Dent Assoc

Topical acyclovir in the management of herpes labialis

Br J Dermatol