Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.

Acyclovir is an antiviral drug used in the treatment and prevention of herpes simplex and varicella-zoster viral infections. The major problem in the transdermal delivery of acyclovir is the permeation in sufficient amounts to deeper layers of the skin and into the systemic circulation. Acyclovir is a hydrophilic substance with a low partition coefficient, resulting in poor penetration through the excellent barrier of the skin, the stratum corneum. In an attempt to enhance the transdermal permeability of acyclovir, the aim of this study was to employ terpenes as possible penetration enhancers. Terpenes are constituents of natural essential oils, with widespread medicinal use including in aromatherapy. The terpenes used in this study were 1,8-cineole, limonene, menthol, menthone, and 13- myrcene. Terpenes are not only used as penetration enhancers, but are even more often present in drugs and cosmetics. Limited studies have been done concerning the penetration of terpenes through the skin. Thus, not only the effect of the terpenes on the penetration of acyclovir, but also the penetration of the terpenes themselves were studied. The influence of acyclovir on the penetration of the terpenes was also determined. In vitro permeation experiments were performed on human skin using Franz diffusion cells. The skin was pretreated with a 5 % solution of the terpene in ethanol and left for 30 minutes to enable ethanol evaporation and terpene incorporation into the skin. Saturated aqueous solutions of acyclovir (pH 7.4) were added in the donor compartment before and after skin pre-treatment. The acyclovir concentration retrieved from the receptor compartment of the Franz cells was analyzed by HPLC. The amount of terpene that penetrated were semi-quantitatively determined by GC. Penetration of acyclovir was significantly enhanced by two terpenes, viz. 1,8-cineole and menthol. The extent of enhancement was, however, not large enough to be of clinical use. The enhancement in acyclovir penetration observed upon ethanol pre-treatment alone, or in the presence of limonene, menthone or ~-myrcene, was not significant. Penetration enhancement of acyclovir by the terpenes was in accordance with previous studies, which postulated better enhancement of hydrophilic drugs by hydrophilic terpenes. Large percentages of the terpenes with log P values within the optimum log P range (1 - 3) penetrated, as was found with menthone and menthol. Penetration decreased accordingly as the log P, and thus lipophilicity, increased. Stratum corneum retention is regarded as the most plausible explanation for this phenomenon. In the case of 1,8- cineole, enhancer pooling in the stratum corneum could be a possible reason for its poor penetration. Acyclovir significantly influenced the penetration profiles of some of the terpenes, but no clear explanation could be given. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

The skin forms an attractive and accessible route for systemic delivery of drugs as alternative to other methods of administration, such as the oral and parental methods because of the problems associated with last mentioned methods. The lipophilic character of the stratum corneum, coupled with its intrinsic tortuosity, ensures that it almost always provides the principal barrier to the entry of drug molecules into the skin. Due to the fact that methotrexate (MTX) and acyclovir (ACV) have poor penetration properties through the skin, the aim of this study was to enhance the permeation of methotrexate and acyclovir with the use of two lamellar gel phase systems (LPGS) (Physiogel® NT and Physiogel® Dermaquadrille) and with Emzaloid® as transdermal drug delivery systems. Three different sets of experiments were done in this study: 1) the viscosity of the two Physiogel® creams was measured as an indication of stability and to determine whether the internal structure of the Physiogel® creams were affected by the investigated drugs; 2) the drug release rate from the three drug delivery vehicles was measured with a Vankel ® dissolution apparatus; 3) in vitro permeation studies were preformed using vertical Franz diffusion cells with human epidermal skin clamped between the donor and receptor compartments. The skin was hydrated with PBS buffer for one hour before 1% mixtures of the drugs in both the Physiogel® creams and Emzaloid® were applied to the donor chamber. Samples were taken at 2, 4, 6, 8, 10, 12 and 24 hours. It was then analysed by HPLC for methotrexate and acyclovir. The fluxes of drug permeation were determined. The viscosity measurements confirmed that the internal structure of the two Physiogel® creams was not influenced by the drugs. Acyclovir and methotrexate were both released from the delivery vehicles. There was an enhancement of acyclovir through the skin from one of the Physiogel® creams. The permeability of methotrexate in the presence of the two Physiogel® vehicles was not significantly enhanced. Emzaloid® as delivery vehicle increased the penetration of both drugs through the skin significantly. The lamellar gel phase system mimics the structure of the stratum corneum, but does not improve the drug permeation through the stratum corneum significantly. The utilisation of Emzaloid® as a drug delivery system could be advocated from these findings. As could be seen from the penetration profiles Emzaloid® was a superior delivery system for methotrexate and acyclovir compared to the lamellar gel phase systems. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.

Acyclovir is an antiviral drug used in the treatment and prevention of herpes simplex and varicella-zoster viral infections. The major problem in the transdermal delivery of acyclovir is the permeation in sufficient amounts to deeper layers of the skin and into the systemic circulation. Acyclovir is a hydrophilic substance with a low partition coefficient, resulting in poor penetration through the excellent barrier of the skin, the stratum corneum. In an attempt to enhance the transdermal permeability of acyclovir, the aim of this study was to employ terpenes as possible penetration enhancers. Terpenes are constituents of natural essential oils, with widespread medicinal use including in aromatherapy. The terpenes used in this study were 1,8-cineole, limonene, menthol, menthone, and 13- myrcene. Terpenes are not only used as penetration enhancers, but are even more often present in drugs and cosmetics. Limited studies have been done concerning the penetration of terpenes through the skin. Thus, not only the effect of the terpenes on the penetration of acyclovir, but also the penetration of the terpenes themselves were studied. The influence of acyclovir on the penetration of the terpenes was also determined. In vitro permeation experiments were performed on human skin using Franz diffusion cells. The skin was pretreated with a 5 % solution of the terpene in ethanol and left for 30 minutes to enable ethanol evaporation and terpene incorporation into the skin. Saturated aqueous solutions of acyclovir (pH 7.4) were added in the donor compartment before and after skin pre-treatment. The acyclovir concentration retrieved from the receptor compartment of the Franz cells was analyzed by HPLC. The amount of terpene that penetrated were semi-quantitatively determined by GC. Penetration of acyclovir was significantly enhanced by two terpenes, viz. 1,8-cineole and menthol. The extent of enhancement was, however, not large enough to be of clinical use. The enhancement in acyclovir penetration observed upon ethanol pre-treatment alone, or in the presence of limonene, menthone or ~-myrcene, was not significant. Penetration enhancement of acyclovir by the terpenes was in accordance with previous studies, which postulated better enhancement of hydrophilic drugs by hydrophilic terpenes. Large percentages of the terpenes with log P values within the optimum log P range (1 - 3) penetrated, as was found with menthone and menthol. Penetration decreased accordingly as the log P, and thus lipophilicity, increased. Stratum corneum retention is regarded as the most plausible explanation for this phenomenon. In the case of 1,8- cineole, enhancer pooling in the stratum corneum could be a possible reason for its poor penetration. Acyclovir significantly influenced the penetration profiles of some of the terpenes, but no clear explanation could be given. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

The skin forms an attractive and accessible route for systemic delivery of drugs as alternative to other methods of administration, such as the oral and parental methods because of the problems associated with last mentioned methods. The lipophilic character of the stratum corneum, coupled with its intrinsic tortuosity, ensures that it almost always provides the principal barrier to the entry of drug molecules into the skin. Due to the fact that methotrexate (MTX) and acyclovir (ACV) have poor penetration properties through the skin, the aim of this study was to enhance the permeation of methotrexate and acyclovir with the use of two lamellar gel phase systems (LPGS) (Physiogel® NT and Physiogel® Dermaquadrille) and with Emzaloid® as transdermal drug delivery systems. Three different sets of experiments were done in this study: 1) the viscosity of the two Physiogel® creams was measured as an indication of stability and to determine whether the internal structure of the Physiogel® creams were affected by the investigated drugs; 2) the drug release rate from the three drug delivery vehicles was measured with a Vankel ® dissolution apparatus; 3) in vitro permeation studies were preformed using vertical Franz diffusion cells with human epidermal skin clamped between the donor and receptor compartments. The skin was hydrated with PBS buffer for one hour before 1% mixtures of the drugs in both the Physiogel® creams and Emzaloid® were applied to the donor chamber. Samples were taken at 2, 4, 6, 8, 10, 12 and 24 hours. It was then analysed by HPLC for methotrexate and acyclovir. The fluxes of drug permeation were determined. The viscosity measurements confirmed that the internal structure of the two Physiogel® creams was not influenced by the drugs. Acyclovir and methotrexate were both released from the delivery vehicles. There was an enhancement of acyclovir through the skin from one of the Physiogel® creams. The permeability of methotrexate in the presence of the two Physiogel® vehicles was not significantly enhanced. Emzaloid® as delivery vehicle increased the penetration of both drugs through the skin significantly. The lamellar gel phase system mimics the structure of the stratum corneum, but does not improve the drug permeation through the stratum corneum significantly. The utilisation of Emzaloid® as a drug delivery system could be advocated from these findings. As could be seen from the penetration profiles Emzaloid® was a superior delivery system for methotrexate and acyclovir compared to the lamellar gel phase systems. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.

The aim of this in vitro study was to investigate the efficacy of the novel Pheroid™ technology system in a semi-solid dosage form, for the topical delivery of acyclovir (5% w/w), an anti-viral agent and ketoconazole (2% w/w) an anti-fungal agent. The human immununodeficiency virus (HIV) had an immense impact on the spectrum of diagnosis of cutaneous diseases since its first manifestation in the late 1970's (Yen-More et al., 2000:432). The skin is the most commonly affected organ in HIV infected individuals with skin manifestations present in up to 92% of HIV-positive patients. According to Ramdial (2000:113) the skin may also be the first or the only organ affected throughout the course of the HIV/AIDS disease. HIV/AIDS patients are more susceptible to infections due to their compromised immune systems (Durden & Elewski, 1997:200) and an exceptionally wide range of infectious skin manifestations presents in HIV/AIDS infected individuals, some of which are viral and fungal. Acyclovir is an anti-viral active against herpes simplex virus type 1 and type 2, varicella-zoster virus, Epstein-Barr virus and the cytomegalovirus (Hayden, 2001:1317). The anti-fungal drug, ketoconazole has activity against the majority of pathogenic fungi which include Candida species and Histoplasma capsulatum (Bennett, 2001:1301). It is appropriate to formulate a topical product containing both acyclovir and ketoconazole because viral and fungal cutaneous manifestations are regularly encountered in combination in HIV/AIDS infected individuals,. This combination topical product may be useful in the treatment of viral and fungal opportunistic skin manifestations. Curing these skin lesions may also assist to improve the state of mind and wellbeing of infected individuals. The skin, however, acts as a barrier against diffusion of substances through the underlying tissue. The main problem in transdermal and dermal delivery of actives is to overcome the stratum corneum, the skin's natural barrier (Menon, 2002:4). The Pheroid™ delivery system can promote the absorption and increase the efficacy of a selection of active ingredients in dermatological preparations (Grobler et al., 2008:284). The aim of this study was to formulate a stable semi-solid product containing Pheroid™ to determine whether Pheroid™ technology would enhance the flux and/or delivery of acyclovir and ketoconazole to the epidermal and dermal layers of the skin. In vitro studies and tape stripping were used to determine the effect that the Pheroid™ delivery system had on skin permeation of acyclovir and ketoconazole in semi-solid formulations. The formulae containing no Pheroid™ were used as a control against which the efficacy of the formulations containing Pheroid™ was measured. The stability of the formulated semi-solid products was examined over a period of 6 months according to the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003) and the Medicines control council (MCC) of South Africa (2006). The formulated products were stored at three different temperatures. The stability tests included the assay of the actives and other attributes in the formulation, pH, viscosity, mass loss and particle size observation. These tests were conducted at 0, 1, 2, 3 and 6 months. The results demonstrated that the transdermal flux, epidermal and dermal penetration of acyclovir was enhanced by the Pheroid™ cream formulation. Ketoconazole's transdermal flux as well as delivery to the epidermal and dermal layers of the skin was improved by the Pheroid™ emulgel formula. The topical delivery of ketoconazole and acyclovir was thus enhanced by Pheroid™ technology. The Pheroid™ formulations, however, did not meet the requirements for stability according to the ICH and MCC. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

The aim of this in vitro study was to investigate the efficacy of the novel Pheroid™ technology system in a semi-solid dosage form, for the topical delivery of acyclovir (5% w/w), an anti-viral agent and ketoconazole (2% w/w) an anti-fungal agent. The human immununodeficiency virus (HIV) had an immense impact on the spectrum of diagnosis of cutaneous diseases since its first manifestation in the late 1970's (Yen-More et al., 2000:432). The skin is the most commonly affected organ in HIV infected individuals with skin manifestations present in up to 92% of HIV-positive patients. According to Ramdial (2000:113) the skin may also be the first or the only organ affected throughout the course of the HIV/AIDS disease. HIV/AIDS patients are more susceptible to infections due to their compromised immune systems (Durden & Elewski, 1997:200) and an exceptionally wide range of infectious skin manifestations presents in HIV/AIDS infected individuals, some of which are viral and fungal. Acyclovir is an anti-viral active against herpes simplex virus type 1 and type 2, varicella-zoster virus, Epstein-Barr virus and the cytomegalovirus (Hayden, 2001:1317). The anti-fungal drug, ketoconazole has activity against the majority of pathogenic fungi which include Candida species and Histoplasma capsulatum (Bennett, 2001:1301). It is appropriate to formulate a topical product containing both acyclovir and ketoconazole because viral and fungal cutaneous manifestations are regularly encountered in combination in HIV/AIDS infected individuals,. This combination topical product may be useful in the treatment of viral and fungal opportunistic skin manifestations. Curing these skin lesions may also assist to improve the state of mind and wellbeing of infected individuals. The skin, however, acts as a barrier against diffusion of substances through the underlying tissue. The main problem in transdermal and dermal delivery of actives is to overcome the stratum corneum, the skin's natural barrier (Menon, 2002:4). The Pheroid™ delivery system can promote the absorption and increase the efficacy of a selection of active ingredients in dermatological preparations (Grobler et al., 2008:284). The aim of this study was to formulate a stable semi-solid product containing Pheroid™ to determine whether Pheroid™ technology would enhance the flux and/or delivery of acyclovir and ketoconazole to the epidermal and dermal layers of the skin. In vitro studies and tape stripping were used to determine the effect that the Pheroid™ delivery system had on skin permeation of acyclovir and ketoconazole in semi-solid formulations. The formulae containing no Pheroid™ were used as a control against which the efficacy of the formulations containing Pheroid™ was measured. The stability of the formulated semi-solid products was examined over a period of 6 months according to the International Conference of Harmonisation (ICH) Tripartite Guidelines (2003) and the Medicines control council (MCC) of South Africa (2006). The formulated products were stored at three different temperatures. The stability tests included the assay of the actives and other attributes in the formulation, pH, viscosity, mass loss and particle size observation. These tests were conducted at 0, 1, 2, 3 and 6 months. The results demonstrated that the transdermal flux, epidermal and dermal penetration of acyclovir was enhanced by the Pheroid™ cream formulation. Ketoconazole's transdermal flux as well as delivery to the epidermal and dermal layers of the skin was improved by the Pheroid™ emulgel formula. The topical delivery of ketoconazole and acyclovir was thus enhanced by Pheroid™ technology. The Pheroid™ formulations, however, did not meet the requirements for stability according to the ICH and MCC. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2007. / "A dissertation in pharmaceutical sciences and chemistry." Advisor: Ashim K. Mitra. Typescript. Vita. Description based on contents viewed July 16, 2008; title from "catalog record" of the print edition. Includes bibliographical references (leaves 173-182). Online version of the print edition.

Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2004. / "A dissertation in pharmaceutical sciences and chemistry." Advisor: Ashim K. Mitra. Typescript. Vita. Description based on contents viewed Feb. 22, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 156-188). Online version of the print edition.

O aciclovir é um anti-viral usado mundialmente para o tratamento de herpes (do tipo HSV-1 e HSV-2). Acredita-se que o vírus da herpes está presente em cerca de 90% das pessoas em estado de latência. O tratamento principal em casos onde a doença se manifesta, lesões nos lábios e mucosas, é o aciclovir. No Brasil, para renovar ou fazer um novo registro de medicamento, a Agência Nacional de Vigilância Sanitária (ANVISA) exige testes que expõem o fármaco a ambientes extremos (ácido, base, luz, calor, umidade, oxidação) para gerar produtos de degradação que dependendo da concentração no produto acabado, devem ser submetidos a ensaios toxicológicos. O estudo de degradação forçada também permite elucidar a estabilidade intrínseca do fármaco, contribuindo para o entendimento do mecanismo de degradação da substância, o que, posteriormente, ajuda a compreender quais fatores físicos e químicos devem ser controlados para manutenção da estabilidade. Este trabalho tem objetivo de validar um método de análise para quantificação do aciclovir e seus produtos de degradação por cromatografia líquida de interação hidrofílica (Hydrophilic interaction chromatography - HILIC) com detecção por arranjo de diodos (DAD) como também degradar a amostra em diferentes ambientes. / Acyclovir is an anti-viral used worlwide for herpes treatment (HSV-1 and HSV-2 types). It is estimated that herpes virus is present in almost 90% of people in his latent state. Acylcovir is the main treatment in cases where virus expresses itself. In Brazil, to renew or to make a new registration of medicines, National Agency of Sanitary Surveillance (ANVISA) demands tests to expose the medicine to extreme conditions (acid, basic, light, heat, humidity, oxidation) in order to generate degradation products that, depending on the concentration of the row product, will undergoes toxicological assays. The forced degradation study also allow to elucidate the intrinsic stability of medicine, contributing to understand the degradation mechanism of the substance leading to help the understanding of which physical and chemical factors must be controlled to keep stability. The main objective of this work is to validate a method of analysis to quantify acyclovir and his degradation products using Hydrophilic Interaction Liquid Chromatography (HILIC) based on Diode Array detection as well as to degraded the sample in different conditions.