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Topical carbenoxolone sodium in the management of herpes simplex infection
British Journal of Oral and Maxillofacial Surgery (1984) 22, 138-145 0 1984 The British Association of Oral and Maxillofacial Surgeons
TOPICAL CARBENOXOLONE
SODIUM IN THE MANAGEMENT
OF HERPES
SIMPLEX INFECTION
MAXINEPARTRIDGE, B.D.s.,F.D.s.R.c.s., andD. E. POSWILLO,D.D.s.,D.s~., F.D.S.R.C.S., F.R.A.C.D.S., F.I.Bml.,F.R.C.Path. Department
of Oral Surgery,
The Royal Dental Hospital, Leicester London WC2
Square,
Summary. Topical Carbenoxolone was discovered by chance to be a highly effective anti-viral agent and was subsequently used in the management of Herpetic gingivostomatitis and recurrent Herpes labialis. A marked reduction in the healing time and pain associated with these lesions was noted. A discussion of the possible mechanisms of action of Carbenoxolone is included.
Introduction
Recent advances in anti-viral chemotherapy have failed to produce an agent which has been shown to be consistently effective, without harmful side-effects, in the management of mucocutaneous herpes simplex infection. The lesions produced by this ancient scourge are generally mild and self-limiting but for patients who have severe and frequent attacks the lesions may be disfiguring and annoying. Herpes virus infection was previously regarded principally as a childhood illness but in Western countries, with a high standard of living, an increasing number of adult cases are appearing, probably due to the better resistance to these illnesses in childhood. Thirty per cent of all patients who have primary herpetic stomatitis develop recurrent infections later in life. Patients receiving immunosuppressive therapy, especially those with reticula-endothelial cancers, have an increased susceptibility to these latent infections as cell-mediated immunity plays an important part in the defence mechanisms against the virus and an increasing number of individuals are presenting with herpes simplex or zoster infection. Herpes virus is dermatrophic and thus amenable to topical therapy. Treatment aims to reduce the severity of the acute attack and the chronicity and the recurrence rate of subsequent attacks. This must be done without subjecting the patient to acute toxic side effects, such as depression of the immune system or chronic adverse reactions, such as an increased risk of dysplastic change. Treatments available to date often fall short of these criteria and their use in minor recurrent infection seems unjustified. However, in view of the provocative suggestion that herpes simplex virus may be associated with dysplastic change, safe and effective treatment remains the ultimate goal. Carbenoxolone is synthesised from glycyrrhetic acid which is the aglycone of glycyrrhizin found in glycyrrhizia glabra or liquorice root. Glycyrrhizic acid has been shown to inhibit both the growth and the cytopathic effects of several unrelated viruses, including herpes simplex virus, Pompei et al. (1980). Carbenoxolone was subsequently shown to have highly significant activity against herpes virus both in vitro, Tyrell (1981), and in vivo, Poswillo and Roberts (1981). This anti-viral activity is increased using the cyclohexane dicarboxylic acid analogue of (Received
11 October
1982; accepted 27 January
138
1983)
TOPICAL
CARBENOXOLONE
SODIUM
139
Carbenoxolone, Cicloxolone. These compounds are all triterpenoids. Extracts of liquorice root have been shown to have anti-bacterial activity, Mitsheria et al. (1980), and this useful property helps to reduce the severity of secondary infection usually associated with these lesions. Soluble Carbenoxolone granules were prepared by the manufacturer. Two grammes were disolved in 30 ml of warm tap water as required to give a 0.067 per cent mouth rinse as the solution, once prepared, is unstable. Topical treatment was devised and used initially in the management of recurrent oral ulceration as a result of the observation that a number of patients receiiing pyrogastrone for peptic oesophagitis reported a reduction in the incidence and severity of chronic oral ulceration, Fergusson (1980). A reduction in the discomfort and healing time of oral ulceration had already been reported, Samuel (1967), Schmelzle et al. (1975). It seemed possible that the proven ability of Carbenoxolone to increase the resistance of the gastric mucosa to breakdown, Lipkin (1971), and to increase mucosal blood flow, Johnston and McIsaac (1980)) Starllinger et al. (1981)) might be responsible for these observed changes as the oral and gastric mucosa are similar in many respects; the oral mucosa being specialised due to its position at the head of the alimentary system. The mouth rinse was subsequently given to a dentist suffering from severe primary herpes infection and the treatment gave a dramatic improvement in symptoms much greater than could be expected relying on the healing potentiating properties of Carbenoxolone alone. This chance finding promoted a further open trial and a multi-centre double blind placebo controlled trial is now in progress. Case Reports Primary infection
Primary herpes infection presents characteristically with gingivitis and multiple shallow ulcers throughout the mucosa (Figs. 1 & 2). Herpes virus was isolated by laboratory culture at the onset of treatment for 12 patients and levels of antibody to the virus were measured at Day One and Day Ten. With topical Carbenoxolone therapy used six times daily for three days, the lesions have disappeared (Figs. 3 & 4). The most dramatic improvement being the consistent lack of pain and dysphagia after 24 to 48 hours treatment, with ulceration and lymphadenopathy gradually resolving after a further one to three days. It can be difficult to demonstrate convincingly the therapeutic efficacy of treatment of these lesions as natural healing begins within three to four days and because of the variable course of the disease among different persons, but all of our patients treated with Carbenoxolone have shown a reduction in time to complete healing of five to six days as compared to controlled cases (Table I). Recurrent infection
This generally presents as an area of swollen labial mucosa on which develop multiple vesicles which rupture to leave a crusted mass which gradually heals over ten to 14 days. It may affect a small area of the lip or the whole of the labial mucosa and the lesions may extend around the nose or on the chin. Am aqueous two per cent cream was developed to treat these recurrences and used in placebo controlled double blind study involving 50 patients where herpes virus was isolated from the lesions and previous infection was confirmed by measurement of herpes simplex virus antibody titre. Figure 5 shows unusually severe painful recurrent infection of
140
BRITISH
JOURNAL
OF
ORAL
&
MAXILLOFACIAL
SURGERY
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Figures 1 and 2- Characteristic oral ulceration and gingivitis associated with primary herpes simplex virusinfection. Figures 3 and 4-Resolution of lesions after topical Carbenoxolone therapy was given six hourly for 72 hours.
24 hours duration. Topical Carbenoxolone was used six times daily; after 24 hours (Fig. 6) the patient was pain free and the erythema was already beginning to fade. After 48 hours the lesion had disappeared (Fig. 7). Half of the cases treated to date, all of whom had a long history of recurrent infection, have had no recurrence within six months; in the remainder, new lesions have been aborted within 48 hours of treatment. Other anti-viral agents have given no significant improvement in preventing recurrent infections. Cases of herpes zoster have been successfully treated using a combination of the mouth rinse and cream and to date there have been no reports of post-herpetic neuralgia. Topical treatment is also being evaluated in the management of radiation mucositis as the anti-inflammatory and healing potentiating effects may be of therapeutic use both in reducing pain and potentiating repair of ulcerated tissue. Discussion
These results suggest that Carbenoxolone and its analogues are more effective than other currently available anti-viral drugs, particularly for recurrent infection. Idoxuridine five per cent has been ‘shown to shorten the healing time of these lesions (Juel-Jenson & MacCallum, 1965), but may cause skin irritation at this concentration and further studies have not shown this therapy to be consistently
TOPICAL
CARBENOXOLONE
SODIUM
141
Fig. 6
Fig. 5
Fig. 7 Figure 5-Severe recurrent mucocutaneous herpes prior to treatment. Figure &-Shows that healing is already occurring after 24 hours. Figure 7-Resolution of the lesions after a further 48 hours of treatment.
effective. If given systemically it may cause suppression of the myeloid and immune systems. Isolated case reports have suggested an increased incidlence of squamous cell carcinoma of the lip, developing at sites where recurrent herpes labialis has been treated with idoxuridine. Idoxuridine may activate oncogenic virus genes with the production of tumour virus particles (Stewart et cd., 1980), because it has the disadvantage as a thymidine analogue of being incorporated into host and viral DNA. Newer anti-virals take advantage of the difference between host and cellular metabolism. Acylovir (Zovirax), for instance, is undergoing extensive clinical trials but must be given intravenously because topical treatment is ineffective against herpes simplex virus 1 (Spurance et al., 1982), and strains of both herpes simplex and varicella zoster virus vary in their sensitivity to this drug. An increased incidence of resistant strains following therapy with Acylovir have been reported (Burns et al., 1982). Topical ether, which acts by destroying the lipid coat of the virus, is the only agent previously considered to be consistently effective against herpes labialis (Pasricha, 1973). Recent scientific trials have shown that it is no more effective than placebo treatment (Guinan et al., 1980). The exact effect-of Carbenoxolone on virus replication is as yet unknown. The drug is known to be a potent membrane stabiliser (Hossenbocus & Colin Jones, 1975) and its inhibitory effect may be due to the prevention of multiple cycles of
142
BRITISH
JOURNAL
OF
ORAL
&
MAXILLOFACIAL
Fig.
8
Fig.
9
SURGERY
Fig. 10 Figure
&Facial
herpes
prior to treatment.
Figure ~--TWO days post-treatment. post-treatment.
Figure
KLFour
days
virus release across the cell membrane. However, by the time that most virus infections are diagnosed, viral shedding has often already reached a peak; most cellular damage has already been done and the anti-inflammatory and healing potentiating effects of Carbenoxolone probably contribute significantly to its therapeutic effect. These actions include cortisol-like activity due to the chemical structure of the molecule; it is also a saponin and, therefore, has a general detergent or cleansing action. Recent work (Nakagawa & Asami, 1980), Symons et al., 1978), has shown that concentrations of triterpenoids below 10F4 M reduce
TOPICAL
Fig.
Figure
11-Severe
CARBENOXOLONE
Fig.
11
labial
herpes
prior
to treatment.
143
SODIUM
Figure
12-Five
12
days post-treatment.
Table I
Reduction in time to complete healing; Carbenoxolone with placebo.
treated group compared
io Days
to Complete
Healing
enzyme release from lysosome granules and may, therefore, reduce cell damage. The proven increase in mucosal blood flow after Carbenoxolone treatment may aid the repair process (Johnston & Mclsaac, 1980; Starlinger et al., 1981). Certain prostaglandins PG, PGE2, PGIz which are produced by gastric mucosa have been shown to accelerate ucler healing in viva (Miller 6i Jacobson, 1975; Robert et al., 1979). Carbenoxolone inhibits prostaglandin inactivating enzymes in vitro (Peskar, 1980), and if inhibition occurs in vivo an increase in the level of cytoprotective prostaglandins may contribute to the healing effect of triterpenoids. Carbenoxolone has been established in the management nf gastric and duodenal ulceration for 18 years and no teratogenic or carcinogenic side--effects have been reported. Systemic treatment has been associated with the development of mineralocorticoid side effects in a small proportion of older patients but no significant carbenoxolone serum concentrations have been noted after topical treatment. Early animal laboratory studies suggest that systemic therapy, given orally, intravenously or perhaps intrathecally may be considered in the future, thus increasing the value of these triterpenoids in the management of viral infections.
144
BRITISH
JOURNAL
OF
ORAL
&
MAXILLOFACIAL
SURGERY
Acknowledgements We thank the late Dr S. Gottfied of Biorex Laboratories Ltd. for his encouragement and supplies of sodium Carbenoxolone. The Photographic Department of The Royal Dental Hospital produced the illustrations; Miss J. Cooper and Mr I. Howard typed the manuscript: we thank them also. References Burns, H., Santos, G. W., Saral, R., Laskin, 0. L., Lietman, P. S., McLaren, C. & Barry, D. W. (1982) Isolation and Characteristics of Resistant Herpes Simplex Virus after Acyclovir Therapy. The Lancet, (i), 421. Communication. Fergusson, B . (1980).-Personal Guinan, M. E., MacCalman, J., Kern, E. S., Overall, J. C., Spotswood, L. & Spraunane, S. (1980). Topical ether and Herpes Simplex Labialis. Journal of the American Medical Association, 243, 1059.
Hossenbocus, A. & Colin Jones, D. G. (1975). Protection of the Human Gastric Mucosa from Asprin Membrane Stabiliser by Carbenoxolone. Fourth Symposium on Carbenoxolone. Butterworths, London. Johnston, B. J. & McIsaac, R. L. (1981). The Effect of Some Anti-ulcer Agents on Mucosal Blood Flow. British Journal of Pharmacology, 73, 308. Lipkin, M. (1971). Carbenoxolone Sodium and the Rate of Extrusion of Gastric Epthelial Cells. Gut, 125, 99. MacCallum, F. U. & Juel Jensen, B. E. (1966). Herpes Simplex virus skin infections in man treated with lodoxuridine in Dimethyl Sulphoxide. Results of double-blind controlled trial. British Medical Journal. ii, 805. Miller, T. A. &Jacobson, E. D. (1979). Gastrointestinal Cytoprotection by Prostaglandins. Gut, 20,75. Mitsheria, L. A., Young, L. P., Clark, D. &. Beal, J. C. (1980). Anti-microbial Iso Flavonoids and Related Substances from Glycrrhizia Glabra. L. var Typica. Journal of Natural Products, 43, 259. Nakagawa, K. & Asami, M. (1980). Effect of Glycrrhizin on Hepatic Lysozomal Systems. Japanese Journal
of Pharmacology,
31, 850.
Pasricha, J. S., Nayyar, K. C. & Pasricha (1973). A New Treatment for Treatment of Herpes Simplex. Archives
of Dermatology,
107, 775.
Peskar, B. M. (1980). Effect of Carbenoxolone on Prostaglandin Synthesing and Metabolising Enzymes and Correlation with Gastric Mucosal Carbenoxolone Concentrations. Scandinavian Journal of Gastroenterology, 15, Supp 65, 109. Pompei, R., Pani, A., Flore, 0.) Marcialis, M. A. & Loddo, B. (1980). Anti-viral Activity of Glycrrhizic Acid. Experientia, 36, 304. Poswillo, D. E. & Roberts, G. J. (1981). Topical Carbenoxolone for Orofacial Herpes Simplex Infection. Lance& (i), 143. Robert, A., Nezamis, J. E., Lancaster, C. & Manchar, A. J. (1979). Cytoprotection by Prostaglandins in Rats. Gastroenterology, 77, 433. Samuel, 0. W. (1967). Periadenitis Mucosa Necrotica Recurrens Treated with Topical Carbenoxolone Gel. Practitioner, 199, 220. Schmelzle, R., Rolffs, J. & Warner, H. (1975). Experience with a new Gel for the Treatment of Inflammatory and Traumatic Mucosal Lesions of the Lips and Mouth. Quintessenz, 26, 10. Spurance, S. L., Schnipper, L. E., Overall, J. C., Kern, E. R., Wesler, B., Modlin, J., Wenerstrom, C. T., Burton, C., Arndt, K. A., Chiu, G. L. & Crumpacker, C. S. (1982). Treatment of Herpes Simplex Labialis with Topical Acyclovir polyethylene glycol. Journal of Infective Diseases, 146, 85. Starlinger, M., Schiessel, R., Chen Road Hung, & Silen, W. (1981). H+ Back Diffusion Stimulating Gastric Mucosal Blood Flow in the Rabbit Fundus. Surgery, 89, 232. Stewart S. E.. Kasnic. G. & Dravcott, C. (1972‘). Activitation of Viruses in Human Tumours bv . 5-Iododeoxyuridink and Dimeihyl Sulfokide. ‘Dimethyl Sulphoxide. Science, 18, 198. Symons, A. H., Johnson, B. & Parke, D. V. (1978). The Effect of Sodium Carbenoxolone on Lysosomal Enzyme Release. Biochemical Pharmacology, 27, 2461.
TOPICAL CARBENOXOLONE
SODIUM IN THE MANAGEMENT
OF HERPES
SIMPLEX INFECTION
MAXINEPARTRIDGE, B.D.s.,F.D.s.R.c.s., andD. E. POSWILLO,D.D.s.,D.s~., F.D.S.R.C.S., F.R.A.C.D.S., F.I.Bml.,F.R.C.Path. Department
of Oral Surgery,
The Royal Dental Hospital, Leicester London WC2
Square,
Summary. Topical Carbenoxolone was discovered by chance to be a highly effective anti-viral agent and was subsequently used in the management of Herpetic gingivostomatitis and recurrent Herpes labialis. A marked reduction in the healing time and pain associated with these lesions was noted. A discussion of the possible mechanisms of action of Carbenoxolone is included.
Introduction
Recent advances in anti-viral chemotherapy have failed to produce an agent which has been shown to be consistently effective, without harmful side-effects, in the management of mucocutaneous herpes simplex infection. The lesions produced by this ancient scourge are generally mild and self-limiting but for patients who have severe and frequent attacks the lesions may be disfiguring and annoying. Herpes virus infection was previously regarded principally as a childhood illness but in Western countries, with a high standard of living, an increasing number of adult cases are appearing, probably due to the better resistance to these illnesses in childhood. Thirty per cent of all patients who have primary herpetic stomatitis develop recurrent infections later in life. Patients receiving immunosuppressive therapy, especially those with reticula-endothelial cancers, have an increased susceptibility to these latent infections as cell-mediated immunity plays an important part in the defence mechanisms against the virus and an increasing number of individuals are presenting with herpes simplex or zoster infection. Herpes virus is dermatrophic and thus amenable to topical therapy. Treatment aims to reduce the severity of the acute attack and the chronicity and the recurrence rate of subsequent attacks. This must be done without subjecting the patient to acute toxic side effects, such as depression of the immune system or chronic adverse reactions, such as an increased risk of dysplastic change. Treatments available to date often fall short of these criteria and their use in minor recurrent infection seems unjustified. However, in view of the provocative suggestion that herpes simplex virus may be associated with dysplastic change, safe and effective treatment remains the ultimate goal. Carbenoxolone is synthesised from glycyrrhetic acid which is the aglycone of glycyrrhizin found in glycyrrhizia glabra or liquorice root. Glycyrrhizic acid has been shown to inhibit both the growth and the cytopathic effects of several unrelated viruses, including herpes simplex virus, Pompei et al. (1980). Carbenoxolone was subsequently shown to have highly significant activity against herpes virus both in vitro, Tyrell (1981), and in vivo, Poswillo and Roberts (1981). This anti-viral activity is increased using the cyclohexane dicarboxylic acid analogue of (Received
11 October
1982; accepted 27 January
138
1983)
TOPICAL
CARBENOXOLONE
SODIUM
139
Carbenoxolone, Cicloxolone. These compounds are all triterpenoids. Extracts of liquorice root have been shown to have anti-bacterial activity, Mitsheria et al. (1980), and this useful property helps to reduce the severity of secondary infection usually associated with these lesions. Soluble Carbenoxolone granules were prepared by the manufacturer. Two grammes were disolved in 30 ml of warm tap water as required to give a 0.067 per cent mouth rinse as the solution, once prepared, is unstable. Topical treatment was devised and used initially in the management of recurrent oral ulceration as a result of the observation that a number of patients receiiing pyrogastrone for peptic oesophagitis reported a reduction in the incidence and severity of chronic oral ulceration, Fergusson (1980). A reduction in the discomfort and healing time of oral ulceration had already been reported, Samuel (1967), Schmelzle et al. (1975). It seemed possible that the proven ability of Carbenoxolone to increase the resistance of the gastric mucosa to breakdown, Lipkin (1971), and to increase mucosal blood flow, Johnston and McIsaac (1980)) Starllinger et al. (1981)) might be responsible for these observed changes as the oral and gastric mucosa are similar in many respects; the oral mucosa being specialised due to its position at the head of the alimentary system. The mouth rinse was subsequently given to a dentist suffering from severe primary herpes infection and the treatment gave a dramatic improvement in symptoms much greater than could be expected relying on the healing potentiating properties of Carbenoxolone alone. This chance finding promoted a further open trial and a multi-centre double blind placebo controlled trial is now in progress. Case Reports Primary infection
Primary herpes infection presents characteristically with gingivitis and multiple shallow ulcers throughout the mucosa (Figs. 1 & 2). Herpes virus was isolated by laboratory culture at the onset of treatment for 12 patients and levels of antibody to the virus were measured at Day One and Day Ten. With topical Carbenoxolone therapy used six times daily for three days, the lesions have disappeared (Figs. 3 & 4). The most dramatic improvement being the consistent lack of pain and dysphagia after 24 to 48 hours treatment, with ulceration and lymphadenopathy gradually resolving after a further one to three days. It can be difficult to demonstrate convincingly the therapeutic efficacy of treatment of these lesions as natural healing begins within three to four days and because of the variable course of the disease among different persons, but all of our patients treated with Carbenoxolone have shown a reduction in time to complete healing of five to six days as compared to controlled cases (Table I). Recurrent infection
This generally presents as an area of swollen labial mucosa on which develop multiple vesicles which rupture to leave a crusted mass which gradually heals over ten to 14 days. It may affect a small area of the lip or the whole of the labial mucosa and the lesions may extend around the nose or on the chin. Am aqueous two per cent cream was developed to treat these recurrences and used in placebo controlled double blind study involving 50 patients where herpes virus was isolated from the lesions and previous infection was confirmed by measurement of herpes simplex virus antibody titre. Figure 5 shows unusually severe painful recurrent infection of
140
BRITISH
JOURNAL
OF
ORAL
&
MAXILLOFACIAL
SURGERY
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Figures 1 and 2- Characteristic oral ulceration and gingivitis associated with primary herpes simplex virusinfection. Figures 3 and 4-Resolution of lesions after topical Carbenoxolone therapy was given six hourly for 72 hours.
24 hours duration. Topical Carbenoxolone was used six times daily; after 24 hours (Fig. 6) the patient was pain free and the erythema was already beginning to fade. After 48 hours the lesion had disappeared (Fig. 7). Half of the cases treated to date, all of whom had a long history of recurrent infection, have had no recurrence within six months; in the remainder, new lesions have been aborted within 48 hours of treatment. Other anti-viral agents have given no significant improvement in preventing recurrent infections. Cases of herpes zoster have been successfully treated using a combination of the mouth rinse and cream and to date there have been no reports of post-herpetic neuralgia. Topical treatment is also being evaluated in the management of radiation mucositis as the anti-inflammatory and healing potentiating effects may be of therapeutic use both in reducing pain and potentiating repair of ulcerated tissue. Discussion
These results suggest that Carbenoxolone and its analogues are more effective than other currently available anti-viral drugs, particularly for recurrent infection. Idoxuridine five per cent has been ‘shown to shorten the healing time of these lesions (Juel-Jenson & MacCallum, 1965), but may cause skin irritation at this concentration and further studies have not shown this therapy to be consistently
TOPICAL
CARBENOXOLONE
SODIUM
141
Fig. 6
Fig. 5
Fig. 7 Figure 5-Severe recurrent mucocutaneous herpes prior to treatment. Figure &-Shows that healing is already occurring after 24 hours. Figure 7-Resolution of the lesions after a further 48 hours of treatment.
effective. If given systemically it may cause suppression of the myeloid and immune systems. Isolated case reports have suggested an increased incidlence of squamous cell carcinoma of the lip, developing at sites where recurrent herpes labialis has been treated with idoxuridine. Idoxuridine may activate oncogenic virus genes with the production of tumour virus particles (Stewart et cd., 1980), because it has the disadvantage as a thymidine analogue of being incorporated into host and viral DNA. Newer anti-virals take advantage of the difference between host and cellular metabolism. Acylovir (Zovirax), for instance, is undergoing extensive clinical trials but must be given intravenously because topical treatment is ineffective against herpes simplex virus 1 (Spurance et al., 1982), and strains of both herpes simplex and varicella zoster virus vary in their sensitivity to this drug. An increased incidence of resistant strains following therapy with Acylovir have been reported (Burns et al., 1982). Topical ether, which acts by destroying the lipid coat of the virus, is the only agent previously considered to be consistently effective against herpes labialis (Pasricha, 1973). Recent scientific trials have shown that it is no more effective than placebo treatment (Guinan et al., 1980). The exact effect-of Carbenoxolone on virus replication is as yet unknown. The drug is known to be a potent membrane stabiliser (Hossenbocus & Colin Jones, 1975) and its inhibitory effect may be due to the prevention of multiple cycles of
142
BRITISH
JOURNAL
OF
ORAL
&
MAXILLOFACIAL
Fig.
8
Fig.
9
SURGERY
Fig. 10 Figure
&Facial
herpes
prior to treatment.
Figure ~--TWO days post-treatment. post-treatment.
Figure
KLFour
days
virus release across the cell membrane. However, by the time that most virus infections are diagnosed, viral shedding has often already reached a peak; most cellular damage has already been done and the anti-inflammatory and healing potentiating effects of Carbenoxolone probably contribute significantly to its therapeutic effect. These actions include cortisol-like activity due to the chemical structure of the molecule; it is also a saponin and, therefore, has a general detergent or cleansing action. Recent work (Nakagawa & Asami, 1980), Symons et al., 1978), has shown that concentrations of triterpenoids below 10F4 M reduce
TOPICAL
Fig.
Figure
11-Severe
CARBENOXOLONE
Fig.
11
labial
herpes
prior
to treatment.
143
SODIUM
Figure
12-Five
12
days post-treatment.
Table I
Reduction in time to complete healing; Carbenoxolone with placebo.
treated group compared
io Days
to Complete
Healing
enzyme release from lysosome granules and may, therefore, reduce cell damage. The proven increase in mucosal blood flow after Carbenoxolone treatment may aid the repair process (Johnston & Mclsaac, 1980; Starlinger et al., 1981). Certain prostaglandins PG, PGE2, PGIz which are produced by gastric mucosa have been shown to accelerate ucler healing in viva (Miller 6i Jacobson, 1975; Robert et al., 1979). Carbenoxolone inhibits prostaglandin inactivating enzymes in vitro (Peskar, 1980), and if inhibition occurs in vivo an increase in the level of cytoprotective prostaglandins may contribute to the healing effect of triterpenoids. Carbenoxolone has been established in the management nf gastric and duodenal ulceration for 18 years and no teratogenic or carcinogenic side--effects have been reported. Systemic treatment has been associated with the development of mineralocorticoid side effects in a small proportion of older patients but no significant carbenoxolone serum concentrations have been noted after topical treatment. Early animal laboratory studies suggest that systemic therapy, given orally, intravenously or perhaps intrathecally may be considered in the future, thus increasing the value of these triterpenoids in the management of viral infections.
144
BRITISH
JOURNAL
OF
ORAL
&
MAXILLOFACIAL
SURGERY
Acknowledgements We thank the late Dr S. Gottfied of Biorex Laboratories Ltd. for his encouragement and supplies of sodium Carbenoxolone. The Photographic Department of The Royal Dental Hospital produced the illustrations; Miss J. Cooper and Mr I. Howard typed the manuscript: we thank them also. References Burns, H., Santos, G. W., Saral, R., Laskin, 0. L., Lietman, P. S., McLaren, C. & Barry, D. W. (1982) Isolation and Characteristics of Resistant Herpes Simplex Virus after Acyclovir Therapy. The Lancet, (i), 421. Communication. Fergusson, B . (1980).-Personal Guinan, M. E., MacCalman, J., Kern, E. S., Overall, J. C., Spotswood, L. & Spraunane, S. (1980). Topical ether and Herpes Simplex Labialis. Journal of the American Medical Association, 243, 1059.
Hossenbocus, A. & Colin Jones, D. G. (1975). Protection of the Human Gastric Mucosa from Asprin Membrane Stabiliser by Carbenoxolone. Fourth Symposium on Carbenoxolone. Butterworths, London. Johnston, B. J. & McIsaac, R. L. (1981). The Effect of Some Anti-ulcer Agents on Mucosal Blood Flow. British Journal of Pharmacology, 73, 308. Lipkin, M. (1971). Carbenoxolone Sodium and the Rate of Extrusion of Gastric Epthelial Cells. Gut, 125, 99. MacCallum, F. U. & Juel Jensen, B. E. (1966). Herpes Simplex virus skin infections in man treated with lodoxuridine in Dimethyl Sulphoxide. Results of double-blind controlled trial. British Medical Journal. ii, 805. Miller, T. A. &Jacobson, E. D. (1979). Gastrointestinal Cytoprotection by Prostaglandins. Gut, 20,75. Mitsheria, L. A., Young, L. P., Clark, D. &. Beal, J. C. (1980). Anti-microbial Iso Flavonoids and Related Substances from Glycrrhizia Glabra. L. var Typica. Journal of Natural Products, 43, 259. Nakagawa, K. & Asami, M. (1980). Effect of Glycrrhizin on Hepatic Lysozomal Systems. Japanese Journal
of Pharmacology,
31, 850.
Pasricha, J. S., Nayyar, K. C. & Pasricha (1973). A New Treatment for Treatment of Herpes Simplex. Archives
of Dermatology,
107, 775.
Peskar, B. M. (1980). Effect of Carbenoxolone on Prostaglandin Synthesing and Metabolising Enzymes and Correlation with Gastric Mucosal Carbenoxolone Concentrations. Scandinavian Journal of Gastroenterology, 15, Supp 65, 109. Pompei, R., Pani, A., Flore, 0.) Marcialis, M. A. & Loddo, B. (1980). Anti-viral Activity of Glycrrhizic Acid. Experientia, 36, 304. Poswillo, D. E. & Roberts, G. J. (1981). Topical Carbenoxolone for Orofacial Herpes Simplex Infection. Lance& (i), 143. Robert, A., Nezamis, J. E., Lancaster, C. & Manchar, A. J. (1979). Cytoprotection by Prostaglandins in Rats. Gastroenterology, 77, 433. Samuel, 0. W. (1967). Periadenitis Mucosa Necrotica Recurrens Treated with Topical Carbenoxolone Gel. Practitioner, 199, 220. Schmelzle, R., Rolffs, J. & Warner, H. (1975). Experience with a new Gel for the Treatment of Inflammatory and Traumatic Mucosal Lesions of the Lips and Mouth. Quintessenz, 26, 10. Spurance, S. L., Schnipper, L. E., Overall, J. C., Kern, E. R., Wesler, B., Modlin, J., Wenerstrom, C. T., Burton, C., Arndt, K. A., Chiu, G. L. & Crumpacker, C. S. (1982). Treatment of Herpes Simplex Labialis with Topical Acyclovir polyethylene glycol. Journal of Infective Diseases, 146, 85. Starlinger, M., Schiessel, R., Chen Road Hung, & Silen, W. (1981). H+ Back Diffusion Stimulating Gastric Mucosal Blood Flow in the Rabbit Fundus. Surgery, 89, 232. Stewart S. E.. Kasnic. G. & Dravcott, C. (1972‘). Activitation of Viruses in Human Tumours bv . 5-Iododeoxyuridink and Dimeihyl Sulfokide. ‘Dimethyl Sulphoxide. Science, 18, 198. Symons, A. H., Johnson, B. & Parke, D. V. (1978). The Effect of Sodium Carbenoxolone on Lysosomal Enzyme Release. Biochemical Pharmacology, 27, 2461.