- 4

eton to normal.[1] Estrogens are currently the treatment of References choice in preventing postmenopausal bone loss.[l] They have additional benefits on cardiovascular risk. Treatment I. Consensus development conference: diagnosis, prophylaxis and treat­ should be started early in the menopause and continued for ment of osteoporosis. Am 1 Med 1991; 94: 646-9 2. Griffine GT, Allen SH. Estrogen replacement therapy at menopause: at least 5 years. how benefits outweigh risks. Postgrad Med 1994; 96(5): 131-40 However, there is no consensus as to whether all women 3. Gennari C, Nuti R, Agnusdei D, et al. Management of osteoporosis and should be treated, or just those judged to be at highest risk Paget's disease: an appraisal of the risks and benefits of drug treat­ of developing osteoporosis (e.g. natural or surgical meno­ ment. Drug Saf 1994; 11: 179-95 4. Kanis lA. What constitutes evidence for drug efficacy in osteoporosis? pause at <45 years of age). The use of calcitriol in the Drug Aging 1993; 3: 391-9 prevention of postmenopausal osteoporosis has not been 5. Dechant KL, Goa KL. Calcitriol: a review of its use in the treatment of investigated. postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosis. Drugs Aging 1994; 5: 300-17 Of the various drugs used in the treatment of patients 6. Cooper C, Aihie A. Osteoporosis: recent advances in pathogenesis and with established postmenopausal osteoporosis, there are treatment. Q1M 1994; 87: 203-9 few or no comparative data to assess relative efficacy. In 7. British National Formulary No. 28. London: The Pharmaceutical Press, addition, available data for some of these agents are equiv­ 1994; 286-8, 299-300, 371-2 ocal. Adequate dietary calcium is important, and supple­ 8. Physicians GenRx. New York: Data Pharmaceutica Inc., 1994 9. Dunn Cl, Fitton A, Sorkin EM. Etidronic acid: a review of its pharma­ ments may be necessary. cological properties and therapeutic efficacy in resorptive bone dis­ There are marked geographical differences in the use ease. Drug Aging 1994; 5: 466-74 of the various drugs. In the US and the UK, the initial 10. Riggs BL, Hodgson SF, O'Fallon, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. New choice in a patient with established postmenopausal os­ Engl 1 Med 1990; 322: 802-9 teoporosis is an estrogen.l6,15] Bisphosphonates and cal­ II. Tilyard MW, Spears GFS, Thomson 1, et al. Treatment of postme no­ citonin are the most commonly used alternatives. It is pausal osteoporosis with calcitriol or calcium. New Engl 1 Med worth noting that calcitonin has considerably higher ac­ 1992;326: 357-62 quisition costs than the other agents (see Differential 12. Ott SM, Chesnut CH. Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med 1989; 110: 267-74 Features table). However, this drug may be particularly 13. Gallagher lC, Goldgar D. Treatment of postmenopausal osteoporosis appropriate in the first 6 weeks after a fracture because with high doses of synthetic calcitriol. Ann Intern Med 1990; 113: of its additional analgesic properties.l6] 649-55 14. Aloia JF, Vaswani A, Yeh lK, et al. Calcitriol in the treatment of Results from the largest study of calcitriol, which postmenopausal osteoporosis. Am 1 Med 1988; 84: 401-8 showed that it prevented fractures, indicate that calcitriol 15. Lindsay R. Prevention and treatment of osteoporosis. Lancet 1993; should be evaluated further. 341: 801-5

Although the drug appears to be effective topically in Amorolfine: topical therapy patients with superficial fungal infections of the skinp-4] the lack of trials comparing amorolfine with the plethora of for mild onychomycosis available agents hinders evaluation of its role in these indi­ cations. Thus, this article will consider the use of amorolfine nail Amorolfine is a novel antifungal drug that paint in fungal infections of the nail (onychomycosis), a has been formulated as a nail paint. This pain! has shown condition in which topical therapy has hitherto been disap­ promise as a topical therapy for onychomyco is. pointing and in which the results of trials of amorolfine have Approximately one-half of paticnts with mild disea e not been encouraging.l5] involving the nail matrix and predominantly dermatophyte infection have achieved mycological and clinical cure in rela­ tively small clinical trials conducted to date. Efficacy appears Onychomycosis to be greater in finger- versu toenail. The drug has also Onychomycosis may be caused by a variety of organ­ produced some encouraging results as an adjuvant to oral isms including dermatophytes (e.g. Trichophyton rubrum), griseofulvin. yeasts (e.g, Candida albicans) and moulds (e.g. When applied to the nails in a paint formulation, amorolfine Scopulariopsis brevicaulis).l5] Of these, the dermatophytes has been well tolerated. Fewer than 2% of treated patients have are the most frequent causative organisms.l5] expericnced adverse events, and aU of the reported adver e Onychomycosis is characterised by discolouration of the event have been mild and locali cd to the ite of application. nail, hyperkeratosis and separation of the nail from the nail The drug appear to be a uitable alternative to other topical bed (onycholysis). In addition, onychomycosis is often sec­ agents for u e in patients with mild disease. However, patients ondary to, or accompanied by, fungal infections of the skin with more extensive disease, including nail matrix involve­ or other nail disorders. ment, require systemic therapy. There are 4 main types of onychomycosis, as follows. ll ] 1 Distal and lateral subungual. This is the commonest form, Amorolfine t is a novel antifungal agent, structurally in which the infection starts at the distal edge or side ofthe unrelated to other available antifungal drugs. [1] It is applied nail and progresses proximally. topically for the treatment of superficial fungal infections t Amorolfine is not available in Australia, Canada, The Netherlands, Spain of the skin and nails. or the US.

Vol. 5, No.5; March 20, 1995 1172-0360195/()()()5-004/$Ol.OO CAdis International limited. AU rights rese",ed 2 Superficial white. An uncommon form mainly observed in toenails, in which white 'islands' of infection arise in the Adis Evaluation superficial layers of the nail plate and may be scraped off. 3 Proximal subungual. An uncommon form in which the Key points in the overall evaluation of topical infection progresses distally from the nail fold. amorolfine in patients with onychomycosis 4 Total dystrophic. A severe form of onychomycosis that may CLINICAL BENEFITS ______arise from any of the preceding presentations, and involv­ ing total destruction of the nail plate. • Appears to be more effective than alternative topical It has been estimated that almost 3% of the UK popula­ therapies tion is affected by dermatophyte nail inf~ctions.l6] • Well tolerated • Requires less frequent application than other topical agents Amorolfine POTENTIAL LIMITATIONS ______Amorolfine is a morpholine drug that, in common with other antifungal agents, inhibits the formation of ergosterol, • Suitable only for mild disease without nail matrix involvement which is a component of the fungal cell membrane.[l] How­ ever, amorolfine inhibits enzymes at a later stage in the • Therapy must be continued for 6 to 12 months without conversion of acetyl-coenzyme A to ergosterol than the interruption azole or allylamine antifungals. Amorolfine has in vitro activity against a wide range of There was no statistically significant difference in cure rates fungi, with dermatophytes and dimorphic fungi being the when amorolfine 5% nail paint was applied once weekly or most susceptible.[l] twice weekly (clinical and mycological cure was reported In vivo evaluations suggest that the drug is inactive in in 46 and 52% of patients, respectively))9] systemic fungal infections, possibly because of rapid meta­ Both prolonged duration of treatment and relatively bolism, extensive protein binding or reduced activity at core short duration of onychomycosis appear to increase the body temperatures)l] However, animal studies have dem­ likelihood of clinical and mycological cure with amorolfine onstrated that the drug is active in cutaneous Trichophyton therapy) 1] mentagrophytes infections and vaginal candidiasis.[l] In addition, amorolfine appeared to be more effective in Pharmacokinetics patients with T. mentagrophytes infection than.T. rubrum infection)8.9] The drug also appears to have greater efficacy The permeation of amorolfine into human nail appears in fingernail infections than in toenail infections)l] to vary according to: Amorolfine was well tolerated in both of these dose­ • nail layer (with more drug being present in the uppermost finding trials. Mild, localised adverse effects were reported layers) by :::;2% of patients and did not require drug discontinua­ • disease (soft, diseased nails are less retentive than healthy, tion)8.9] hard, compact nails) There has been one nonblinded trial evaluating the use • vehicle (penetration is better with the commercially avail­ of amorolfine 5% nail paint as an adjuvant to twice-weekly able methylene chloride base than with ethanol, but worse oral therapy with griseofulvin)IO] One group of patients than with penetration enhancers). [1] received amorolfine and griseofulvin 1 g/day for 2 months However, it appears from in vitro permeation studies that followed by amorolfine alone for 4 months. The other group amorolfine attains sufficient concentrations in both the nail received griseofulvin 1 g/day for 2 months then 0.5 g/day plate and bed to have fungistatic and fungicidal activity for a further 4 months. Patients receiving amorolfine had against fungal species including dermatophyies and dimor­ higher mycological cure rates than those receiving phic fungi.[1] griseofulvin monotherapy at both 2 (42 vs 13%) and 6 months (67 vs 45%).[10] Clinical trials While this study indicates that amorolfine may have an There do not appear to have been any placebo-controlled adjuvant role in patients requiring systemic therapy, the trials of amorolfine nail paint in the treatment of onycho­ results require confirmation in a more rigorously designed mycosis. study. Future studies would preferably include other com­ Trials involving a total of >600 patients have evaluated parators, such as combined therapy for 6 months and the efficacy and safety of 2 amorolfine nail paint concentra­ amorolfine mono therapy. In addition, it remains to be seen tions (5 vs 2%) and dosage intervals (once vs twice whether amorolfine would be a useful adjuvant to systemic weekly).[8.9] In these trials, patients had mild nail disease therapy with more recently introduced antifungal agents. (affecting :::;80% of the nail surface with intact lunula and matrix), predominantly distal subungual infections affect­ Other drugs used in onychomycosis ing the toenails (>73% of patients) and generally caused by dermatophytes (T. rub rum in 51 to 59% of patients and T. Topical therapy plays a minor role in the therapy of mentagrophytes in 15 to 22%). Concomitant skin infections onychomycosis. Systemic therapy is appropriate for the were treated with amorolfine 0.5% cream. Treatment for majority of patients with onychomycosis, particularly when onychomycosis was continued until complete cure or for a infection extends proximally to the posterior nail fold)5.7] maximum of 6 months. The benefits and limitations of some orally administered Application of 5% nail paint was associated with signif­ drugs used in the treatment of onychomycosis are summarised icantly higher overall cure rates than 2% nail paint (38 vs in table 1. Although there is a lack of comparative trials of these 12%, respectively) when each was applied once weekly)8] agents, itraconazole and terbinafine appear to be preferable to

1172·0360/95/0005·005/$01.00 ©Adis International Limited. All rights reserved Vol. 5, No.5; March 20, 1995 Table 1. Comparison of the efficacy, benefits and limitations of orally administered antifungal agents used in the treatment of onychomycosis[5,7, 11 J

Feature Griseofulvin Ketoconazole Itraconazole Terbinafine

Cure rates (%1 Toenoils 10-50 50 73-79 80-85 Fingernails .,80 ",80 64 71

Benefits Well tolerated Broad spectrum of antifungal Well tolerated Well tolerated activity Broad spectrum of Fungicidal in vitro at low antifungal activity concentrations Persists in nails for long short treatment courses (3-6 periods; short treatment months for toenails; 6 weeks courses (3 months) for fingernails) appeor appear effective effective

Limitations Only active in dermatophyte May cause hepatitis Interacts with ather drugsO In vivo activity limited to infections Prolonged treatment dermatophytes Prolonged treatment required required (4-6 months far May couse reversible (4-6 months for fingernails; fingernails; 12·15 months cholestasis (1 in 40 000 12-15 months for toenails) for toenails) patients) Interacts with other drugsO Interacts with other drugsO Interacts with other drugsO

a Predominantly those metabolised by the hepatic cytochrome P450 enzymes, such as anticoagulants and phenobarbital (phenobarbitone).

the older agents since they have produced higher cure rates, Prescribing and formulary considerations are not associated with a significant risk of hepatitis, and may be effective with shorter treatment courses. The data relating to the efficacy of amorolfine in patients There are few topical alternatives to amorolfine. with onychomycosis may be considered to be preliminary. Tioconazole t nail paint is commercially available in the There appear to have been no published trials employing a UK, and is compared with amorolfine in the Differential treatment duration of >6 months, even though 9 to 12 Features table. months is the recommended duration of treatment for toe­ Although the 2 have not been directly compared, nail disease.[13] Follow-up periods after treatment cessation tioconazole appears to be less effective than amorolfine, and have also been short (3 months), which confounds any requires more frequent administration. conclusions regarding the risk of relapse following initial In another trial, a paste of bifonazole t I % and urea therapy. 40% applied daily under occlusion was associated with a In addition, amorolfine monotherapy has not been com­ mycological and clinical remission rate of 46% at 24 pared with either placebo or alternative antifungal therapies weeks.lI2] However, this approach appears to be less con­ to date. venient and no more effective for patients than amorolfine Trials of amorolfine monotherapy have been limited to nail paint. patients with mild nail plate disease and no matrix involve­ ment.[8,9] Thus, the drug may be useful in clinical practice Differential Features for patients with similarly mild disease. For these patients, available data suggest that amorolfine 5% nail paint may be Comparison of the features of amorolfine 5% and preferable to tioconazole 28% nail paint (see Differential tioconazole 28% nail paints! 1,13,14] Features table).

Feature Amorolfine 5% Tioconazole Nonetheless, the majority of patients will continue to 28% require systemic therapy.l5,7] While preliminary data suggest that amorolfine may be Drug class Morpholine Imidazole derivative a useful adjuvant to oral griseofulvin therapy,[IO] this re­ quires confirmation. The role of amorolfine as an adjuvant Mechanism of action Inhibition of Inhibition of to oral therapy with an azole (e.g. itraconazole) or allylam­ ergosterol ergosterol biosynthesis biosynthesis ine (e.g. terbinafine) antifungal has not been evaluated, and (/).7 a-isomerase (C·14 so cannot be recommended at present. and /l1d-reductase) demethylase) Another potential use for amorolfine in patients with In vitro activity onychomycosis is as an adjuvant following chemical or Dematophytes ./ ./ surgical nail avulsion. Once again, there is no evidence Pathogenic yeasts .//x ./ currently that amorolfine is effective in this situation. Mycological and 38-55% :s;22% clinical cure rate in onychomycosis References 1. Haria M, Bryson HM. Amorolfine. A review of its pharmacological prop­ Fr:\uency of Once or twice Twice daily app ication weekly erties and therapeutic potential in the treatment of onychomycosis and other superficial fungal infections. Drugs 1995; 49: 103-20 Acquisition cost 2. del Palacio A, Gip L, Bergstraesser M, et a!. Dose-finding study of In the UK (£) 34.38 (5ml) 27.38 (12ml) amorolfine cream (0.125%, 0.25% and 0.5%) in the treatment of dermatomycoses. Clin Exp Dermatol 1992; 17 Supp!. 1: 50-5 Symbols: ./ = drug is generally active; .//x = drug has variable activity. t Tioconazole nail paint is not available in Australia, Canada, Denmark, France or the US; bifonazole is not available in Australia or the US.

VoL 5, No.5; March 20, 1995 1172-0360/95/0005-006/$01.00 "Adis International Limited. All rights reserved 3. Nolting S. Semig G, Friedrich HK, et a!. Double-blind comparison of lacquer 5% in onychomycosis, once-weekly versus twice-weekly. amorolfine and bifonazole in the treatment of dennatomycoses. Clin Clin Exp Dennato) 1992; 17 Supp!. ): 44-9 Exp Dennatol 1992; 17 Supp!. I: 56-60 10. Lauharanta J, Zaug M, Polak A, et a!. Combination of amorolfine with 4. Nolting S, Reinel D, Semig G, et a!. Amorolfine spray in the treatment of griseofulvin: in vitro activity and clinical results in onychomycosis. foot mycoses (a dose-finding study). Br J Dermatol1993; 129: 170-4 JAMA South East Asia 1993; 9 Supp!. 4: 23-7 5. Hay RJ. Onychomycoses. Agents of choice. Dennatol Clin 1993; II: 161-9 II. Hay RJ, Clayton YM, Moore MK, et a!. An evaluation of itraconazole in 6. Roberts TD. Prevalence of dennatophyte onychomycosis in the United the management of onychomycosis. Br J Dermatol 1988; 119: 359-66 Kingdom: results of an omnibus survey. Br J Dermatol 1992; 126 12. Hay RJ, Roberts DT, Doherty VR, et a!. The topical treatment of onycho­ Supp!. 39: 23-7 mycosis using a new combined urea/imidazole preparation. Clin Exp 7. Roberts DT. Oral therapeutic agents in fungal nail disease. J Am Acad Dermatol1988; 13: 164-7 Dermatol 1994; 31 (3 Pt 2): 78-81 13. British National Fonnulary No. 28. London: The Phannaceutical Press, 8. Lauharanta J. Comparative efficacy and safety of amorolfine nail lacquer 1994; 449-51 2% versus 5% once weekly. Clin Exp Dennatol 1992; 17 Supp!. I: 41-3 14. Hay RJ, Mackie RM, Clayton YM. Tioconazole nail solution - an open study of 9. Reinel D, Clarke C. Comparative efficacy and safety of amorolfine nail its efficacy in onychomycosis. Clin Exp Dennato11985; 10: 111-5

However, despite promising immunological responses, Many avenues explored in studies using other HSV-2 glycoprotein vaccines have failed to prevent infection in patients at risk of acquiring genital search for herpes vaccines HSV.l9,1O] Thus far, the only indication that subunit vaccines are of Vaccine development may be the key to controlling clinical benefit has come from a trial involving vaccination herpes simplex virus (HSV), since attempts at eradicating of patients with a history of recurrent genital herpes.[ll] In the virus once infection is acquired have been universally these patients, 2 doses of vaccine reduced the median num­ unsuccessful. Advances in recombinant DNA technology ber of recurrent episodes from 6/year in placebo recipients have expanded the options available for vaccine develop­ to 4/year in vaccine recipients.lll] Means of enhancing the ment. Potential approaches include: efficacy of this vaccine are being sought, since the prophy­ • live vaccines using either avirulent HSV strains, replica­ lactic efficacy of vaccination in this trial was less than the tion-incompetent viruses or avirulent carrier viruses ex­ protection offered by prophylactic aciclovir.[ll] pressing HSV glycoproteins • killed HSV vaccines Live vaccines • subunit vaccines Live vaccines may include modified forms of HSV or • genetic immunisation.[I] use another virus expressing HSV glycoproteins as a vector. In addition, vaccines are being evaluated both as primary Vaccines using live vectors have not yet been evaluated in protection against infection and as a means of reducing clinical trials. recurrent disease once infection has been acquired. Vaccines using vaccinia and adenovirus vectors have protected animals against primary infection.[l] In addition, Vaccine development intranasal administration of a recombinant adenovirus vec­ tor expressing glycoprotein B of HSV-l has been shown to Subunit vaccines induce mucosal humoral and cell-mediated immunity in mice.[l2] This may be important for protection against ini­ Subunit vaccines composed of HSV glycoproteins ap­ tial infectionJl2] pear to have been most extensively evaluated to date, with some vaccines in phase III trials. Strains of HSV that do not cause disease have also been In preclinical trials, HSV-l and HSV-2 glycoprotein studied as potential vaccines, since prior infection with vaccines have been shown to produce high antibody titres, mutant viruses has been shown to protect animals against HSV infection.[l] However, the only avirulent virus vaccine prevent primary infection and protect against the estab­ lishment of latent infections in sensory gangliap,3] evaluated in clinical trials to date appears to have poor immunogenicity.ll] Moreover, there is concern that mutant Administration of HSV-l glycoprotein vaccines with immunostimulants such as interleukin-2 appears to enhance viral strains may revert to pathogenic strains.[l] the protective efficacy of the vaccines.l4] This may be be­ Another approach is to use HSV strains in which a gene cause these vaccines produce both humoral and cell-medi­ essential for replication has been modified. These viruses ated immunity.l4] are then incapable of replication, and cannot reactivate to produce infectious HSV even if latent infection becomes Various other adjuvants have been evaluated, and shown established.[l] In animal models of HSV-2, this type of to increase antibody titres and/or protection against infec­ tion.[5-7] These results have been confirmed in clinical tri­ vaccine provided lOO% protection against primary disease when administered subcutaneouslyJJ3] In addition, vaginal als. Among patients without evidence of infection with either HSV-l or HSV-2, administration of a glycoprotein administration in animals with established HSV-2 infection reduced recurrence rates by 50%.lJ3] vaccine elicited both a positive antibody response and a strong cellular response.l8] Antibody responses similar to those seen after natural Alternative approaches infection were observed after 3 doses of vaccine in another Development of killed HSV vaccines has been relatively trial. In addition, antibody responses were faster and cellu­ limited. Nonetheless, 2 killed HSV vaccines have been lar responses were longer-lasting when patients received the shown to be immunogenic in preliminary trials.ll ] vaccine with an adjuvant (monophosphoryl lipid A).l8] A novel approach to conferring protection against infec­ Phase III studies of this vaccine are currently underway.l8] tion is genetic immunisation. DNA or RNA encoding for a

1172-0360/95/0005-007/$01.00 ©Adis International Limited. All rights reserved VoL 5, No.5; March 20, 1995