How To Prevent Toenail Fungus Naturally
Confounding Problems Controlling Drug Costs And Best Drug Selection Owing To Pharmaceutical Company Activities
Direct-to-consumer advertising policy by industry has also indirectly become a problem for therapeutics committees. These advertisements often encourage consumers to demand pricey drugs over cheaper ones that work just as well. The clinicians on the hospital staff then often make similar demands to the therapeutics committee to add the more expensive agents to the formulary. The percentage of industry spending on direct-to-consumer advertising has increased dramatically in the past 10 years. A review of this activity in 2002 by Competitive Media Reporting showed that about 60 of a company's spending on a drug may come from this form of advertising. The major classes of drugs that use this form of advertisement include, in decreasing order, anti-inflammatories, antihistamines, antihyperlipidemics, antiasthmatics, antiulcer drugs, antidepressants, erectile dysfunction drugs, weight loss drugs, oral contraceptives, genital herpes drugs, toenail fungus agents, and hormones. It is...
Cutaneous mycoses are perhaps the most common fungal infections of humans and are usually referred to as tinea (Latin for worm or ringworm ). The gross appearance of the lesion is that of an outer ring of the active, progressing infection, with central healing within the ring. These infections may be characterized by another Latin noun to designate the area of the body involved. Examples include Tinea corporis, which is ringworm of the body Tinea cruris, which is ringworm of the groin (i.e., jock itch ) Tinea capitis, which is ringworm of the scalp and hair Tinea barbae which is ringworm of the beard and Tinea unguium, which is ringworm of the nail. Members of the genus Trichophyton are widely distributed and are the most important and common causes of infections of the feet and nails they may be responsible for tinea corporis, tinea capitis, tinea unguium, and tinea barbae. They are most commonly seen in adult infections, which vary in their clinical manifestations. Most cosmopolitan...
Mertin and Lippold 35,36,40 modified Franz diffusion cells to measure nail permeability characteristics and drug uptake into nails. For onychomycosis treatment, they indicated, not only the flux of an antifungal drug through the nail plate is of importance, but also the antifungal potency, which is expressed as minimum inhibitory concentration (MIC). An efficacy coefficient, E, was therefore introduced, which should be maximized for high therapeutic effectiveness. Thus, for maximum efficacy, a high flux of drug through the nail and a low MIC are desired characteristics.
New treatments in development for onychomycosis are listed in Table 2. Currently, most treatments that are in clinical trials represent re-formulations of known an-tifungal agents combined with penetration enhancers in an effort to increase penetration through the nail plate. There are two treatments in clinical trials that contain novel antifungal agents. The first, in Phase 2, is a topical treatment that generates nitric oxide. The second, in Phase 3, is a topical treatment containing abafungin (7), a membrane integrity antagonist that has antibacterial and antifun-gal activity. In addition to the treatments listed, azoline and ravuconazole, two oral triazole antifungal agents are in clinical trials for fungal infections and include onychomycosis as a potential indication. Table 2. Onychomycosis treatments in preclinical and clinical development
Allvlamines - The allylamine mechanism of action reversibly inhibits squalene epoxidase, a key enzyme in ergosterol biosynthesis, resulting in accumulation of intracellular squalene, which blocks new sterol synthesis and diminishes membrane ergosterol content. The best-known compound is terbinafine (Lamisil, 19) that is available as both an oral formulation and a topical preparation for the treatment of dermatophyte infections (37,38). Terbinafine has good antifungal activity against C. albicans and the maleate salts are used for the systemic and topical treatment of fungal infections, especially fungal sinusitis infection and onychomycosis (39,40).
Aspergillus species are capable not only of causing disseminated infection, as is seen in immunocompromised patients, but also of causing a wide variety of other types of Infections, including a pulmonary or sinus fungus ball, allergic bronchopulmonary aspergillosis, external otomycosis (a fungus ball of the external auditory canal), mycotic keratitis, onychomycosis (infection of nail and surrounding tissue), sinusitis, endocarditis, and central nervous system infection. Most often, immunocompromised patients acquire a primary pulmonary infection that becomes rapidly progressive and may disseminate to virtually any organ.
Two in vivo efficacy models in guinea pigs have been reported. In the first study, the authors infected the nails and toes of guinea pigs creating both onychomycosis and tinea pedis (fungal infection of the surrounding skin). They then used this model to show the efficacy of a topically applied triazole in comparison with amorolfine and terbinafine. All three were effective in clearing the tinea pedis, but only the experimental triazole showed efficacy against onychomycosis 27 . The second model was developed as an optimized in vivo model for dermatophytosis. The authors shaved and abraded the skin on the back of guinea pigs and infected the site with T. mentagrophytes. After the infection was established, the animals were treated with oral and topical formulations of terbinafine and observed for improvement of the infection 56 . In this study, 1 topical terbinafine treatment had 100 clinical and mycological efficacy. Although this is a model for dermatophytosis, this model was used...
Onychomycosis is difficult to permanently cure. Treatment failures and relapses are common, which exacerbate the problem 8-10 . Onychomycosis is treated both systemically and topically. Current systemic treatments include terbinafine (1), itraconazole (2) and griseofulvin (3). Current topical treatments include ciclopirox (4), amorolfine (5) and tioconazole (6).
Currently, systemic treatment is the most effective method of curing onychomycosis. Even so, between 20-25 of patients fail to respond 11 . Terbina-fine (1) and itraconazole (2) are the two systemic treatments of choice with ter-binafine showing greater efficacy than itraconazole and lower rates of recurrence The commonly used antifungal agent, fluconazole, has also been prescribed, offlabel, for the treatment of onychomycosis.
Treatment of onychomycosis by topical methods has been met with limited success and reasons for this will be explored in more detail in Section 3. As with treating skin fungal infections such as tinea pedis (athletes foot), topical application for onychomycosis would seem the obvious choice. However, unlike the stratum corneum, the nail plate is a more difficult barrier to penetrate, requiring the drug to have much different physicochemical properties than are required for skin penetration. The two main topical treatments used today are ciclopirox and am-orolfine, both of which are formulated in lacquers that are painted onto the infected nails. The lacquer dries to leave a water-insoluble film on top of the infected nail, which then acts like a drug depot releasing the drug into the nail plate 21,22 . Tioconazole has also been used but has been largely replaced by ciclopirox and amorolfine.
Allylamines are antifungal agents targeted to squalene epoxidase, an enzyme necessary for ergosterol biosynthesis. Naftifine (12) was the first allylamine agent introduced in therapy in the early 1980s as 1 cream or gel for topical use. It has fungicidal activity against dermatophytes and fungistatic activity against Candida species. Its sensitizing capacity seems to be greater than in the commonly used azoles 58 . Terbinafine (13) was approved in 1990s in the UK and USA for the treatment of onychomycosis. It is the most frequently prescribed oral antifungal agent in North America, for onychomycosis. Eighteen randomized controlled trials have shown terbinafine to be highly effective with mycological cure of 76 . 13 has an established safety profile and very low occurrence of drug interactions 59 . An improved antifungal composition for topical application to the skin and nails has been developed for allylamines (naftifine or terbinafine) 60 . A formulation to provide a product having...
Nails infected with onychomycosis are thicker than healthy nails due to the presence of the dermatophyte and the damage they have caused. The effect of nail thickness on penetration has been investigated and found to have an inverse relationship as the nail increases in thickness drug penetration is reduced 46 . In the same study, the authors compared penetration of 5-fluorouracil though healthy nails versus fungal infected nails. They concluded that there was no significant difference between healthy and infect nails. However, they did not investigate heavily infected nail plates because the thickness of the uneven plate could not be accurately measured and that the uneven nail plate would collapse in water. They Efficacy rates of onychomycosis agents are widely believed to improve if penetration of antifungal agents through the nail plate is increased. Initial research has focused upon modifying environmental conditions, using penetration enhancers, to allow larger molecules to...
Since a complete cure is highly improbable without good nail penetration, in vitro nail penetration studies are becoming one of the first screening tools used in the selection of compounds for treatment of onychomycosis. Once a compound has been identified that exhibits good penetration properties, the next step in lead optimization is to assess efficacy in a model of onychomycosis. This is a relatively new area of research and few models of onychomycosis exist. Several of these are summarized below.
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