Oral antifungal medication for toenail onychomycosis.

BACKGROUND: Fungal infection of the toenails, also called onychomycosis, is a common problem that causes damage to the nail's structure and physical appearance. For those severely affected, it can interfere with normal daily activities. Treatment is taken orally or applied topically; however, traditionally topical treatments have low success rates due to the nail's physical properties. Oral treatments also appear to have shorter treatment times and better cure rates. Our review will assist those needing to make an evidence-based choice for treatment. OBJECTIVES: To assess the effects of oral antifungal treatments for toenail onychomycosis. SEARCH METHODS: We searched the following databases up to October 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We sought to identify unpublished and ongoing trials by correspondence with authors and by contacting relevant pharmaceutical companies. SELECTION CRITERIA: RCTs comparing oral antifungal treatment to placebo or another oral antifungal treatment in participants with toenail onychomycosis, confirmed by one or more positive cultures, direct microscopy of fungal elements, or histological examination of the nail. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 48 studies involving 10,200 participants. Half the studies took place in more than one centre and were conducted in outpatient dermatology settings. The participants mainly had subungual fungal infection of the toenails. Study duration ranged from 4 months to 2 years.We assessed one study as being at low risk of bias in all domains and 18 studies as being at high risk of bias in at least one domain. The most common high-risk domain was 'blinding of personnel and participants'.We found high-quality evidence that terbinafine is more effective than placebo for achieving clinical cure (risk ratio (RR) 6.00, 95% confidence interval (CI) 3.96 to 9.08, 8 studies, 1006 participants) and mycological cure (RR 4.53, 95% CI 2.47 to 8.33, 8 studies, 1006 participants). Adverse events amongst terbinafine-treated participants included gastrointestinal symptoms, infections, and headache, but there was probably no significant difference in their risk between the groups (RR 1.13, 95% CI 0.87 to 1.47, 4 studies, 399 participants, moderate-quality evidence).There was high-quality evidence that azoles were more effective than placebo for achieving clinical cure (RR 22.18, 95% CI 12.63 to 38.95, 9 studies, 3440 participants) and mycological cure (RR 5.86, 95% CI 3.23 to 10.62, 9 studies, 3440 participants). There were slightly more adverse events in the azole group (the most common being headache, flu-like symptoms, and nausea), but the difference was probably not significant (RR 1.04, 95% CI 0.97 to 1.12; 9 studies, 3441 participants, moderate-quality evidence).Terbinafine and azoles may lower the recurrence rate when compared, individually, to placebo (RR 0.05, 95% CI 0.01 to 0.38, 1 study, 35 participants; RR 0.55, 95% CI 0.29 to 1.07, 1 study, 26 participants, respectively; both low-quality evidence).There is moderate-quality evidence that terbinafine was probably more effective than azoles for achieving clinical cure (RR 0.82, 95% CI 0.72 to 0.95, 15 studies, 2168 participants) and mycological cure (RR 0.77, 95% CI 0.68 to 0.88, 17 studies, 2544 participants). There was probably no difference in the risk of adverse events (RR 1.00, 95% CI 0.86 to 1.17; 9 studies, 1762 participants, moderate-quality evidence) between the two groups, and there may be no difference in recurrence rate (RR 1.11, 95% CI 0.68 to 1.79, 5 studies, 282 participants, low-quality evidence). Common adverse events in both groups included headache, viral infection, and nausea.Moderate-quality evidence shows that azoles and griseofulvin probably had similar efficacy for achieving clinical cure (RR 0.94, 95% CI 0.45 to 1.96, 5 studies, 222 participants) and mycological cure (RR 0.87, 95% CI 0.50 to 1.51, 5 studies, 222 participants). However, the risk of adverse events was probably higher in the griseofulvin group (RR 2.41, 95% CI 1.56 to 3.73, 2 studies, 143 participants, moderate-quality evidence), with the most common being gastrointestinal disturbance and allergic reaction (in griseofulvin-treated participants) along with nausea and vomiting (in azole-treated participants). Very low-quality evidence means we are uncertain about this comparison's impact on recurrence rate (RR 4.00, 0.26 to 61.76, 1 study, 7 participants).There is low-quality evidence that terbinafine may be more effective than griseofulvin in terms of clinical cure (RR 0.32, 95% CI 0.14 to 0.72, 4 studies, 270 participants) and mycological cure (RR 0.64, 95% CI 0.46 to 0.90, 5 studies, 465 participants), and griseofulvin was associated with a higher risk of adverse events, although this was based on low-quality evidence (RR 2.09, 95% CI 1.15 to 3.82, 2 studies, 100 participants). Common adverse events included headache and stomach problems (in griseofulvin-treated participants) as well as taste loss and nausea (in terbinafine-treated participants). No studies addressed recurrence rate for this comparison.No study addressed quality of life. AUTHORS' CONCLUSIONS: We found high-quality evidence that compared to placebo, terbinafine and azoles are effective treatments for the mycological and clinical cure of onychomycosis, with moderate-quality evidence of excess harm. However, terbinafine probably leads to better cure rates than azoles with the same risk of adverse events (moderate-quality evidence).Azole and griseofulvin were shown to probably have a similar effect on cure, but more adverse events appeared to occur with the latter (moderate-quality evidence). Terbinafine may improve cure and be associated with fewer adverse effects when compared to griseofulvin (low-quality evidence).Only four comparisons assessed recurrence rate: low-quality evidence found that terbinafine or azoles may lower the recurrence rate when compared to placebo, but there may be no difference between them.Only a limited number of studies reported adverse events, and the severity of the events was not taken into account.Overall, the quality of the evidence varied widely from high to very low depending on the outcome and comparison. The main reasons to downgrade evidence were limitations in study design, such as unclear allocation concealment and randomisation as well as lack of blinding.

Probable Griseofulvin-Induced Drug Reaction with Eosinophilia and Systemic Symptoms in a Child.

A 9-year-old boy presented with fever, rash, anterior cervical lymphadenopathy, high liver enzymes, atypical lymphocytosis, and eosinophilia (drug reaction with eosinophilia and systemic symptoms [DRESS]). His history was notable for having taken griseofulvin for 3 weeks prior to onset of these findings. He improved after treatment with oral prednisone. We present a rare case of probable DRESS secondary to griseofulvin.

[Severe cutaneous drug reactions to misused griseofulvin: 2 cases]. / Deux cas de toxidermies graves secondaires à un mésusage de la griséofulvine.

BACKGROUND: Griseofulvin is an antifungal drug known to cause drug rash. However, it is widely prescribed outside its classic indications. Herein, we describe 2 cases in which griseofulvin was prescribed for off-label indications. PATIENTS AND METHODS: Case No. 1. A 51-year-old woman was referred to the department of internal medicine for management of Stevens-Johnson Syndrome (SJS). The symptoms appeared 17 days after she had taken griseofulvin for inguinal intertrigo. Case No. 2. A 19-year-old female patient consulted for toxic epidermal necrolysis (TEN) affecting 30% of her body surface, with a positive Nikolsky sign and severe mucosal lesions. These symptoms appeared 9 days after she began taking griseofulvin, which had initially been prescribed for her husband for mycosis. DISCUSSION: Toxic epidermal necrolysis, a condition chiefly of drug-related origin, is a severe mucocutaneous syndrome characterized by massive keratinocytic apoptosis. Although there are few scientific publications referring to griseofulvin-induced drug eruption, they deserve to be mentioned since this drug is widely used for purposes other than the approved indications and can cause life-threatening reactions. CONCLUSION: We report two cases of toxic epidermal necrolysis related to the misuse of griseofulvin. It is important to bear in mind the precautions for use of oral antifungal drugs, which are strictly reserved for use against resistant or diffuse forms of mucocutaneous fungal infections.

Treatments for Cutaneous Lichen Planus: A Systematic Review and Meta-Analysis.

BACKGROUND: Cutaneous lichen planus (CLP) is an inflammatory dermatosis. Its chronic relapsing course and frequently spontaneous regression hamper the assessment of treatment effectiveness. OBJECTIVE: To evaluate the efficacy of available treatment modalities for CLP. DATA SOURCES: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov registry. METHODS: We performed a systematic review of the current literature. All randomized controlled trials, nonrandomized case-control studies, and cohort studies with more than one treatment arm were included. The primary outcomes were complete response and time to complete response. The secondary outcomes were partial response, relapse, time to relapse, reduction of itch, the adverse event rate, and withdrawal due to adverse events. DATA SYNTHESIS: Sixteen studies met the inclusion criteria, of which 11 were randomized controlled trials. Most trials had a small sample size. In the rare studies in which variants other than generalized or classic lichen planus were included, they could not be analyzed separately. Body-of-evidence quality ranged from very low to moderate. Acitretin, sulfasalazine, and griseofulvin were associated with increased overall response rates in comparison with placebo. Narrow-band ultraviolet B radiation (NBUVB) was more effective than 6 weeks' low-dose prednisolone in achieving a complete response, and prednisolone was more effective than enoxaparin. Hydroxychloroquine was more effective than griseofulvin in achieving an overall response. Betamethasone valerate 0.1% ointment had comparable efficacy to calcipotriol ointment. Methotrexate was effective, with a nonsignificant difference in the complete response rate in comparison with oral betamethasone. In nonrandomized controlled trials, oral psoralen plus ultraviolet A photochemotherapy (PUVA) had comparable efficacy to a PUVA bath and NBUVB. Psoralen plus sunlight exposure (PUVASOL) and betamethasone dipropionate 0.05% cream were effective relative to a short course of oral metronidazole. CONCLUSIONS: Several effective treatment options are available for CLP. Further well-designed studies are warranted to investigate the efficacy of topical glucocorticoids-the current first-line therapy-as well as other treatment modalities, and the treatment of different variants of CLP.

Griseofulvin and/or Terbinafine Induced Toxic Epidermal Necrolysis in an Adult Female Patient - A Case Report.

An 18 years old female patient, who was taking treatment for tinea cruris developed Toxic Epidermal Necrolysis (TEN) due to therapeutic dose of griseofulvin with concomitant use of terbinafine. Both the drugs were stopped; patient's condition was gradually improved after starting the treatment. As per WHO-UMC causality assessment criteria, association between reaction and drug was possible (for both griseofulvin and terbinafine). Griseofulvin and terbinafine, both are widely used as an oral antifungal agent to treat fungal infections, careful monitoring is required in the initial periods of the treatment to prevent such type of serious adverse drug reaction. We report a case of TEN possibly caused by griseofulvin with concomitant use of terbinafine resulting in diagnostic difficulty.

Unusual Cause and Presentation of Collapsing Focal Segmental Glomerulosclerosis.

Collapsing focal segmental glomerulosclerosis (c-FSGS), a structural variant of focal segmental glomeruloslecrosis (FSGS), is considered to be the most aggressive FSGS form. Most patients present with severe nephrotic syndrome and often have rapidly progressing renal failure and progression to end-stage kidney disease. We are reporting a 28-year-old previously healthy woman, who was started on griseofulvin for onchomycosis; she subsequently developed acute renal failure with significant proteinuria. Exposure to the drug caused dramatic decline in the renal function. Renal biopsy was compatible with c-FSGS. To the best of our knowledge, this is the first case of biopsy-proven griseofulvin-associated c-FSGS. Our patient showed rapid improvement in renal function after discontinuation of griseofulvin. Universally, c-FSGS carries poor prognosis, but this case is unique because patient showed rapid improvement in renal function with a short duration after cessation of griseofulvin.

[Generalized exanthematous pustular dermatophytid, a rare clinical presentation of dermatophytid reaction]. / La dermatophytide exanthématique et pustuleuse généralisée (DEPG), une présentation clinique rare de dermatophytide.

BACKGROUND: Dermatophytids are immunologically mediated dermatologic presentations secondary to sensitization to a dermatophyte infection. They are most frequently associated with toe-web intertrigo and usually present as localized, palmar, pruriginous vesicular eruptions. We report three original cases of generalized exanthematous pustular dermatophytid associated with kerions. PATIENTS: Two boys aged 11 and 6 years, and one girl aged 6 years initially presented with kerion secondary to Trichophyton tonsurans (case 1), Trichophyton soudanense (case 2) and Trichophyton mentagrophytes (case 3), respectively. Two to three days after initiation of griseofulvin treatment, all patients presented with a pustular eruption extending from the head to the trunk, associated in one case with fever of 39°C and inflammatory chondritis. Samples obtained from the pustular lesions were sterile, serum inflammatory markers were within the normal range and skin lesions resolved on oral corticosteroid treatment (prednisone 0.75 mg/kg, case 1) or high-potency topical steroids (cases 2 and 3) given as an adjunct to griseofulvin treatment (19 to 23 mg/kg/d). DISCUSSION: Dermatophytids occur during the acute phase of infection or within a few days of treatment initiation. Lesions are remote from the infection site, contain no dermatophyte, and resolve after treatment of the infection. We report three original cases of generalized exanthematous pustular dermatophytid, associated in one case with fever and inflammatory chondritis. The main differential diagnosis is acute generalized exanthematous pustulosis secondary to antifungal drugs. Differences in clinical presentation between the two enable the appropriate diagnosis to be made as well as continued use of the antifungal medication needed to cure the patient. General or topical steroids may also be used in combination.

Drug-mediated rash: erythema multiforme versus Stevens-Johnson syndrome.

A 92-year-old woman presented with an acute onset generalised maculopapular rash with associated mucosal involvement, on a background of recent start of griseofulvin. The rash progressed rapidly over 2 days to involve most of her body, however, mucosal involvement was limited to her oral mucosa. Characteristic target lesions appeared at 72 h, and a diagnosis of erythema multiforme secondary to griseofulvin was made after further investigation and skin biopsy. The patient was monitored closely for progression of the rash and other indicators of more severe dermatological conditions such as Stevens-Johnson syndrome. She was managed symptomatically, with resolution of the rash in 4 weeks and full recovery to her premorbid level of functioning. This case details the diagnostic and management approach to erythema multiforme, a condition that warrants thorough consideration for the differential of Stevens-Johnson syndrome.

Protective action of antioxidants on hepatic damage induced by griseofulvin.

Erythropoietic protoporphyria (EPP) is a disease associated with ferrochelatase deficiency and characterized by the accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver, and skin. In some cases, a severe hepatic failure and cholestasis were observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in mice such as PROTO IX accumulation followed by cellular damage as wells as necrotic and inflammatory processes. The antioxidant defense system was also altered. The aim was to evaluate the possible protective effect of different antioxidant compounds: trolox (Tx), ascorbic acid (Asc), the combination Tx and Asc, melatonin (Mel), and the polyphenols: ellagic acid, quercetin, chlorogenic acid, caffeic acid, gallic acid, and ferulic acid on liver damage and oxidative stress markers in a mouse model of EPP. Coadministration of Gris with Tx, Asc, and its combination, or Mel mainly affected heme biosynthetic pathway, resulting in a decrease in ALA-S activity which was increased by Gris, while the tested polyphenols exerted a protective effect on oxidative stress, decreasing lipid peroxidation and the activity of some antioxidant enzymes. In conclusion, antioxidant compounds can only protect partially against the liver damage induced by Gris, reducing oxidative stress or acting on heme regulation.

Meta-analysis of randomized, controlled trials comparing particular doses of griseofulvin and terbinafine for the treatment of tinea capitis.

Two oral antifungal agents, griseofulvin and terbinafine, have regulatory approval in the United States, but it is unknown whether one has superior overall efficacy. Genus-specific differences in efficacy are believed to exist for the two agents. It is not clear at what doses and durations of treatment these differences apply. The goals of this meta-analysis were to determine whether a statistically significant difference in efficacy exists between these agents at a given dose and duration of each in tinea capitis infections overall and to determine whether a genus-specific difference in efficacy exists for these two treatments at a given dose and duration of each. We performed a literature search for clinically and methodologically similar randomized controlled trials comparing 8 weeks of griseofulvin (6.25-12.5 mg/kg/day) to 4 weeks of terbinafine (3.125-6.25 mg/kg/day) in the treatment of tinea capitis. A meta-analysis was performed using the Mantel-Haenszel method and random effects model; results were expressed as odds ratios with 95% confidence intervals. Meta-analysis of randomized controlled trials did not show a significant difference in the overall efficacy of the two drugs at the doses specified, but specific efficacy differences were observed based on the infectious species. For tinea capitis caused by Microsporum spp., griseofulvin is superior (p = 0.04), whereas terbinafine is superior for Trichophyton spp. infection (p = 0.04). Our results support species-specific differences in treatment efficacy between griseofulvin and terbinafine and provide a clinical context in which this knowledge may be applied.

Impairment of heme biosynthesis induces short circadian period in body temperature rhythms in mice.

It has been demonstrated that the function of mammalian clock gene transcripts is controlled by the binding of heme in vitro. To examine the effects of heme on biological rhythms in vivo, we measured locomotor activity (LA) and core body temperature (T(b)) in a mouse model of porphyria with impaired heme biosynthesis by feeding mice a griseofulvin (GF)-containing diet. Mice fed with a 2.0% GF-containing diet (GF2.0) transiently exhibited phase advance or phase advance-like phenomenon by 1-3 h in terms of the biological rhythms of T(b) or LA, respectively (both, P < 0.05) while mice were kept under conditions of a light/dark cycle (12 h:12 h). We also observed a transient, ~0.3 h shortening of the period of circadian T(b) rhythms in mice kept under conditions of constant darkness (P < 0.01). Interestingly, the observed duration of abnormal circadian rhythms in GF2.0 mice lasted between 1 and 3 wk after the onset of GF ingestion; this finding correlated well with the extent of impairment of heme biosynthesis. When we examined the effects of therapeutic agents for acute porphyria, heme, and hypertonic glucose on the pathological status of GF2.0 mice, it was found that the intraperitoneal administration of heme (10 mg·kg(-1)·day(-1)) or glucose (9 g·kg(-1)·day(-1)) for 7 days partially reversed (50%) increases in urinary δ-aminolevulinic acids levels associated with acute porphyria. Treatment with heme, but not with glucose, suppressed the phase advance (-like phenomenon) in the diurnal rhythms (P < 0.05) and restored the decrease of heme (P < 0.01) in GF2.0 mice. These results suggest that impairments of heme biosynthesis, in particular a decrease in heme, may affect phase and period of circadian rhythms in animals.

Comparative evaluation of griseofulvin, terbinafine and fluconazole in the treatment of tinea capitis.

Tinea capitis (TC) is a common childhood fungal infection which, if untreated, can cause long-term scarring. A number of antifungal drugs with proven efficacy are available for the treatment of TC. However, varying dosage schedules, changes in epidemiology, and rising drug resistance are factors that hamper treatment in some cases. A prospective, non-blinded, cross-sectional study of three commonly used drugs (terbinafine, griseofulvin, and fluconazole) was undertaken in children aged ≤12 years, presenting to a pediatric superspecialty hospital. The comparative efficacies of these three drugs were evaluated. A total of 75 patients (25 in each treatment group) who completed the designated treatment protocol were included in the final analysis. Of these, 60% had non-inflammatory TC and 56% had an ectothrix pattern on hair microscopy. Trichophyton violaceum was the most commonly isolated fungus. Cure rates of 96%, 88%, and 84% were achieved with griseofulvin, terbinafine, and fluconazole, respectively. Overall, seven patients required prolonged therapy. No side effects to therapy were seen. Griseofulvin remains the drug of choice in the treatment of TC. Terbinafine was the second best agent and offered the advantage of a shorter course of therapy. Fluconazole had comparatively low cure rates but was easier to administer than the other two medications.

Guidelines for the management of tinea capitis in children.

Practice guidelines for the treatment of tinea capitis (TC) from the European Society for Pediatric Dermatology are presented. Tinea capitis always requires systemic treatment because topical antifungal agents do not penetrate the hair follicle. Topical treatment is only used as adjuvant therapy to systemic antifungals. The newer oral antifungal agents including terbinafine, itraconazole, and fluconazole appear to have efficacy rates and potential adverse effects similar to those of griseofulvin in children with TC caused by Trichophyton species, while requiring a much shorter duration of treatment. They may be, however, more expensive (Grading of recommendation A; strength of evidence 1a). Griseofulvin is still the treatment of choice for cases caused by Microsporum species. Its efficacy is superior to that of terbinafine (Grading of recommendation A; strength of evidence 1b), and although its efficacy and treatment duration is matched by fluconazole (Grading of recommendation A; strength of evidence 1b) and itraconazole (Grading of recommendation A; strength of evidence 1b), griseofulvin is cheaper. It must be noted, however, that griseofulvin is nowadays not available in certain European countries (e.g., Belgium, Greece, Portugal, and Turkey).

In vitro/in vivo phototoxic risk assessments of griseofulvin based on photobiochemical and pharmacokinetic behaviors.

The present investigation aims to establish efficacious screening strategy to clarify the phototoxic potential of pharmaceutical substances and its possible pathways by characterizing both photobiochemical properties and pharmacokinetic profiles. Photochemical behavior of griseofulvin, as model compounds, was evaluated by reactive oxygen species (ROS) assay, and the photogenotoxic potential was also assessed by DNA binding assay, DNA photocleavage assay, and atomic force microscopy. Pharmacokinetic (PK) study was also carried out after dermal and oral administration of griseofulvin in rats. ROS assay suggested the phototoxic potential of griseofulvin via type II photochemical pathways, and the photogenotoxic risk of griseofulvin was also proposed as evidenced by high affinity toward DNA and potent DNA photocleaving activity. PK profiling and in vivo phototoxicity testing demonstrated that a highly concentrated griseofulvin in the skin might cause phototoxic skin reactions in rats, whereas oral administration of griseofulvin in single dosing regimen (20mg/kg) resulted in 10(3)-fold less skin deposition than phototoxic skin concentration of griseofulvin. Upon these findings, the phototoxic potential of griseofulvin might not be severe at least in a single oral dosing regimen, whereas it might be phototoxic in dermal administration. The combination use of photobiochemical and pharmacokinetic data would be valuable to provide reliable prediction on phototoxic risk and possible toxic pathways of new drug entities in the early stage of drug discovery.

Fungal nail infections: diagnosis and management.

1) Fungal nail infection, or onychomycosis, mainly affects toenails. Infections are generally asymptomatic. Spontaneous regressions, but also complications, appear to be rare. Discomfort and cosmetic complaint are occasionally reported; 2) After a review of the literature based on the standard Prescrire procedure, we examined the diagnosis and management of fungal nail infections; 3) Clinical signs of fungal nail infections are non-specific. Alternative diagnoses include psoriasis and nail microtrauma. Nail hyperkeratosis and leukonychia are useful diagnostic pointers. Matrix involvement has important implications in the choice of treatment; 4) Detection of fungal structures by direct examination of a nail sample is strongly suggestive of fungal nail infection. In contrast, cases of negative direct examination with positive culture must be interpreted with caution, as contamination is frequent; 5) Antifungal lacquers (5% amorolfine and 8% ciclopirox) applied to the nails cure about 30% of fungal infections and sometimes cause mild irritation. There is no firm evidence that these solutions are any more effective than other topical antifungals applied daily to the affected nail. Trimming, filing or grinding the nail, in addition to these drug treatments, is likely to be beneficial, but these measures have not been evaluated; 6) Chemical nail destruction with a combination of urea and bifonazole, followed by treatment with an antifungal ointment, can be used when the nail is markedly thickened. Non-comparative trials have shown cure rates close to 70% at three months when the matrix is not involved, and 40% with matrix involvement. Drug application is inconvenient and local reactions are frequent. Surgical nail avulsion carries a risk of local infection and permanent nail dystrophy; 7) Oral terbinafine is effective in more than 50% of cases but its cutaneous, hepatic and haematological adverse effects are severe in about 1 in 2000 patients and can be life-threatening; 8) It is better to treat Candida nail infections with oral azoles (ketonazole, itraconazole) than with terbinafine. These treatments carry a risk of serious adverse effects and numerous drug interactions; 9) Fungal nail infections are usually mild. Treatments with potentially severe adverse effects must therefore be used with caution. It is better not to treat fungal nail infections if the risks outweigh the expected benefits.