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Gut Nov 2022Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC....
OBJECTIVE
Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis.
DESIGN
Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses.
RESULTS
SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth.
CONCLUSION
This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.
Topics: Animals; Azoxymethane; Bile Acids and Salts; Carcinogenesis; Cell Proliferation; Cholesterol; Colorectal Neoplasms; Dysbiosis; Fluorouracil; Mice; Occludin; Oxaliplatin; RNA, Messenger; Squalene Monooxygenase; Terbinafine
PubMed: 35232776
DOI: 10.1136/gutjnl-2021-325851 -
Indian Journal of Pharmacology 2019Dermatophytic infections are the common fungal infections aggravated by hot and humid climate. Terbinafine and itraconazole are commonly used oral antifungal agents for... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVES
Dermatophytic infections are the common fungal infections aggravated by hot and humid climate. Terbinafine and itraconazole are commonly used oral antifungal agents for the same. However, resistance to these drugs is being seen increasingly when used in the conventional doses and duration. Therefore, this study was designed to compare the efficacy of terbinafine and itraconazole in increased dosages and duration in the treatment of tinea corporis and tinea cruris.
MATERIALS AND METHODS
In this randomized comparative study, patients of tinea cruris and tinea corporis were randomly divided into two groups of 160 each and were given oral terbinafine (Group I) and oral itraconazole (Group II) for 4 weeks. The scores and percentage change in scores of pruritus, scaling, and erythema were evaluated at 2 and 4 weeks.
RESULTS
At the end of week 4, mycological cure was seen in 91.8% after 4 weeks in the itraconazole group as compared to 74.3% of patients in the terbinafine group. There was a significant improvement in percentage change in pruritus, scaling, and erythema in both the groups from 0 to 4 weeks. On comparing groups, the percentage change was significantly different in scaling from 0 to 2 weeks (5.4 vs. -4.8) and 2-4 weeks (16.7 vs. 29.6) between Group I and Group II, respectively. Clinical global improvement was better with itraconazole. Mild adverse effects such as gastrointestinal upset, headache, and taste disturbances were observed which were comparable in both the groups.
CONCLUSIONS
Itraconazole and terbinafine seem to be equally effective and safe in the treatment of tinea cruris and tinea corporis.
Topics: Administration, Oral; Adult; Antifungal Agents; Erythema; Female; Humans; Itraconazole; Male; Middle Aged; Pruritus; Terbinafine; Tinea; Treatment Outcome; Young Adult
PubMed: 31142947
DOI: 10.4103/ijp.IJP_578_17 -
Mycoses Jul 2022Treatment of tinea pedis and onychomycosis is complicated by high rates of reinfection and the emergence of terbinafine-resistant strains of Trichophyton spp. Effective...
BACKGROUND
Treatment of tinea pedis and onychomycosis is complicated by high rates of reinfection and the emergence of terbinafine-resistant strains of Trichophyton spp. Effective disinfection of contaminated socks is an important measure. Appropriate washing reduces the risk of reinfection and is paramount in treating tinea pedis and onychomycosis.
OBJECTIVES
The aim of this study was to describe the effect of commonplace disinfection methods using socks pieces inoculated with terbinafine-resistant or terbinafine-susceptible isolates of Trichophyton spp.
METHODS
Sock pieces were inoculated with seven terbinafine-resistant isolates of Trichophyton spp. with known mutations in the SQLE-gene (T. rubrum (n = 3), T. interdigitale (n = 1) and T. indotineae (n = 3)) and six terbinafine-susceptible isolates of Trichophyton spp. (T. rubrum (n = 3) and T. interdigitale (n = 3)). Methods of disinfection included soaking in a quaternary ammonium (QAC) detergent (0.5, 2 and 24 h), freezing at -20°C (0.5, 12 and 24 h), domestic and steam washing (both at 40°C with detergent). Sock pieces were cultured for 4 weeks following disinfection. The primary end point was no growth at the end of week 4.
RESULTS
Soaking in a QAC-detergent for 24 h procured at disinfectant rate of 100% (13/13), whilst soaking in 0.5 and 2 h had a disinfectant rate of 46.2% (6/13) and 84.6% (11/13), respectively. Domestic washing (40°C with detergent) produced a disinfectant rate of 7.7% (1/13). Freezing at -20°C (0.5, 12 and 24 h) and steam washing (40°C with detergent) had no disinfectant properties.
CONCLUSIONS
Soaking in a QAC-detergent for 24 h effectively disinfected sock pieces contaminated with dermatophytes.
Topics: Antifungal Agents; Arthrodermataceae; Detergents; Disinfectants; Disinfection; Drug Resistance, Fungal; Humans; Microbial Sensitivity Tests; Onychomycosis; Reinfection; Steam; Terbinafine; Tinea Pedis; Trichophyton
PubMed: 35535729
DOI: 10.1111/myc.13468 -
Revista Do Instituto de Medicina... Sep 2015Considered to be an emerging endemic mycosis in Latin America, paracoccidioidomycosis is characterized by a chronic course and involvement of multiple organs in... (Review)
Review
Considered to be an emerging endemic mycosis in Latin America, paracoccidioidomycosis is characterized by a chronic course and involvement of multiple organs in immunocompromised hosts. Infection sequelae are mainly related to pulmonary and adrenal insufficiency. The host-parasite interaction results in different expressions of the immune response depending on parasite pathogenicity, fungal load and genetic characteristics of the host. A few controlled and case series reports have shown that azoles and fast-acting sulfa derivatives are useful treatment alternatives in milder forms of the disease. For moderate/severe cases, more prolonged treatments or even parenteral routes are required especially when there is involvement of the digestive tract mucosa, resulting in poor drug absorption. Although comparative studies have reported that shorter treatment regimens with itraconazole are able to induce cure in chronically-infected patients, there are still treatment challenges such as the need for more controlled studies involving acute cases, the search for new drugs and combinations, and the search for compounds capable of modulating the immune response in severe cases as well as the paradoxical reactions.
Topics: Amphotericin B; Antifungal Agents; Azoles; Central Nervous System Fungal Infections; Drug Resistance; Humans; Naphthalenes; Paracoccidioidomycosis; Randomized Controlled Trials as Topic; Severity of Illness Index; Sulfonamides; Terbinafine
PubMed: 26465367
DOI: 10.1590/S0036-46652015000700007 -
American Family Physician Feb 2001Onychomycosis accounts for one third of fungal skin infections. Because only about one half of nail dystrophies are caused by fungus, the diagnosis should be confirmed... (Review)
Review
Onychomycosis accounts for one third of fungal skin infections. Because only about one half of nail dystrophies are caused by fungus, the diagnosis should be confirmed by potassium hydroxide preparation, culture or histology before treatment is started. Newer, more effective antifungal agents have made treating onychomycosis easier. Terbinafine and itraconazole are the therapeutic agents of choice. Although the U.S. Food and Drug Administration has not labeled fluconazole for the treatment of onychomycosis, early efficacy data are promising. Continuous oral terbinafine therapy is most effective against dermatophytes, which are responsible for the majority of onychomycosis cases. Intermittent pulse dosing with itraconazole is as safe and effective as short-term continuous therapy but more economical and convenient. With careful monitoring, patients treated with the newer antifungal agents have a good chance of achieving relief from onychomycosis and its complications.
Topics: Adult; Antifungal Agents; Child; Clinical Trials as Topic; Combined Modality Therapy; Diagnosis, Differential; Drug Costs; Drug Interactions; Fluconazole; Humans; Itraconazole; Naphthalenes; Onychomycosis; Patient Education as Topic; Recurrence; Teaching Materials; Terbinafine; Treatment Failure
PubMed: 11237081
DOI: No ID Found -
Molecular Therapy : the Journal of the... Oct 2022Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the...
Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by terbinafine, an approved antifungal drug, might inhibit the development of CRC. A population-based study from Sweden identified a total of 185 patients who received terbinafine after their CRC diagnosis and found that they had a decreased risk of death (hazard ratio = 0.50) and metastasis (hazard ratio = 0.44) compared with patients without terbinafine administration. In multiple mouse models of CRC, administration of terbinafine decreased the fungal load, the fungus-induced myeloid-derived suppressor cell (MDSC) expansion, and the tumor burden. Fecal microbiota transplantation from mice without terbinafine treatment reversed MDSC infiltration and partially restored tumor proliferation. Mechanistically, terbinafine directly impaired tumor cell proliferation by reducing the ratio of nicotinamide adenine dinucleotide phosphate (NADP) to reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), suppressing the activity of glucose-6-phosphate dehydrogenase (G6PD), resulting in nucleotide synthesis disruption, deoxyribonucleotide (dNTP) starvation, and cell-cycle arrest. Collectively, terbinafine can inhibit CRC by reversing fungal dysbiosis, suppressing tumor cell proliferation, inhibiting fungus-induced MDSC infiltration, and restoring antitumor immune response.
Topics: Animals; Antifungal Agents; Colorectal Neoplasms; Deoxyribonucleotides; Dysbiosis; Glucosephosphate Dehydrogenase; Mice; NADP; Terbinafine
PubMed: 35765243
DOI: 10.1016/j.ymthe.2022.06.015 -
American Family Physician Oct 2021Onychomycosis is a chronic fungal infection of the fingernail or toenail bed leading to brittle, discolored, and thickened nails. Onychomycosis is not just a cosmetic... (Review)
Review
Onychomycosis is a chronic fungal infection of the fingernail or toenail bed leading to brittle, discolored, and thickened nails. Onychomycosis is not just a cosmetic problem. Untreated onychomycosis can cause pain, discomfort, and physical impairment, negatively impacting quality of life. Onychomycosis should be suspected in patients with discolored nails, nail plate thickening, nail separation, and foul-smelling nails. Accurate diagnosis is important before initiating treatment because therapy is lengthy and can cause adverse effects. A potassium hydroxide preparation with confirmatory fungal culture, periodic acid-Schiff stain, or polymerase chain reaction is the preferred diagnostic approach if confirmative testing is cost prohibitive or not available. Treatment decisions should be based on severity, comorbidities, and patient preference. Oral terbinafine is preferred over topical therapy because of better effectiveness and shorter treatment duration. Patients taking terbinafine in combination with tricyclic antidepressants, selective serotonin reuptake inhibitors, atypical antipsychotics, beta blockers, or tamoxifen should be monitored for drug-drug interactions. Topical therapy, including ciclopirox 8%, efinaconazole 10%, and tavaborole 5%, is less effective than oral agents but can be used to treat mild to moderate onychomycosis, with fewer adverse effects and drug-drug interactions. Nail trimming and debridement used concurrently with pharmacologic therapy improve treatment response. Although photodynamic and plasma therapies are newer treatment options that have been explored for the treatment of onychomycosis, larger randomized trials are needed. Preventive measures such as avoiding walking barefoot in public places and disinfecting shoes and socks are thought to reduce the 25% relapse rate.
Topics: Administration, Oral; Administration, Topical; Antifungal Agents; Diagnosis, Differential; Humans; Onychomycosis; Terbinafine
PubMed: 34652111
DOI: No ID Found -
Journal of Clinical Microbiology Aug 2023Dermatophytes are common causes of skin, hair, and nail infections in humans. The most common species causing infections in humans are Trichophyton rubrum, Trichophyton...
Dermatophytes are common causes of skin, hair, and nail infections in humans. The most common species causing infections in humans are Trichophyton rubrum, Trichophyton mentagrophytes, and Trichophyton interdigitale. Outbreaks of recalcitrant dermatophytosis have been reported in parts of South Asia, including those caused by a hypervirulent and resistant species, Trichophyton indotineae. We evaluated the antifungal susceptibility profiles of dermatophytes received by our laboratory from institutions across North America between 2021 and 2022 and performed species identification for isolates deemed to demonstrate resistance. Susceptibility testing was performed by CLSI broth microdilution methods, and species identification was performed by DNA sequence analysis. During this 2-year period, 271 dermatophyte isolates were included, the majority of which demonstrated low MIC values for terbinafine (geometric mean [GM] and modal MIC, 0.031 μg/mL and 0.008 μg/mL, respectively) and the azoles itraconazole, posaconazole, and voriconazole (0.035 to 0.049 μg/mL and ≤0.03 μg/mL). However, 18.6% of the isolates tested were resistant to terbinafine (MIC ≥ 0.5 μg/mL), including 21 T. rubrum and 21 T. indotineae isolates. These isolates were received from several different states in the United States and two provinces in Canada. In contrast, resistance to itraconazole was relatively rare. We also searched our laboratory database for earlier isolates that were resistant to terbinafine and identified 3 additional T. indotineae isolates, the earliest of which was from 2017. These results demonstrate that terbinafine resistance in dermatophytes was relatively common over this 2-year period and that T. indotineae is present in multiple areas in North America. Continued surveillance is warranted.
Topics: Humans; Terbinafine; Trichophyton; Itraconazole; Arthrodermataceae; Microbial Sensitivity Tests; Antifungal Agents; North America; Drug Resistance, Fungal
PubMed: 37432126
DOI: 10.1128/jcm.00562-23 -
The Journal of Dermatological Treatment Dec 2023Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic... (Review)
Review
Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic antifungal agents. Device-based treatments are targeted to specific regions of the nail, have favorable safely profiles, and do not interfere with systemic agents. They may be an effective alternative therapy for onychomycosis especially with increasing reports of squalene epoxidase gene mutations and potential resistance to terbinafine therapy. In this review, we discuss four devices used as antifungal treatments and three devices used as penetration enhancers for topical agents. Lasers, photodynamic therapy, microwaves, and non-thermal plasma have the capacity to inactivate fungal pathogens demonstrated through studies. Efficacy rates for these devices, however, remain relatively low pointing toward the need to further optimize device or usage parameters. Ultrasound, nail drilling, and iontophoresis aid in improving the permeability of topical agents through the nail and have been investigated as adjunctive therapies. Due to the paucity in clinical data, their efficacy in treating onychomycosis has not yet been established. While the results of clinical studies point toward the potential utility of devices for onychomycosis, further large-scale randomized clinical trials following regulatory guidelines are required to confirm current results.
Topics: Humans; Onychomycosis; Antifungal Agents; Terbinafine; Nails; Photochemotherapy; Administration, Topical
PubMed: 37807661
DOI: 10.1080/09546634.2023.2265658 -
Journal of the American Academy of... May 1998Two new systemic antifungal agents, terbinafine and itraconazole, have expanded the choices for treatment of onychomycosis. The pharmacokinetic and pharmacologic... (Comparative Study)
Comparative Study Review
BACKGROUND
Two new systemic antifungal agents, terbinafine and itraconazole, have expanded the choices for treatment of onychomycosis. The pharmacokinetic and pharmacologic properties provide the basis of their activity and are related to their efficacy and safety in dermatophyte infections.
OBJECTIVE
We describe the pharmacodynamics, pharmacokinetics, and pharmacology of terbinafine and itraconazole and the features that form a framework for comparing their efficacy. PHARMACODYNAMICS: Both terbinafine and itraconazole ultimately block ergosterol synthesis; terbinafine disrupts fungal cell wall synthesis earlier (squalene to squalene epoxide) than does itraconazole (lanosterol to ergosterol). In vitro, terbinafine exposure results in a toxic accumulation of squalene and decreased production of ergosterol. Minimal inhibitory concentrations (MICs) of terbinafine for dermatophytes are essentially equal to minimal fungicidal concentrations (MFCs). However, the MFCs of itraconazole are much higher than the MICs. PHARMACOLOGIC PROFILE: Both itraconazole and terbinafine penetrate keratinizing tissue; levels reached in nail plate exceed those in plasma. Therapeutic levels of the itraconazole persist in nails for up to 6 months after discontinuation of 3 months of therapy (200 mg/day) and during various pulsed cycles. After discontinuation of 1 month of therapy, terbinafine persists at therapeutic levels in the nail. Itraconazole has an affinity for mammalian cytochrome P-450 enzymes as well as for fungal P-450-dependent enzyme, and thus has the potential for clinically important interactions (e.g., astemizole, terfenadine, rifampin, oral contraceptives, H2 receptor antagonists, warfarin, cyclosporine). Terbinafine is not metabolized through this system and has little potential for drug-drug interactions.
CONCLUSION
The low MFCs exhibited by terbinafine for dermatophytes may be important in its clinical efficacy and low relapse rates. The safety profile of terbinafine directly reflects its mechanism of action.
Topics: Antifungal Agents; Arthrodermataceae; Candida; Dermatomycoses; Dose-Response Relationship, Drug; Ergosterol; Humans; Itraconazole; Metabolic Clearance Rate; Nails; Naphthalenes; Terbinafine
PubMed: 9594936
DOI: 10.1016/s0190-9622(98)70483-9