Molecular Epidemiology and Antifungal Susceptibility Profile in Nakaseomyces glabrata Species Complex: A 5-Year Countrywide Study.

BACKGROUND: The current study aimed to identify Iranian Nakaseomyces (Candida) glabrata complex species in the clinical isolates and determine their antifungal susceptibility profile. METHODS: In total, 320 N. glabrata clinical isolates were collected from patients hospitalized in different geographical regions of Iran. The initial screening was performed by morphological characteristics on CHROMagar Candida. Each isolate was identified by targeting the D1/D2 rDNA using a multiplex-PCR method. To validate the mPCR method and determine genetic diversity, the ITS-rDNA region was randomly sequenced in 40 isolates. Additionally, antifungal susceptibility was evaluated against nine antifungal agents following the CLSI M27-A4 guidelines. RESULTS: All clinical isolates from Iran were identified as N. glabrata. The analysis of ITS-rDNA sequence data revealed the presence of eight distinct ITS clades and 10 haplotypes among the 40 isolates of N. glabrata. The predominant clades identified were Clades VII, V, and IV, which respectively accounted for 22.5%, 17.5%, and 17.5% isolates. The widest MIC ranges were observed for voriconazole (0.016-8 µg/mL) and isavuconazole (0.016-2 µg/mL), whereas the narrowest ranges were seen with itraconazole and amphotericin B (0.25-2 µg/mL). CONCLUSION: Haplotype diversity can be a valuable approach for studying the genetic diversity, transmission patterns, and epidemiology of the N. glabrata complex.

The critical role of gut-brain axis microbiome in mental disorders.

The Gut-brain axis is a bidirectional neural and humoral signaling that plays an important role in mental disorders and intestinal health and connects them as well. Over the past decades, the gut microbiota has been explored as an important part of the gastrointestinal tract that plays a crucial role in the regulation of most functions of various human organs. The evidence shows several mediators such as short-chain fatty acids, peptides, and neurotransmitters that are produced by the gut may affect the brain's function directly or indirectly. Thus, dysregulation in this microbiome community can give rise to several diseases such as Parkinson's disease, depression, irritable bowel syndrome, and Alzheimer's disease. So, the interactions between the gut and the brain are significantly considered, and also it provides a prominent subject to investigate the causes of some diseases. In this article, we reviewed and focused on the role of the largest and most repetitive bacterial community and their relevance with some diseases that they have mentioned previously.

Anti-biofilm properties of eucalyptol in combination with antifungals against Candida albicans isolates in patients with hematological malignancy.

Oral candidiasis is a fungal infection caused mainly by Candida albicans and it is a major problem among hematologic malignancy patients. Biofilm formation is an attributable factor to both virulence and drug resistance of Candida species. The aim of the study was to evaluate the biofilm-producing ability of oral C. albicans isolates and to evaluate the inhibitory activity of eucalyptol on Candida biofilm, alone and in combination with antifungal agents. Samples were collected from the oral cavity of 106 patients with hematologic malignancy. The isolated yeasts were identified by PCR-sequencing. Then C. albicans isolates were analyzed for their biofilm-producing ability by crystal violet staining and MTT assay. The minimum biofilm inhibition concentrations (MBIC) of eucalyptol, amphotericin B, itraconazole, and nystatin and the in vitro interaction of eucalyptol with these drugs were tested according to CLSI-M-27-A3 protocol and checkerboard methods, respectively. From 106 patients, 50 (47.2%) were confirmed for oral candidiasis [mean ± SD age 39 ± 14 years; female 31 (62%) and male 19 (38%)]. C. albicans was isolated from 40 of 50 (80%) patients. From 40 C. albicans isolates, 24 (60%) and 16 (40%) were moderate and weak biofilm producer, respectively. The geometric mean MBIC of amphotericin B, itraconazole, nystatin and eucalyptol were 3.93 µg/mL, 12.55 µg/mL, 0.75 µg/mL and 798 µg/mL, respectively. Eucalyptol interacted synergistically with amphotericin B, itraconazole and nystatin against 12.5, 10, and 22.5% of isolates, respectively. Eucalyptol demonstrated promising activity against biofilm of C. albicans when tested alone or combined with antifungal drugs.

Biliary co-infection by multidrug-resistant Candida glabrata and Candida albicans in a case of pancreatic cancer with cholangitis: A case report and review of literature.

Herein, we report a case of pancreatic cancer with acute cholangitis secondary to biliary obstruction. Empirical antibiotic therapy did not change the clinical presentation. Blood cultures were sterile; however, bile culture was positive for yeasts. Our laboratory analysis revealed a biliary coinfection by multidrug-resistant C. glabrata and C. albicans. The patient was successfully treated with endoscopic biliary drainage.

Antifungal Effect of Probiotic Lactobacillus casei on Drug-Resistant Oral Candida albicans Isolated from Patients with Hematological Malignancy: an in vitro Study.

Statement of the Problem: Candida albicans (C. albicans) is recognized as the most common opportunistic pathogen in patients with an impaired immune system, and due to the frequent use of antifungal medicine, a variety of drug-resistant species are developing. Probiotics are a part of the human microbiome and natural competitors of Candida by producing lactic acid, low pH, and other secreted metabolites. The role of probiotics in preventing fungal infections has always been discussed. Purpose: This study aimed to investigate the antifungal effect of Lactobacillus casei (L. casei) on fluconazole- and amphotericin B-resistant C. albicans species isolated from the oral cavity of acute myeloid leukemia patients. Materials and Method: In this experimental study, eight strains of fluconazole- and amphotericin B-resistant C. albicans were used. The antifungal effects of probiotic L. casei and nystatin were measured by the co-aggregation method 1, 2, and 4 h after beginning the study. After each hour of exposure, C. albicans and L. casei colonies were counted. Results: L. casei had a significant ability to aggregate with both fluconazole- and amphotericin B-resistant C. albicans in all designated intervals, which increased with time. In the first hour of the study, no significant difference was observed between the effects of L. casei on the two drug-resistant strains. However, as time passed, it had a more significant antifungal effect on fluconazole, compared to amphotericin B resistant species (p Value<0.001). Cell counts showed that the number of fungal cells decreased significantly as time passed (p< 0.001). Conclusion: L. casei had a significant ability to aggregate with both drug-resistant C. albicans species and showed higher antifungal activity on fluconazole-resistant than amphotericin B-resistant species.

Rapid discrimination of Candida species based on optical diffraction pattern.

Candidiasis occurs mainly in immunocompromised patients. Rapid detection of Candida species can play a major role in the successful management of fungal infections and treatment monitoring. Detection and discrimination of five common strains of Candida species was performed using the optical elastic scattering diffraction pattern of their colonies. Using laser light with 632 nm wavelength and the designed optical system, optical diffraction patterns of C. albicans (ATCC12261), C. tropicalis (ATCC20336), C. glabrata (15545), C. guilliermondii (20216), and C. parapsilosis (22019) were recorded, processed and analyzed. The results of our study show that based on the different structure of Candida species and dissimilar structure of their colonies, the difference between acquired diffraction patterns are recognizable. In addition, through extraction of statistical feature of the diffraction pattern images and using classification techniques, the detection and discrimination could be performed in a semi-automatic way. The analysis of the colonies of five different Candida species by the optical diffraction patterns generated from the interaction of the laser with colonies' structures demonstrated that the technique had the potential to be applied for the detection and discrimination of various species.

Investigation of the antifungal effects of curcumin against nystatin-resistant Candida albicans.

Background: Emergence of nystatin-resistant Candida albicans (C. albicans) strains has raised some concerns in the recent years. Recent scientific evidence proves that turmeric, especially curcumin, has anti-inflammatory and anti-fungal activity. The aim of this study was the investigation of the antifungal effects of curcumin against nystatin-resistant C. albicans. Materials and Methods: This in vitro, experimental study evaluated standard-strain (ATCC 16201) and 10 nystatin-resistant C. albicans strains. The antifungal activity and minimum inhibitory concentration (MIC) of curcumin were evaluated using the CLSI-M27-A3, and the MIC of curcumin was compared with that of nystatin. The results were analyzed using the one-way ANOVA. Results: The MIC of curcumin was 15.6, 32.25, 15.6, 7.8, 32.25, 15.6, 15.6, 15.6, 32.25, and 15.6 µg/mL for the 10 resistant strains and 62.5 µg/mL for the standard strain of C. albicans. Curcumin in the above-mentioned concentrations significantly inhibited the proliferation of nystatin-resistant C. albicans strains (P < 0.001). Conclusion: According to this research, it was shown that curcumin with MIC value of 7.8-32.25 µg/mL has inhibitory effects on nystatin-resistant C. albicans strains.

Oral Candida colonization and anti-fungal susceptibility pattern in patients with hematological malignancy.

Background and Purpose: Candidiasis is regarded as one of the most important fungal infections and a cause of disease and mortality in patients with hematological malignancy. Accordingly, antifungal prophylaxis is of significant importance in this regard. This study aimed to identify the epidemiology of Candida colonization and evaluate its antifungal susceptibility pattern in patients with hematological malignancy. Materials and Methods: In this study, the samples were collected from the oral cavity of 100 patients, and Candida colonization was confirmed by fungal culture. Candida strains were also identified by ITS-PCR. In vitro antifungal susceptibility tests against fluconazole, amphotericin B, and caspofungin were performed according to CLSI M60. Results: Demographic characteristics, comorbidities, distribution of Candida species (spp.), and antifungal susceptibility were analyzed in this study. The study participants included 100 patients with a mean age of 15.48%±48.74 years (age range: 17-84 years). Regarding gender distribution, the majority (64%) of the patients were male. In terms of the distribution of underlying hematologic malignancy, 27% of the cases had lymphoma. The most commonly isolated species among patients were C. albicans complex (49%; n=49), C. glabrata (39%; n=39), and co-colonization of C. albicans complex and C. with C. glabrata (10%; n=10). The overall resistance of C. albicans complex was 5% to fluconazole (n=5) and 2% to amphotericin B (n=2). Furthermore, C. glabrata showed 11% (n=11) resistance to fluconazole and was susceptible to amphotericin B. All Candida spp. isolated from patients who were susceptible to caspofungin. Conclusion: The high rate of colonization of Candida spp., especially the significant increase in the frequency of C. glabrata in patients with blood malignancies and the gradual increase in resistance to fluconazole, necessitate a change in the use of antifungal drugs for the prevention and experimental treatment of hematological malignancy.

Investigation the effects of silver nanoparticles and gold nanoparticles on expression of bap and csu genes in biofilm formation of Acinetobacter baumannii.

Background and Objectives: Acinetobacter baumannii is one of the main pathogens of the hospital and causes various infections. csu A/BABCDE involved in the initial surface attachment during biofilm formation and bap gene produces specific proteins at the cell surface that play a direct role in formation of biofilm and the infectivity of this bacterium. The aim of this study was to investigate the effect of silver nanoparticles and gold nanoparticles on the expression of bap and csu genes in the Acinetobacter baumannii biofilm formation. Materials and Methods: The susceptibility test was performed to determine the MIC of silver nanoparticles, gold nanoparticles and gold-vancomycin nanoparticles performed by broth dilution method on A. baumannii strains. The ability of biofilms formation in strains treated by MIC of silver nanoparticles and gold-vancomycin nanoparticles were evaluated by microtiter plate method and A. baumannii ATCC19606 used as control. Expression of the csu and bap genes were determinded by measuring the cognate mRNA level by real-time PCR. Results: In present study, gold nanoparticles could not prevent the growth and biofilm formation of A. baumannii strains. The MIC concentration of silver nanoparticles and vancomycin- gold nanoparticles were 6.25 µg/ml and 0.625 µg/ml respectively and MBC concenteration of nanoparticles for 70% of strain was 12.5 µg/ml and 1.25 µg/ml respectively. Real-time PCR and data analysis, determined that the expression of bap, csuC and csuE genes in A. baumannii strains treated with MIC concentration (6.25 µg/ml) of silver nanoparticles decreased compared to control groups. Also, the expression of csuC and csuE genes in strains treated with MIC concentration (0.625 µg/ml) of vancomycin -gold nanoparticles increased, however the expression of bap was decreased compared to the control groups. Conclusion: Due to the inhibitory effect of silver nanoparticles and gold-vancomycin nanoparticles against A. baumannii biofilm formation and genes expression, they can probably be used for prevent of biofilm formation in medical instrument or can be use for treatment of infections with or without antibiotic.

Promising effects of corticosteroid treatment in combination with antifungal agents in a patient with Aspergillus meningitis.

Although Aspergillus meningitis is poorly responsive to current guidelines for treatment, we describe a dramatic response of Aspergillus meningitis in a patient to treatment using a combination of corticosteroids with guideline's suggested antifungal agents. Administration of corticosteroids in patients with Aspergillus meningitis is rarely reported in previous studies.

Phylogenetic relationship of Fusarium species isolated from keratitis using TEF1 and RPB2 gene sequences.

Background and Objectives: Fusarium species are known to be one of the common causes of keratitis. This study was conducted to identify Fusarium spp. causing keratitis and to investigate their genetic diversity using TEF1 and RPB2 gene sequences. Materials and Methods: Twenty-four clinical isolates of Fusarium were isolated from the patient with keratitis. Phylogenetic analysis of two-locus of the 24 clinical isolates and three reference strains was carried out using the maximum parsimony and RAxML methods. Results: Based on gene sequences of the 24 clinical isolates, 17, 4, and 3 isolates were identified as Fusarium solani species complex (FSSC), Fusarium fujikuroi species complex (FFSC), and Fusarium oxysporum, respectively. FFSC include F. proliferatum (n=1), F. globosum (n=1), F. verticillioides (n=1), and F. brevicatenulatum (n=1), respectively. Conclusion: Given that sequence of a sole gene can be challenging and on the other hand, due to the high resistance to antifungal drugs, identification of Fusarium species is of substantial significance. In this study, by designing a novel set of primers for the RPB2 area and using TEF1 primer, we were able to differentiate 24 Fusarium spp. isolated from patients with keratitis.

Analysis of molecular resistance to azole and echinocandin in Candida species in patients with vulvovaginal candidiasis.

Background and Purpose: Vulvovaginal candidiasis (VVC) is considered the most common mucosal infection caused by Candida species. Azoles were considered the first-line treatment for VVC or recurrent vulvovaginal candidiasis (RVVC) in both healthy and immunocompromised populations. Recently, azole-resistant isolates, especially among non-albicans Candida samples have been encountered. This study aimed to evaluate the antifungal susceptibility profile of Candida spp. isolated from VVC or RVVC patients and assess the molecular resistance mechanism of Candida spp. to azole and echinocandin. Materials and Methods: Point mutation analysis was performed on the ERG11 and FKS candidate genes of azole- and caspofungin-resistant Candida albicans and Candida glabrata isolates. Real-time polymerase chain reaction was performed to gain insight into the differential expression of ERG11 mRNA. Results: Variations in the amino acid D116E were observed in fluconazole- and itraconazole-resistant C. albicans strains, and changes in amino acid E517Q were observed only in fluconazole-resistant C. albicans strains. No polymorphisms were observed in the complete sequence alignment of the ERG11 gene in one azole-resistant C. glabrata isolate. The mutation triggered the changes in the amino acid serine in the reference gene FKS1 by the leucine at position 642 (S642L) of the isolates. Conclusion: In patients with persistent or recurrent infection, the choice of an antifungal agent is often challenging and requires monitoring of the antifungal susceptibility of the colonizing strain. C. albicans and C. glabrata isolates can be resistant to azole and caspofungin antifungal agents without mutations in the ERG 11 and HS1 regions of the FKS1 gene.

Alginate-based multifunctional films incorporated with sulfur quantum dots for active packaging applications.

Sulfur quantum dots (SQDs) were fabricated using a facile hydrothermal method and used for the preparation of functional food packaging film and compared the properties with other sulfur-based fillers like elemental sulfur (ES) and sulfur nanoparticles (SNP). The SQDs have an average size of 5.3 nm and were very stable in aqueous suspension. Unlike other sulfur-based fillers, the SQD showed high antioxidant, antibacterial and antifungal activity, but no cytotoxicity was found for L929 mouse fibroblasts even after long-term exposure of 48 h. When sulfur-based fillers were added to the alginate film, SQD was more evenly dispersed in the polymer matrix than SNP and ES. The addition of SQD to the alginate film increased the film's UV barrier property by 82% and tensile strength by 18%. Also, the addition of SQDs to the films did not affect the stiffness (elastic modulus, EM) and water vapor barrier permeability (WVP) of the films. In addition, SQD-added films exhibited excellent antioxidant and strong antibacterial activity against bacterial (E. coli and L. monocytogenes) and fungal (A. niger and P. chrysogenum) food pathogens. When the film was applied as a bread packaging test, the SQD-added film prevented mold growth for 14 days, unlike the ES and SNP-added films.

Meyerozyma guilliermondii species complex: review of current epidemiology, antifungal resistance, and mechanisms.

Meyerozyma guilliermondii has been accepted as a complex composed of Meyerozyma guilliermondii, Meyerozyma carpophila, and Meyerozyma caribbica. M. guilliermondii is a saprophyte detected on human mucosa and skin. It can lead to serious infections in patients with risk factors like chemotherapy, immunodeficiency, gastrointestinal or cardiovascular surgery, and oncology disorders. Most deaths related to M. guilliermondii infections occur in individuals with malignancy. In recent decades, incidence of M. guilliermondii infections is increased. Sensitivity of this microorganism to conventional antifungals (e.g., amphotericin B, fluconazole, micafungin and anidulafungin) was reduced. Prophylactic and empirical uses of these drugs are linked to elevated minimal inhibitory concentrations (MICs) of M. guilliermondii. Drug resistance has concerned many researchers across the world. They are attempting to discover appropriate solution to combat this challenge. This study reviews the most important mechanisms of resistance to antifungals developed by in M. guilliermondii species complex.

Effects of Cosmetic Preservatives on Healthy Facial Skin Microflora.

Objective: The present study was designed to evaluate the effects of seven common preservatives used in Iranian cosmetic products on facial skin microflora. Methods: Fifteen healthy volunteers, aged 20 to 35 years, were recruited. Three symmetrical sites from the cheeks of each volunteer were selected and samples were collected. DNA was extracted from the culture using the boiling method. The fungi's internal transcribed spacer (ITS) region was amplified using ITS1/ITS4 primers, for 16s to identify bacteria and Staphylococcus specific primers. The effects of the preservatives were assessed based on growth on broth culture media. Results: Primary identification was based on yeast on CHROM agar, in which 15 different yeasts were isolated; then, PCR was used to identified the species as: C. albicans (n: 14; 93%), C. orthopsilosis (n: 1; 7%). One primary identified yeast on Dixon media was precisely differentiated as M. furfur using the PCR method. Fifteen primary identified cocci on tryptic soy agar media were identified as Staphylococcus epidermis. All the preservatives showed to inhibit the growth of isolated fungi, but not that of bacterial microflora. Conclusion: The present study showed preservatives in cosmetic products can alter skin microflora while also preventing the growth of pathogenic bacteria.

The in vitro effect of nanoliposomal amphotericin B against two clinically important dermatophytes.

AIMS: The present study aimed to investigate the antifungal activity of amphotericin B-loaded nanoliposomes against Trichophyton interdigitale and Trichophyton rubrum. Moreover, it was attempted to assess the obtained resistance in vitro. METHODS: In total, 29 archived clinical strains, namely, T. interdigitale (n = 16) and T. rubrum (n = 13), were included in this study. These strains were determined using a previous ITS1-ITS2 region sequence. Moreover, a liposomal formulation of amphotericin B was formulated by a thin-film hydration method. Particle size, polydispersity index (PdI), and zeta potential (ZP) were measured by a Zetasizer. Furthermore, physicochemical properties, such as appearance, aggregation of particles, particle size, PdI, and ZP, were determined at 0-, 1-, and 3-month intervals. A scanning electron microscope (SEM) was also used to examine nanoparticles structure. The minimum inhibitory concentration (MIC) of amphotericin B-loaded nanoliposomes, itraconazole, efinaconazole, terbinafine, and ciclopirox was determined according to the protocol of the broth microdilution method of CLSI M38-A2. The morphological changes of T. interdigitale and T. rubrum strains exposed to the amphotericin B-loaded nanoliposomes were observed using SEM. RESULTS: The amphotericin B-loaded nanoliposomes displayed a lower MIC compared to those of the amphotericin B and liposomes when used separately. Based on the results, amphotericin B-loaded nanoliposomes induced no drug resistance in any of the tested strains. CONCLUSION: Accordingly, amphotericin B-loaded nanoliposomes can be a potent antifungal for the topical treatment of onychomycosis. There was no in vitro evidence regarding the resistance of the tested strains to amphotericin B-loaded nanoliposomes. This reflects that amphotericin B-loaded nanoliposomes have a low probability to induce drug resistance in dermatophyte species.

Herbal Therapy for the Management of Seborrheic Dermatitis: A Narrative Review.

INTRODUCTION: Dandruff and Seborrheic Dermatitis (SD) are similar skin conditions with different degrees ofseverity. Since the current therapies cannot remove dandruff efficiently, herbal extracts with better effectiveness and fewer side effects are used in the pharmaceutical and cosmetic industries. Due to the adverse effects of chemical drugs, the use of natural products and traditional medicine has significantly increased over the past few decades. Therefore, in this review, we reported the herbs used as anti-dandruff agents in traditional medicine worldwide. METHODS: The review was conducted on the literature available on the medicinal utility of certain plants as anti-dandruff agents using PubMed and Google Scholar and the following search terms: Dandruff and plants or medicinal plant and dandruff treatment, and essential oil and dandruff. RESULTS: Since the current therapies cannotefficiently remove dandruff, herbal extracts with better effectiveness and fewer side effects are used in the pharmaceutical and cosmetic industries. Nowadays, there are numerous different types of herbal antidandruff shampoos. They are effective and safe without the side effects of chemical agents. Recently, herbal medicine has attracted a great deal of scientific attention. Clinical evidence on the therapeutic effects of herbal products has resulted in the study of far more herbs for their therapeutic roles. CONCLUSION: Herbal therapy plays a significant role in the development of favorable therapeutics, either alone or in combination with conventional antibiotics. However, the major challenges in this regard include finding compounds with satisfactorily lower MICs, low toxicity, and high bioavailability for effective and safe use in humans and animals.

A Case of Terbinafine-Resistant Tinea Cruris Caused by Trichophyton tonsurans.

A 26-year-old male patient referred to our center with a history of extremely itchy crusted skin lesions in his groins for one year. Moreover, his friend, a 25-year-old male, also developed similar lesions in the groin after using the shared pool, whose condition also did not improve with similar treatment. A regular mycology test (direct and culture test) was performed, as well as molecular examination. The antifungal susceptibility assay to terbinafine, itraconazole, posaconazole, fluconazole, and voriconazole was conducted according to the Clinical and Laboratory Standards Institute M38 third ed. The sequencing study identified T. tonsurans as the causative organism in both patients. The abovementioned organism isolated from both patients displayed resistance against terbinafine and fluconazole (MIC ≥ 4 µg/ml and MIC ≥ 8 µg/ml, respectively). Moreover, the susceptibility of both subjects to posaconazole (0.313 µg/ml), voriconazole (0.25-0.0625 µg/ml), and (1 µg/ml) itraconazole increased. The present report aimed to emphasize the increase in antifungal resistance and a demand for antifungal stewardship, to control this public health threat.

Susceptibility Pattern of Caspofungin-Coated Gold Nanoparticles Against Clinically Important Candida Species.

Purpose: The present study was performed to examine whether caspofungin-coated gold nanoparticles (CAS-AuNPs) may offer the right platform for sensitivity induction in resistant isolates. Methods: A total of 58 archived Candida species were enrolled in the research. The identification of Candida spp. was performed using polymerase chain reaction-restriction fragment length polymorphism and HWP1 gene amplification approaches. The conjugated CAS-AuNPs were synthesized and then characterized using transmission electron microscopy (TEM) and Zetasizer system to determine their morphology, size, and charge. Furthermore, the efficacy was assessed based on the Clinical and Laboratory Standards Institute M60. Finally, the interaction of CAS-AuNPs with Candida element was evaluated via scanning electron microscopy (SEM). Results: According to the TEM results, the synthesized CAS-AuNPs had a spherical shape with an average size of 20 nm. The Zeta potential of CAS-AuNPs was -38.2 mV. Statistical analyses showed that CAS-AuNPs could significantly reduce the minimum inhibitory concentration against C. albicans (P =0.0005) and non-albicans Candida (NAC) species (P < 0.0001). All isolates had a MIC value of ≥ 4 µg/ml for CAS, except for C. glabrata. The results of SEM analysis confirmed the effects of AuNPs on the cell wall structure of C. globrata with the formation of pores. Conclusion: According to findings, CAS-AuNPs conjugates had significant antifungal effects against Candida spp. Therefore, it can be concluded that the encapsulation of antifungal drugs in combination with NPs not only diminishes side effects but also enhances the effectiveness of the medications.