Clotrimazole causes membrane depolarization and induces sub G0 cell cycle arrest in Leishmania donovani.

Clotrimazole is an FDA approved drug and is widely used as an antifungal agent. An extensive body of research is available about its mechanism of action on various cell types but its mode of killing of Leishmania donovani parasites is unknown. L. donovani causes Visceral Leishmaniasis which is a public health problem with limited treatment options. Its present chemotherapy is expensive, has adverse effects and is plagued with drug resistance issues. In this study we have explored the possibility of repurposing clotrimazole as an antileishmanial drug. We have assessed its efficacy on the parasites and attempted to understand its mode of action. We found that it has a half-maximal inhibitory concentration (IC50) of 35.75 ± 1.06 µM, 12.75 ± 0.35 µM and 73 ± 1.41 µM in promastigotes, intracellular amastigotes and macrophages, respectively. Clotrimazole is 5.73 times more selective for the intracellular amastigotes as compared to the mammalian cell. Effect of clotrimazole was reduced by ergosterol supplementation. It leads to impaired parasite morphology. It alters plasma membrane permeability and disrupts plasma membrane potential. Mitochondrial function is compromised as is evident from increased ROS generation, depolarized mitochondrial membrane and decreased ATP levels. Cell cycle analysis of clotrimazole treated parasites shows arrest at sub-G0 phase suggesting apoptotic mode of cell death.

Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins.

Statins, a family of FDA-approved cholesterol-lowering drugs that inhibit the rate-limiting enzyme of the mevalonate metabolic pathway, have demonstrated anticancer activity. Evidence shows that dipyridamole potentiates statin-induced cancer cell death by blocking a restorative feedback loop triggered by statin treatment. Leveraging this knowledge, we develop an integrative pharmacogenomics pipeline to identify compounds similar to dipyridamole at the level of drug structure, cell sensitivity and molecular perturbation. To overcome the complex polypharmacology of dipyridamole, we focus our pharmacogenomics pipeline on mevalonate pathway genes, which we name mevalonate drug-network fusion (MVA-DNF). We validate top-ranked compounds, nelfinavir and honokiol, and identify that low expression of the canonical epithelial cell marker, E-cadherin, is associated with statin-compound synergy. Analysis of remaining prioritized hits led to the validation of additional compounds, clotrimazole and vemurafenib. Thus, our computational pharmacogenomic approach identifies actionable compounds with pathway-specific activities.

Clotrimazole Inhibits HCC Migration and Invasion by Modulating the ERK-p65 Signaling Pathway.

Purpose: Hepatocellular carcinoma (HCC), has a very high mortality rate and is the most common type of liver cancer. Clotrimazole, a traditional antifungal drug, has garnered considerable attention as a therapeutic strategy for HCC. However, its effects against the migration and invasion of HCC cells as well as the associated underlying mechanisms remain unclear. Therefore, in this study, we investigated its effects on HCC and attempted to elucidate the underlying molecular mechanisms. Methods: CCK-8 was used to investigate the inhibitory effect of clotrimazole on the proliferation of different types of HCC cells, and wound healing and transwell assays were performed to investigate its inhibitory effect on the invasion and migration of the HCC cells. Further, western blotting was employed to detect changes in the expression levels of epithelial mesenchymal transition (EMT)-related proteins, extracellular-regulated protein kinases (ERK), p-ERK, p65, and p-p65. We also used ERK activators in combination with clotrimazole to treat the HCC cell lines. Results: Clotrimazole inhibited the invasion and migration of HCC cells, and mechanistically, it exerted these anti-tumor effects via EMT by repressing ERK phosphorylation. Conclusion: These findings suggest that clotrimazole inhibits HCC metastasis by repressing EMT in an ERK dephosphorylation-dependent manner.

Short review of SEC, a potential dexamethasone-sparing regimen for glioblastoma: Spironolactone, ecallantide, clotrimazole.

This paper presents a short review of data supporting a dexamethasone sparing regimen, SEC, to reduce glioblastoma related brain edema. The conclusion of the reviewed data is that the rationale and risk/benefit ratio favors a pilot study to determine if the three drug regimen of SEC can reduce need for corticosteroid use during the course of glioblastoma. Details of how selected pathophysiological aspects of brain edema occurring during the course of glioblastoma and its treatment intersect with the established action of the three old drugs of SEC indicate that they can be repurposed to reduce that edema. Current first-line treatment of this edema is dexamethasone or related corticosteroids. There are multiple negative prognostic implications of both the edema itself and of dexamethasone, prime among them shortened survival, making a dexamethasone sparing regimen highly desirable. SEC uses spironolactone, an antihypertensive potassium-sparing diuretic acting by mineralocorticoid receptor inhibition, ecallantide acting to inhibit kallikrein activation marketed to treat hereditary angioedema, and clotrimazole, an old antifungal drug that inhibits intermediate conductance Ca++ activated K+ channel (KCa3.1). These three old drugs are well known to most clinicians, have a well-tolerated safety history, and have a robust preclinical database showing their potential to reduce the specific edema of glioblastoma. Additionally, these three drugs were chosen by virtue of each having preclinical evidence of glioblastoma growth and/or migration inhibition independent of their edema reduction action. A clinical study of SEC is being planned.

Blue Liver: Case Report of Blue Liver.

BACKGROUND Although many cases of unusual liver discoloration exist, such as blue liver syndrome which is linked to oxaliplatin-based chemotherapy, our finding was seen in a patient who was not on chemotherapy. A 39-year-old male who presented with jaundice was found to have blue liver discoloration. CASE REPORT A 39-year-old male presented with jaundice of one-month's duration evidenced by elevated total and direct bilirubin. An ultrasound and magnetic resonance cholangiopancreatography (MRCP) demonstrated thickened gall bladder wall but no common bile duct stones. A robotic-assisted laparoscopic cholecystectomy with liver biopsy was performed. Intraoperatively, the liver was noted to be unusually blue in color. During his postoperative course, the patient developed excessive incisional bleeding associated with an increase in international normalized ratio (INR) and increasing direct hyperbilirubinemia. This was managed with blood transfusions, and ursodeoxycholic acid was begun, which resulted in improvement of his bilirubin levels and overall recovery. CONCLUSIONS Drug induced cholestasis and liver injury is a common cause of elevated liver enzymes. However, the unusual blue appearance of the liver should prompt an evaluation for other unusual and rare causes of obstructive jaundice.

Clotrimazole reduces endometriosis and the estrogen concentration by downregulating aromatase.

This study aimed to analyse the effects of clotrimazole (CTZ) on estrogen production pathway in endometriosis progression. Experimental endometriosis was induced by autologous transplantation in female Wistar rats, and then the rats were treated with clotrimazole (200 mg/kg) or vehicle, both orally and intraperitoneally, for 15 consecutive days. Serum estrogen levels and vaginal smear analyses were performed and ERα (estrogen receptor alpha) and CYP19 (cytochrome P450 aromatase) levels in the endometriotic lesions were analysed morphologically and immunohistochemically. The clotrimazole group presented a reduction in serum estrogen levels, which were not influenced by the estrous cycle of the animals. The expression of ERα and CYP19 in endometriotic lesions was also reduced in the clotrimazole group compared to the control group. Moreover, clotrimazole treatment decreased the size of the lesions, as confirmed by histological examination, which showed glandular atrophy for both routes of administration. These results suggest that clotrimazole interferes with the estrogen production pathway by downregulating CYP19 and, therefore, reducing serum estrogen levels. Thus, the drug decreases endometriotic lesion size and consequently disease progression.

Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea.

Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.

Effects of miconazole/clotrimazole and praziquantel combinations against the liver fluke Opisthorchis felineus in vivo and in vitro.

The liver fluke Opisthorchis felineus (Rivolta, 1884) is the causative agent of opisthorchiasis felinea in Eurasia. Opisthorchiasis is a serious human and fish-eating animal's disease affecting bile ducts and the gall bladder. Currently, the main drug for specific therapy of opisthorchiasis is praziquantel. We have previously shown that azole inhibitors of O. felineus cytochrome P450 significantly reduced survival of the worms in vitro. Here, we studied in vitro anthelmintic effects of drug combinations involving azole substances approved by the US Food and Drug Administration together with praziquantel against adult or juvenile O. felineus liver flukes. A synergistic interaction was shown for praziquantel-clotrimazole (CI = 0.68) combination and for praziquantel-miconazole (CI = 0.68) combination against adult helminths in vitro. Praziquantel-miconazole (CI = 0.30) had a strongly synergistic effect against newly excysted metacercariae. We also tested anthelmintic effects of azole substances and their combinations with praziquantel in vivo in an animal model of chemotherapy. The treatment of juvenile worms (1 day postinfection) with 100 mg/kg miconazole resulted in a worm burden reduction (WBR) of 37.5% (P = 0.049), with 100 mg/kg clotrimazole causing a WBR of 31.25% (P = 0.025). The treatment of adult worms (5-6 weeks postinfection) with 100 mg/kg or 200 mg/kg miconazole yielded a WBR of 23.8% (P = 0.01) and 21.4% (P = 0.006), respectively. When praziquantel was administered together with clotrimazole or with miconazole, a WBR slightly greater than the effect of ED50 praziquantel was observed (WBR of 59.5 and 54.7%, respectively).In conclusion, the synergistic effect of the praziquantel-clotrimazole and praziquantel-miconazole combinations observed in vitro was not confirmed in vivo. Thus, this combination chemotherapy revealed no benefits over praziquantel monotherapy in the treatment of opisthorchiasis felinea.

[Effect observation of cleaning up the external auditory canal by otoendoscope combined with Clotrimazole Ointment in the treatment of pregnancy with otitis externa mycotica].

Objective:To investigate the clinical effect of cleaning up the external auditory canal under otoendoscope combined with Clotrimazole Ointment in the treatment of pregnancy with otitis externa mycotica.Method:From May 2015 to May 2017,16 cases of pregnant patients(19 ears)with otitis externa mycotica were divided into two groups:pure cleaning up group and cleaning up combined with medication group.In the pure cleaning up group,external auditory canal were only cleaned up under otoendoscope conventionally in 9 patients(11 ears),while in the cleaning up combined with medication group,Clotrimazole Ointment was topically applied after cleaning up the external auditory canal under otoendoscope in 7 patients(8 ears).After treatment of 2 weeks,the clinical curative effect,adverse reaction and average time interval to take effect were compared at the end of treatment.Result:The total effective rate(100%)in cleaning up combined with medication group's was significantly better than that in pure cleaning up group's(81.81%)(P<0.05);The average time interval to take effect in cleaning up combined with medication groupwas significantly shorter than that in pure cleaning up group's[(2.71±0.70)d vs(5.40±1.96)d,P<0.05].After the two-week treatment,there was a four-week follow-up.Only one patient in pure cleaning up group relapsed.After two-week treatment by Clotrimazole Ointment,this patient was cured.Conclusion:Cleaning up the external auditory canal under otoendoscope combined with Clotrimazole Ointment is effective and safe for the treatment of otitis externa mycotica in pregnant women.The addition of topical application of Clotrimazole Ointment further improve the therapeutic efficacy,as compared to the conventional method of cleaning up the external auditory canal under otoendoscope.We suggest clinical application of this method.

Self-assembled nanomicelles of amphiphilic clotrimazole glycyl-glycine analogue augmented drug delivery, apoptosis and restrained melanoma tumour progression.

In present investigation, self-assembled nanomicelles of amphiphilic clotrimazole glycyl-glycine (CLT-GG-SANMs) analogue were customized for augmenting drug delivery, permeability and apoptosis in B16F1 mouse melanoma cancer cells both in vitro and in vivo following intratumoral (i.t.) route of administration. The mean particle size of CLT-GG-SANMs was measured to be 35.9 ±â€¯3.4 nm in addition to zeta-potential of -17.1 ±â€¯3.5 mV. The shape of CLT-GG-SANMs was visualized to be smooth and spherical as like nanoparticles. The critical micellar concentration (CMC) of CLT-GG-SANMs was estimated to be 17 µg/ml using DPH (1,6-diphenyl-1,3,5-hexatriene) as a UV probe. Modification of CLT to CLT-GG-SANMs induced the amorphization in therapeutic moiety. Next, CLT suspension released only 9.7% of the drug within 1 h under dissolution testing and further analysis up to 48 h did not display any remarkable effect on the drug release. On the other hand, CLT-GG-SANMs released 46.2% of the drug significantly (P < 0.01) higher than CLT suspension at 4 h. The IC50 of CLT-GG-SANMs was measured to be 15.1-µM significantly (P < 0.05) lower than CLT suspension (IC50 > 20 µM) in B16F1 cells. Western blotting and histopathological analysis also supported the superior therapeutic efficacy of CLT-GG-SANMs in terms of higher extent of apoptosis, tumour regression and exhibition of strong antioxidant potential against B16F1 cells induced tumour in C57BL6J mice. In conclusion, in vitro and in vivo therapeutic efficacy analysis indicated that CLT-GG-SANMs may be a potential candidate for translating in to a clinically viable product.

Clotrimazole is effective for the regression of endometriotic implants in a Wistar rat experimental model of endometriosis.

The present work aimed to evaluate molecular, angiogenic and inflammatory changes induced by clotrimazole (CTZ) on endometriosis lesions. For this, thirty female Wistar rats with surgically implanted autologous endometrium were treated with CTZ or vehicle (200 mg/kg) via esophageal gavage for 15 consecutive days. CTZ treatment significantly decreased the growth and the size of the implants, and histological examination indicated regression and atrophy, with no toxicity to the animals. The levels of the angiogenic markers VEGF and VEGFR-2 were significantly decreased in CTZ group. The treatment also promotes a reduction on PGE2 and TNF-α levels. All these effects involve the amelioration of ERK1/2, Akt, AMPK and PERK signaling upon CTZ treatment. In conclusion, CTZ promoted an overall amelioration of endometriosis in a rat model due to the anti-angiogenic properties of the drug. Therefore, our results support the proposal of a clinical trial using CTZ for the treatment of endometriosis.

Vaginal antimycotics and the risk for spontaneous abortions.

BACKGROUND: Spontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-antimycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated. OBJECTIVE: The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal antimycotics. STUDY DESIGN: A historical cohort study was conducted including all clinically apparent pregnancies that began from January 2003 through December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Beer-Sheva, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. Time-varying Cox regression models were constructed adjusting for mother's age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use, and the year of admission. RESULTS: A total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6508 (9.9%) with a spontaneous abortion. Overall, 3246 (5%) pregnancies were exposed to vaginal antimycotic medications until the 20th gestational week: 2712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole. Exposure to vaginal antimycotics was not associated with spontaneous abortions as a group (crude hazard ratio, 1.11; 95% confidence interval, 0.96-1.29; adjusted hazard ratio, 1.11; 95% confidence interval, 0.96-1.29) and specifically for clotrimazole (adjusted hazard ratio, 1.05; 95% confidence interval, 0.89-1.25) and miconazole (adjusted hazard ratio, 1.34; 95% confidence interval, 0.99-1.80). Furthermore, no association was found between categories of dosage of vaginal antimycotics and spontaneous abortions. CONCLUSION: Exposure to vaginal antimycotics was not associated with spontaneous abortions.

Acute vanishing bile duct syndrome after therapy with cephalosporin, metronidazole, and clotrimazole: A case report.

RATIONALE: Vanishing bile duct syndrome (VBDS) consists of a series of diseases characterized by the loss of >50% bile duct in portal areas. Many factors are associated with VBDS including infections, neoplasms, and drugs. Antibiotic is one of the most frequently reported causes of VBDS. PATIENT CONCERNS: A 29-year-old female was admitted because of liver injury for over 3 months. Tests for viruses that can cause hepatitis and autoantibodies were all negative. She was prescribed with antibiotics approximately a week before liver injury while there was no history of alcohol consumption. DIAGNOSES: Liver biopsy demonstrated a loss of intrahepatic bile duct in most of the portal tracts. INTERVENTIONS: This patient was treated with ursodeoxycholic acid, polyene phosphatidylcholine, and bicyclol. Most importantly, the treatments in our hospital were proved by the ethics committee of Department of Infectious Disease, Anhui Provincial Hospital. OUTCOMES: The symptoms were improved. She is still under treatment. LESSONS: VBDS is rare but can be severe. A liver biopsy offers an important evidence for the diagnosis of VBDS, especially for those with a history of susceptible drugs taking.

Immunomodulating and Revascularizing Activity of Kalanchoe pinnata Synergize with Fungicide Activity of Biogenic Peptide Cecropin P1.

Previously transgenic Kalanchoe pinnata plants producing an antimicrobial peptide cecropin P1 (CecP1) have been reported. Now we report biological testing K. pinnata extracts containing CecP1 as a candidate drug for treatment of wounds infected with Candida albicans. The drug constitutes the whole juice from K. pinnata leaves (not ethanol extract) sterilized with nanofiltration. A microbicide activity of CecP1 against an animal fungal pathogen in vivo was demonstrated for the first time. However, a favorable therapeutic effect of the transgenic K. pinnata extract was attributed to a synergism between the fungicide activity of CecP1 and wound healing (antiscar), revascularizing, and immunomodulating effect of natural biologically active components of K. pinnata. A commercial fungicide preparation clotrimazole eliminated C. albicans cells within infected wounds in rats with efficiency comparable to CecP1-enriched K. pinnata extract. But in contrast to K. pinnata extract, clotrimazole did not exhibit neither wound healing activity nor remodeling of the scar matrix. Taken together, our results allow assumption that CecP1-enriched K. pinnata extracts should be considered as a candidate drug for treatment of dermatomycoses, wounds infected with fungi, and bedsores.

Zoon Balanitis Revisited: Report of Balanitis Circumscripta Plasmacellularis Resolving With Topical Mupirocin Ointment Monotherapy.

INTRODUCTION: Zoon balanitis is an idiopathic benign inflammatory condition of the glans penis and prepuce. A patient with biopsy confirmed diagnosis of Zoon balanitis who was successfully treated with topical mupirocin ointment monotherapy is described.

METHOD: A search using PubMed database was performed using the following terms: Zoon balanitis (cases, diagnosis, treatment of), balanitis circumscripta plasmacellularis, and mupirocin. Relevant papers and their reference citations were reviewed and evaluated.

RESULTS: The gold standard of treatment for Zoon balanitis has previously been circumcision. More recently, topical calcineurin inhibitors have been shown to be effective. Our patient had successful resolution of his Zoon balanitis after 3 months of mupirocin ointment monotherapy.

DISCUSSION: Zoon balanitis is a benign inflammatory dermatosis. Previous successful treatment modalities include circumcision, phototherapy, laser therapy, and topical calcineurin inhibitors. Topical mupirocin ointment twice daily resulted in resolution of Zoon balanitis in our patient. Additional evaluation of mupirocin ointment as a therapeutic agent should be considered as a potential first-line therapy in patients with Zoon balanitis.

J Drugs Dermatol. 2017;16(3):285-287.

Effectiveness of Ageratina pichinchensis Extract in Patients with Vulvovaginal Candidiasis. A Randomized, Double-Blind, and Controlled Pilot Study.

Previous clinical studies have demonstrated the antifungal effectiveness of Ageratina pichinchensis extracts when topically administered to patients with dermatomycosis. The objective of this study was to evaluate the effectiveness and tolerability of a 7% standardized extract of A. pichinchensis (intravaginal) in patients with vulvovaginal candidiasis. The extract was standardized in terms of its encecalin content and administered during 6 days to patients with Candida albicans-associated vulvovaginitis. The positive control group was treated with Clotrimazole (100 mg). On day 7 of the study, a partial evaluation was carried out; it demonstrated that 94.1% of patients treated with Clotrimazole and 100% of those treated with the A. pichinchensis extract referred a decrease or absence of signs and symptoms consistent with vulvovaginal candidiasis. In the final evaluation, 2 weeks after concluding administration, 86.6% of patients in the control group and 81.2% (p = 0.65) of those treated with the A. pichinchensis extract demonstrated therapeutic success. Statistical analysis evidenced no significant differences between the two treatment groups. With the results obtained, it is possible to conclude that the standardized extract from A. pichinchensis, intravaginally administered, showed therapeutic and mycological effectiveness, as well as tolerability, in patients with vulvovaginal candidiasis, without noting statistical differences in patients treated with Clotrimazole. Copyright © 2017 John Wiley & Sons, Ltd.

The Effects of Ozonated Olive Oil and Clotrimazole Cream for Treatment of Vulvovaginal Candidiasis.

Context • Vulvovaginal candidiasis is the most common infection of the vulvovagina, which manifests with itching, a burning sensation, and leucorrhea. Some infections have been reported to be tolerant to conventional treatments, especially in immunosuppressed patients. New studies have suggested that ozone, which is the allotropic form of oxygen, may have antifungal effects. Objective • The study intended to compare the effects of ozononated olive oil and clotrimazole in the treatment of vulvovaginal candidiasis. Design • Patients were randomly assigned either to an ozone group or to a clotrimazole group in a randomized, controlled trial. Setting • The study took place in the Department of Gynecology of the School of Medicine at Mashhad University of Medical Sciences in Mashhad, Iran. Participants • Participants were 100 female patients who had been referred to the women's gynecology clinic at the Omolbanin and Ghaem Hospitals and who had confirmed vulvovaginal candidiasis. Intervention • Patients in the ozone group were treated with ozonated olive oil or those in the clotrimazole group were treated with clotrimazole for 7 d. Outcome Measures • Patients were evaluated through an interview and a paraclinical examination at baseline and postintervention. The study measured changes in itching, burning, and leucorrhea using a questionnaire that patients completed at the end of the study and determined the presence of an infection with vaginal candidiasis through a culture both before acceptance into the study and after the treatments, if accepted. Results • Ozone and clotrimazole both reduced symptoms significantly and led to a negative culture for vaginal candidiasis (P < .05). No significant differences existed between the 2 groups in their effects on the symptom of itching and leucorrhea and on the results of the culture (P > .05). However, clotrimazole decreased the burning sensation significantly more than did ozone (P < .05). Conclusions • Considering the potential efficacy of ozonated olive oil in the improvement of the clinical and paraclinical aspects of treatment of patients with vulvovaginal candidiasis, the research team suggests that the treatment can be an effective topical treatment for those patients.

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury.

Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.

Clotrimazole as a pharmaceutical: past, present and future.

Clotrimazole is a broad-spectrum antimycotic drug mainly used for the treatment of Candida albicans and other fungal infections. A synthetic, azole antimycotic, clotrimazole is widely used as a topical treatment for tinea pedis (athlete's foot), as well as vulvovaginal and oropharyngeal candidiasis. It displays fungistatic antimycotic activity by targeting the biosynthesis of ergosterol, thereby inhibiting fungal growth. As well as its antimycotic activity, clotrimazole has become a drug of interest against several other diseases such as sickle cell disease, malaria and some cancers. It has also been combined with other molecules, such as the metals, to produce clotrimazole complexes that show improved pharmacological efficacy. Moreover, several new, modified-release pharmaceutical formulations are also undergoing development. Clotrimazole is a very well-tolerated product with few side effects, although there is some drug resistance appearing among immunocompromised patients. Here, we review the pharmaceutical chemistry, application and pharmacology of clotrimazole and discuss future prospects for its further development as a chemotherapeutic agent.

Squamous cell carcinoma of the penis and topical combination corticosteroid products: a cautionary case.

Squamous cell carcinoma of the penis is fairly uncommon, but an important clinical entity with significant patient morbidity. Early diagnosis is important to allow for conservative management and to avoid aggressive surgical resection. We present a case of an invasive squamous cell carcinoma of the glans penis, which was treated with topical antifungals and corticosteroids for 2 years prior to diagnosis, necessitating partial glansectomy.