Clotrimazole

Clotrimazole, bis-phenyl-(2-chlorophenyl)-1-imidazolyl methane, is a uniquely antifungal compound. In vitro, its spectrum includes dematiaceous, dermatophytes, dimorphic fungi and yeasts species. Its inhibitory concentrations in vitro were ≤ 4μg/mL for most susceptible fungi and ≤1 μg/mL for many species, particularly Trichophyton and Candida. Concentrations >20 μg/mL were fungicidal only [1]. It is also a specific Ca2+ activated K+ channel (Gardos channel) inhibitor [2]. Its IC50 to whole-cell currents in epithelial cells is 9 μmol/l [3].
Gardos channel contributes to pathologic water loss from erythrocytes and results in abnormal hemoglobin and promotes sickling in vitro. To avoid K+ and water loss via this channel was suggested as a potential therapy in vivo [2].
At concentrations ≤0.39 μg/mL, clotrimazole inhibited most isolates of C. neoformans, H. capsulatum and C. immitis. At concentrations < 0.78 μg/mL, clotrimazole did not inhibit one of C. neoformans. At 0.78 μg/mL, clotrimazole was fungicidal for all isolates, except a less susceptible isolate of H. capsulatum [1].
Subjects who had sickle cell anemia were treated with oral clotrimazole (10mg clotrimazole/kg/d for one week, and then daily dose was escalated by 10mg/kg each week). At a dosage of 20mg clotrimazole/kg/d, it was found that the Gardos channel was inhibited, cell K+ content was increased, erythrocyte dehydration was reduced, and hemoglobin levels was somewhat increased in all subjects. There are only three types of adverse effects, i.e. mild/moderate dysuria in all subjects and a reversible increase in plasma aspartic transaminase and alanine transaminase levels in two subjects treated with 30mg clotrimazole/kg/d [2].
References:
[1]. Smith Shadomy. In Vitro Antifungal Activity of Clotrimazole (Bay b 5097), Infection & Immunity. 1971, 4(2): 143-148.
[2]. Carlo Brugnara, Beatrice Gee, Carrie C. Armsby, et al. Therapy with Oral Clotrimazole Induces Inhibition of the Gardos Channel and Reduction of Erythrocyte Dehydration in Patients with Sickle Cell Disease. J. Clin. Invest., 1996, 97(5): 1227-1234.
[3]. Markus Bleich and Richard Warth. The very small-conductance K+ channel KVLQT1 and epithelial function. Pflügers Arch - Eur J Physiol, 2000, 440:202-206.

Formulation and in vitro evaluation of carbopol 934-based modified clotrimazole gel for topical application.[Pubmed:27925034]

An Acad Bras Cienc. 2016 Oct-Dec;88(4):2303-2317.

The aim of present study was to enhance topical permeation of Clotrimazole gel preparation by using various permeability enhancers such as coconut oil, pistachio oil and sodium lauryl sulphate (SLS). Clotrimazole gel preparations were prepared and optimized by using three factor, five level central composite design. A second-order polynomial equation was generated in order to estimate the effect of independent variables i.e. coconut oil (X1), pistachio oil (X2) and sodium lauryl sulphate (X3) at various dependent variables i.e. flux (Y1), lag time (Y2), diffusion coefficient (Y3), permeability coefficient (Y4), and input rate (Y5) of Clotrimazole gel formulations. Ex vivo skin permeation study was performed through rat skin by using modified Franz diffusion cell system. Optimized formulation F8 exhibited highest flux 2.17 microg/cm2/min, permeability coefficient 0.0019 cm/min and input rate 1.543 microg/cm2/min, along with moderate lag time 77.27 min and diffusion coefficient 0.063 cm2/min, which is further supported by anti-fungal activity that exhibited more prominent zone of inhibition against Candida albicans, Aspergillus niger and Mucor. Thus, it can be concluded that permeation of Clotrimazole gel was enhanced by various combination of coconut oil, pistachio oil and sodium lauryl sulphate but optimized formulation F8 containing 0.4 ml pistachio oil, 0.8 ml coconut oil and 0.04 g of SLS exhibited more pronounced and promising effect through rat skin.

Topical treatment of mycotic rhinitis-rhinosinusitis in dogs with meticulous debridement and 1% clotrimazole cream: 64 cases (2007-2014).[Pubmed:28117652]

J Am Vet Med Assoc. 2017 Feb 1;250(3):309-315.

OBJECTIVE To evaluate outcomes for dogs with mycotic rhinitis-rhinosinusitis (MRR) treated by meticulous debridement and topical application of 1% Clotrimazole cream and investigate potential prognostic factors that could help predict whether 1 or multiple treatments would be needed for clinical resolution of the condition. DESIGN Retrospective case series. ANIMALS 64 dogs. PROCEDURES Medical records were reviewed to identify dogs treated for MRR by meticulous debridement and topical application of 1% Clotrimazole cream. Signalment, clinical signs, previous treatments, CT findings, presence of unilateral or bilateral disease, predisposing factors, number and type of treatments, and complications were recorded. Outcome information was obtained from records or by telephone interview with owners. Association of selected factors with the number of treatments needed for clinical resolution was evaluated. RESULTS Clotrimazole was instilled via the trephination site (n = 42) or under endoscopic guidance (22). Thirteen dogs underwent a 5-minute flush with 1% Clotrimazole solution prior to cream application, and 34 received adjunctive oral itraconazole treatment. The MRR was deemed resolved in 58 dogs, and clinical signs persisted in 1 dog. Five dogs died (2 of causes unrelated to MRR) Clotrimazole cream application had results similar to or better than those described in other studies of dogs with MRR. Trephination or adjunctive itraconazole treatment did not influence the number of treatments needed for a successful outcome.

[Clotrimazole and ciclopirox olamine respectively in combination with methylprednisolone aceponate as extemporaneous formulations].[Pubmed:28091698]

Hautarzt. 2017 Apr;68(4):307-315.

The combination of topical fungicide and glucocorticoids has been proven as a successful therapy of cutaneous mycoses with accompanying inflammatory reactions, particularly when used at an early stage. Various national and international therapeutic guidelines recommend this practice. In this context, two individually manufactured formulations have been developed and tested for stability: the combination of methylprednisolone aceponate-a topical glucocorticoid with the therapeutic index of 2.0-with Clotrimazole and with ciclopirox olamine, respectively. This has been conducted in compliance with the requirements for quality controlled extemporaneous formulations and the legal framework of the German Pharmacy Working Regulations (Apothekenbetriebsordnung). There are now two formulations for clinical use that are microbiologically, physically, and chemically stable, which combine methylprednisolone aceponate-a glucocorticoid with a good risk-benefit ratio-with the broad-spectrum fungicides Clotrimazole and, for the first time, ciclopirox olamine.

Comparative efficacy of topical application of tacrolimus and clotrimazole in the treatment of pityriasis versicolor: A single blind, randomised clinical trial.[Pubmed:28120351]

Mycoses. 2017 May;60(5):338-342.

BACKGROUND: Pityriasis versicolor (PV) is a common superficial fungal disease. Possibility of emergence of resistant strains to azoles, and difficulty in differentiation of hypopigmented PV and early vitiligo, encouraged us to evaluate the efficacy of topical tacrolimus (a calcineurin inhibitor agent with proven in vitro anti-Malassezia effect) for PV treatment generally and its effect on PV-induced hypopigmentation specifically. OBJECTIVES: To evaluate the efficacy of topical tacrolimus on pityriasis versicolor. PATIENTS/METHODS: Fifty PV patients were randomly allocated into two equal groups applying either topical clotrimazol or tacrolimus twice daily for 3 weeks. They were evaluated at the beginning of study, in the third and fifth weeks clinically and mycologically (direct smear). RESULTS: Although both treatments resulted in global, clinical, and mycological cure of PV, there was no significant difference regarding the mentioned aspects of cure between tacrolimus and Clotrimazole treated patients. (P-value: .63, .45, and .26, respectively) Tacrolimus had no significant effect on hypopigmentation in the fifth week follow-up. (P-value: .62). CONCLUSIONS: In spite of the lack of efficacy of tacrolimus on PV-induced hypopigmentation, the therapeutic effect on PV introduces tacrolimus as a therapeutic option for PV, especially when early vitiligo is among the differential diagnoses without concerning the aggravating effect of topical corticosteroids on PV.

Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein.[Pubmed:15905360]

Mol Endocrinol. 2005 Sep;19(9):2258-72.

Ligand-dependent signal transduction by nuclear receptors (NRs) includes dynamic exchanges of coactivator (CoA) and corepressor (CoR) proteins. Here we focused on the structural determinants of the antagonist- and inverse agonist-enhanced interaction of the endocrine NR vitamin D receptor (VDR) and the adopted orphan NR constitutive androstane receptor (CAR) from two species with the CoR NR corepressor. We found that the pure VDR antagonist ZK168281 and the human CAR inverse agonist Clotrimazole are both effective inhibitors of the CoA interaction of their respective receptors, whereas ZK168281 resembled more the mouse CAR inverse agonist androstanol in its ability to recruit CoR proteins. Molecular dynamics simulations resulted in comparable models for the CoR receptor interaction domain peptide bound to VDR/antagonist or CAR/inverse agonist complexes. A salt bridge between the CoR and a conserved lysine in helix 4 of the NR is central to this interaction, but also helix 12 was stabilized by direct contacts with residues of the CoR. Fixation of helix 12 in the antagonistic/inverse agonistic conformation prevents an energetically unfavorable free floatation of the C terminus. The comparable molecular mechanisms that explain the similar functional profile of antagonist and inverse agonists are likely to be extended from VDR and CAR to other members of the NR superfamily and may lead to the design of even more effective ligands.

The antifungal antibiotic clotrimazole potently inhibits L-type calcium current in guinea-pig ventricular myocytes.[Pubmed:10323582]

Br J Pharmacol. 1999 Apr;126(7):1531-3.

The antimycotic agent Clotrimazole (CLT) is a promising potential therapeutic agent for a variety of diseases including cancer. Although it is known that CLT alters calcium homeostasis in many cell types, its cardiac effects are virtually unknown. We investigated the effects of CLT on L-type calcium current (ICa,L) and action potentials in guinea-pig ventricular myocytes. CLT (5, 25 and 50 microM) inhibited basal ICa,L by 16, 59 and 93%, respectively. The inhibitory effect of CLT was rapid and the peak effect was attained within 3 min. At a concentration of 25 microM, the inhibitory effect of CLT was partially reversible whereas the response to 50 microM CLT persisted following drug withdrawal. CLT abbreviated action potential duration at 50 and 90% of repolarization and suppressed the plateau significantly. These results indicate that CLT may have important cardiac effects at concentrations used to induce the antiproliferative action of the drug.

Inhibition of Ca2+-activated K+ current by clotrimazole in rat anterior pituitary GH3 cells.[Pubmed:10428416]

Neuropharmacology. 1999 Jul;38(7):979-89.

The ionic mechanism of Clotrimazole, an imidazole antimycotic P-450 inhibitor, was examined in rat anterior pituitary GH3 cells. In perforated-patch whole-cell recording experiments, Clotrimazole reversibly caused an inhibition of the Ca2+-activated K+ current in a dose-dependent manner. The IC50 value of the Clotrimazole-induced inhibition of I(K(Ca)) was 3 microM. In the outside-out configuration of single channel recording, application of Clotrimazole (10 microM) into the bath medium did not change the single channel conductance of large conductance Ca2+-activated K+(BK(Ca)) channels, but it suppressed the channel activity significantly. The change in the kinetic behavior of BK(Ca) channels caused by Clotrimazole in these cells is found to be due to a decrease in mean open time and an increase in mean closed time. Other structurally distinct P-450 inhibitors (e.g. ketoconazole or econazole) also effectively suppressed the amplitude of I(K(Ca)). Clotrimazole (10 microM) blocked both the inactivating and non-inactivating components of the voltage-dependent K+ outward current (I(K(V))), but it produced a slight reduction of L-type Ca2+ inward current (I(Ca,L)) without altering the current-voltage relationship of I(Ca,L). Clotrimazole (10 microM) also increased the firing rate of action potentials. These results provide direct evidence that Clotrimazole is capable of suppressing the activity of BK(Ca) channel in GH3 cells. Because of the non-selective inhibitory effect of Clotrimazole on I(K(Ca)) and I(K(V)), this inhibition is mainly, if not entirely, due to a direct channel blockade. Thus, the present study implies that the blockade of these ionic channels by Clotrimazole would affect hormonal secretion and neuronal excitability.

Clotrimazole, an antimycotic drug, inhibits the sarcoplasmic reticulum calcium pump and contractile function in heart muscle.[Pubmed:9774419]

J Biol Chem. 1998 Oct 23;273(43):28032-9.

Clotrimazole (CLT), an antimycotic drug, has been shown to inhibit proliferation of normal and cancer cell lines and its systemic use as a new tool in the treatment of proliferative disorders is presently under scrutiny (Benzaquen, L. R., Brugnara, C., Byers, H. R., Gattoni-Celli, S., and Halperin, J. A. (1995) Nature Med. 1, 534-540). The action of CLT is thought to involve depletion of intracellular Ca2+ stores but the underlying mechanism has not been defined. The present study utilized membrane vesicles of rabbit cardiac sarcoplasmic reticulum (SR) to determine the mechanism by which CLT depletes intracellular Ca2+ stores. The results revealed a strong, concentration-dependent inhibitory action of CLT on the ATP-energized Ca2+ uptake activity of SR (50% inhibition with approximately 35 microM CLT). The inhibition was of rapid onset (manifested in <15 s), and was accompanied by a 7-fold decrease in the apparent affinity of the SR Ca2+-ATPase for Ca2+ and a minor decrement in the enzyme's apparent affinity toward ATP. Exposure of SR to CLT in the absence or presence of Ca2+ resulted in irreversible inhibition of Ca2+ uptake demonstrating that the Ca2+-bound and Ca2+-free conformations of the Ca2+-ATPase are CLT-sensitive. Introduction of CLT to the reaction medium subsequent to induction of enzyme turnover with Ca2+ and ATP resulted in instantaneous cessation of Ca2+ transport indicating that an intermediate enzyme species generated during turnover undergoes rapid inactivation by CLT. The inhibition of Ca2+ uptake by CLT was accompanied by inhibition of Ca2+-stimulated ATP hydrolysis and Ca2+-induced phosphoenzyme intermediate formation from ATP in the ATPase catalytic cycle. Phosphorylation of the Ca2+-deprived enzyme with Pi in the reverse direction of catalytic cycle and Ca2+ release from Ca2+-preloaded SR vesicles were unaffected by CLT. It is concluded that CLT depletes intracellular Ca2+ stores by inhibiting Ca2+ sequestration by the Ca2+-ATPase. The mechanism of ATPase inhibition involves a drug-induced alteration in the Ca2+-binding site(s) resulting in paralysis of the enzyme's catalytic and ion transport cycle. CLT (50 microM) caused marked depression of contractile function in isolated perfused, electrically paced rabbit heart preparations. The contractile function recovered gradually following withdrawal of CLT from the perfusate indicating the existence of mechanisms in the intact cell to inactivate, metabolize, or clear CLT from its target site.

Clotrimazole is an imidazole derivative, an antifungal compound and is a CYP (cytochrome P450) inhibitor. Clotrimazole has antibacterial activity.

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