Improvement of Skin Permeation of Caffeine, a Hydrophilic Drug, by the Application of Water Droplets Provided by a Novel Humidifier Device.

Recently, a novel humidifier that sprays water fine droplets equipped with a copolymer, poly(3,4-ethylene dioxythiophene)-poly(styrene sulfonate) (PEDOT/PSS) was developed. PEDOT/PSS in the humidifier absorbs water from the environment and releases fine water droplets by heating. In the present study, the effect of hydration on the skin barrier, stratum corneum, was first determined by the application of fine water droplets using the humidifier. The skin-penetration enhancement effect of a model hydrophilic drug, caffeine, was also investigated using the humidifier and compared with a conventional water-evaporative humidifier. More prolonged skin hydration effect was observed after application of the fine water droplet release humidifier using PEDOT/PSS than that using a conventional humidifier. In addition, markedly higher skin permeation of caffeine was observed in both infinite and finite dose conditions. Furthermore, higher skin permeation of caffeine from oil/water emulsion containing caffeine was observed in finite dose conditions by pretreatment with the humidifier using PEDOT/PSS. This device can provide water droplets without replenishing water, so it is more convenient for enhancing the skin permeation of chemical compounds from topical drugs and cosmetic formulations.

Development of Spray Formulations Applied to the Oral Mucosa Using Non-lamellar Liquid Crystal-Forming Lipids.

We examined the physicochemical and biochemical properties of mono-O-(5,9,13-trimethyl-4-tetradecenyl)glycerol ester (MGE), including ease of handling, high bioadhesiveness, quick and stable in vivo self-organization (forming a non-lamellar lyotropic liquid crystal [NLLC]), and high biomembrane permeation enhancement. We prepared MGE oral mucosa-applied spray preparations containing triamcinolone acetonide (TA), which is widely used in the treatment of stomatitis, and we examined the usefulness of the MGE preparations compared with commercially available oral mucosal application preparations containing 2,3-dihydroxypropyl oleate (1-mono(cis-9-octadecenoyl)glycerol (GMO) (previously studied as an NLLC-forming lipid) preparation. As a result, the MGE preparation applied to the oral mucosa can rapidly formed an NLLC with reverse hexagonal or cubic structures, or a mixture, on contact with water. In addition, by adding hydroxypropyl cellulose to the MGE preparation, similar retention properties on the oral mucous membrane were obtained to that using marketed drug preparations. Furthermore, the MGE spray formulation on the oral mucosa showed an equivalent or higher TA release as well as oral mucous membrane permeability compared with commercial formulations. Because MGE forms a stable NLLC and is easy to handle compared with GMO, MGE was considered to be a useful pharmaceutical additive for a spray preparation applied to the oral mucosa in combination.

Safety of Concentrated Bioshell Calcium Oxide Water Application for Surface and Skin Disinfections against Pathogenic Microbes.

Immediately post-production, commercially available bioshell calcium oxide (BiSCaO) water is colorless, transparent, and strongly alkaline (pH 12.8), and is known to possess deodorizing properties and broad microbicidal activity. However, BiSCaO Water may represent a serious safety risk to the living body, given the strong alkalinity. This study aimed to investigate the safety of BiSCaO Water for use as an antiseptic/disinfectant despite concerns regarding its high alkalinity. The change over time in pH of BiSCaO Water was measured during air contact (stirring BiSCaO Water in ambient air). When sprayed on metal, plastic, wood piece, paper, and skin surfaces, the pH of BiSCaO Water decreased rapidly, providing a white powder coating upon drying. Scanning electron microscopy images, energy dispersive X-ray elemental mapping, and X-ray diffractograms showed that the dried powder residues of BiSCaO Water were composed primarily of calcium carbonate. These results suggested that BiSCaO Water is a potent reagent that may overcome the obstacles of being strongly alkaline, making this material appropriate for use in disinfection against pathogenic microbes.

Prolonged Distribution of Tranilast in the Eyes after Topical Application onto Eyelid Skin.

Tranilast, a lipophilic drug with various ophthalmic applications, was used as a model drug to establish the possibility of delivering lipophilic drugs through the eyelid skin. Pharmacokinetics and tissue distribution studies were conducted employing three application methods (topical application onto eyelid skin, eye drops, and intravenous injection in rats) to broaden the significance of delivering drugs through the eyelids. A two-compartment open model analysis was used for intravenous route while a non-compartmental evaluation was used for topical applications to estimate the pharmacokinetic parameters. Eyelid skin application, eye drops, and intravenous administration had mean residence times (MRTs) of 8.07, 1.79, and 3.25 h in the eyeball and 10.8, 1.29, and 2.97 h in the conjunctiva, correspondingly. In the eyeball, topical application of tranilast onto the eyelids corresponded to a 4.5- and 2.5-fold higher MRT compared with eye drops and intravenous administration, respectively. An 8.4- or 3.6-fold higher MRT was observed in the conjunctiva after topical application compared with eye drops or intravenous administration, respectively. This indicated a gradual penetration of tranilast into the eyeball and conjunctiva, subsequently a slow elimination from these target tissues.

Bioshell calcium oxide (BiSCaO) for cleansing and healing Pseudomonas aeruginosa-infected wounds in hairless rats.

BACKGROUND: Scallop shell powder is called bioshell calcium oxide (BiSCaO), which is known to possess deodorizing properties and broad antimicrobial activity against various pathogenic microbes, including viruses, bacteria, spores, and fungi. OBJECTIVE: This study aims to investigate the applications of BiSCaO suspension cleansing in clinical situations, for instance for the prevention and treatment of infections in chronic wounds in healing-impaired patients, without delaying wound healing. METHODS: The bactericidal activities of 1000 ppm BiSCaO suspension; 500 ppm hypochlorous acid; 1000 ppm povidone iodine; and saline were compared to evaluate in vivo disinfection and healing of Pseudomonas aeruginosa-infected wounds in hairless rats. RESULTS: Cleansing of the infected wounds with BiSCaO suspension daily for 3 days significantly enhanced wound healing and reduced the in vivo bacterial counts, in comparison to hypochlorous acid, povidone iodine, and saline. Furthermore, histological examinations showed significantly advanced granulation tissue and capillary formation in the wounds cleansed with BiSCaO suspension than in those cleansed with the other solutions. CONCLUSIONS: This study suggested that the possibility of using BiSCaO suspension as a disinfectant for infected wounds and limiting disinfection to 3 days may be sufficient to avoid the negative effects on wound repair.

Bioshell Calcium Oxide (BiSCaO) Ointment for the Disinfection and Healing of Pseudomonas aeruginosa-Infected Wounds in Hairless Rats.

Bioshell calcium oxide (BiSCaO) possesses deodorizing properties and broad microbicidal activity. This study aimed to investigate the application of BiSCaO ointment for the prevention and treatment of infection in chronic wounds in healing-impaired patients, without delaying wound healing. The bactericidal activities of 0.04, 0.2, 1, and 5 wt% BiSCaO ointment, 3 wt% povidone iodine ointment, and control (ointment only) were compared to evaluate the in vivo disinfection and healing of Pseudomonas aeruginosa-infected wounds in hairless rats. Treatment of the infected wounds with 0.2 wt% BiSCaO ointment daily for 3 days significantly enhanced wound healing and reduced the in vivo bacterial counts compared with povidone iodine ointment and control (no wound cleaning). Although 5 wt% BiSCaO ointment provided the lowest bacterial counts during 3 days' treatment, it delayed wound healing. Histological examinations showed significantly advanced granulation tissue and capillary formation in wounds treated with 0.2 wt% BiSCaO ointment for 3 days compared to wounds treated with the other ointments. This study suggested that using 0.2 wt% BiSCaO ointment as a disinfectant for infected wounds and limiting disinfection to 3 days may be sufficient to avoid the negative effects of BiSCaO on wound repair.

The use of non-traditional models in the study of cancer resistance-the case of the naked mole rat.

Non-traditional model organisms are typically defined as any model the deviates from the typical laboratory animals, such as mouse, rat, and worm. These models are becoming increasingly important in human disease research, such as cancer, as they often display unusual biological features. Naked mole rats (NMRs) are currently one of the most popular non-traditional model, particularly in the longevity and cancer research fields. NMRs display an exceptionally long lifespan (~30 years), yet have been observed to display a low incidence of cancer, making them excellent candidates for understanding endogenous cancer resistance mechanisms. Over the past decade, many potential resistance mechanisms have been characterized. These include unique biological mechanisms involved in genome stability, protein stability, oxidative metabolism, and other cellular mechanisms such as cell cycle regulation and senescence. This review aims to summarize the many identified cancer resistance mechanisms to understand some of the main hypotheses that have thus far been generated. Many of these proposed mechanisms remain to be fully characterized or confirmed in vivo, giving the field a direction to grow and further understand the complex biology displayed by the NMR.

Pharmacokinetics of a weekly transdermal delivery system of tenofovir alafenamide in hairless rats.

Tenofovir alafenamide (TAF) is a potent prodrug of tenofovir (TFV) for HIV prophylaxis, and HIV and HBV treatment. Compared to oral daily doses, transdermal administration of TAF may be more advantageous for long-term adherence by offering sustained drug delivery and reduced dosing frequency. Here, we described the plasma pharmacokinetics (PK) of an optimized once-weekly suspension transdermal delivery system (TDS) for TAF (96 mg/25 cm2 of TDS) in female hairless rats. Over the study period, the TAF TDS delivered an overall low level of TAF (median: 1.43 [0.02-3.28] ng/mL) and a sustained level of the stable metabolite and parent drug, TFV. Relative to the projected exposure corresponding to six-day oral daily doses, a comparable TAF exposure but a substantially lower TFV exposure was resulted from the TAF TDS, suggesting a lower risk of TFV-associated adverse effects. TAF, TFV, and phosphorylated TFVs (TFV-monophosphate and diphosphate) were found distributed in vaginal tissue, the portal of entry for HIV during male-to-female sexual transmission. Skin adhesion and tolerance were acceptable given the animal model used. PK evaluation of the TAF TDS in hairless rats demonstrates the proof of concept that transdermal delivery can be an alternative route for a sustained, once-weekly systemic delivery of TAF.

Evaluation of the Effect of Chronic 94 GHz Exposure on Gene Expression in the Skin of Hairless Rats In Vivo.

Millimeter waves (MMW) are broadband frequencies that have recently been used in several applications in wireless communications, medical devices and nonlethal weapons [i.e., the nonlethal weapon, Active Denial Systems, (ADS) operating at 94-95 GHz, CW]. However, little information is available on their potential effects on humans. These radio-frequencies are absorbed and stopped by the first layer of the skin. In this study, we evaluated the effects of 94 GHz on the gene expression of skin cells. Two rat populations consisting of 17 young animals and 14 adults were subjected to chronic long-term 94 GHz MMW exposure. Each group of animals was divided into exposed and sham subgroups. The two independent exposure experiments were conducted for 5 months with rats exposed 3 h per day for 3 days per week to an incident power density of 10 mW/cm2, which corresponded to twice the ICNIRP limit of occupational exposure for humans. At the end of the experiment, skin explants were collected and RNA was extracted. Then, the modifications to the whole gene expression profile were analyzed with a gene expression microarray. Without modification of the animal's temperature, long-term chronic 94 GHz-MMW exposure did not significantly modify the gene expression of the skin on either the young or adult rats.

Utility of hairless rats as a model for predicting transdermal pharmacokinetics in humans.

This study investigated the use of HWY hairless rats to predict human plasma concentrations of drugs following dermal application.Utilizing a deconvolution method, pharmacokinetic parameters (e.g. in vivo absorption rates) were determined for six transdermal drugs in hairless rats. Obtained data were used to simulate the human plasma concentration-time profiles of transdermal drugs, which were then compared with clinical data in humans. Because hairless rats have lower hair follicle density than do humans, the impact of hair follicle density on skin permeability to hydrophilic compounds was also evaluated.Pharmacokinetic parameters showed low intra-individual variability in hairless rats. Simulated concentration profiles for compounds with logarithm of the octanol-water partition coefficient exceeding two were comparable to clinical data, but simulated concentration profiles for hydrophilic compounds (i.e. bisoprolol and nicotine) at maximum concentration differed from clinical data by more than two-fold. Finally, in vitro permeability to bisoprolol and nicotine was higher in human skin than in hairless rat skin, but hair follicle plugging reduced human skin permeability.In vivo skin absorption data from HWY hairless rats help to predict human concentration profiles for lipophilic compounds. However, the data underestimate human absorption of hydrophilic compounds.

Evaluation iontophoretic delivery of a cationic ketoprofen prodrug for treating nociceptive symptoms in monosodium iodoacetate induced osteoarthritic rat model.

Topical nonsteroidal anti-inflammatory drugs have been used in treatment of osteoarthritis but their efficacy is marginal. One major reason is because of limited drug direct penetration to affected joint and muscle tissues from the topical application. The main purpose of this study was to evaluate a new topical treatment through enhancing the direct drug penetration to local muscle and joint tissues for improving topical treatment of osteoarthritis. A cationic prodrug, ketoprofen choline chloride (KCC) was synthesized for iontophoretic topical delivery. Anodal iontophoretic delivery of KCC and cathodal iontophoretic delivery of ketoprofen to the knee of live hairless rats were evaluated and the drug concentrations in the joint and muscle tissues over the time were determined. In addition, a knee osteoarthritis rat model was induced with intra-articular injection of monosodium iodoacetate solution. Anodal iontophoretic delivery of KCC, cathodal iontophoretic delivery of ketoprofen, or anodal iontophoretic delivery of sodium chloride were applied to the affected knee joint of each rat group, respectively. Knee joint pain was evaluated through a hind paw weight bearing study and knee joint inflammation was evaluated through measuring of the knee diameter. Iontophoretic delivery of KCC showed much higher drug concentration in the knee joint and muscle tissues, compared to iontophoretic delivery of ketoprofen. Treatment of rat knee joint with anodal iontophoresis of KCC also showed significant pain relief and knee inflammation reduction comparing to the control group, while treatment results from cathodal iontophoresis of ketoprofen were mostly not significantly different from the control group.

Potential of biocompatible polymeric ultra-thin films, nanosheets, as topical and transdermal drug delivery devices.

The aim of the present study was to assess the potential of biocompatible polymeric nanosheets as topical and transdermal drug-delivery devices. Nanosheets are two-dimensional nanostructures with a thickness in the nanometer order, and their extremely large aspect ratios result in unique properties, including high transparency, flexibility, and adhesiveness. Nanosheet formulations containing betamethasone valerate (BV) as a model drug and consisting of poly (L-lactic acid) or poly (lactic-co-glycolic) acid were fabricated through a spin-coating-assisted layer-by-layer method using a water-soluble sacrificial membrane. The fabricated formulations could incorporate and release higher amounts of BV compared with a commercial ointment, and the amounts could be controlled by the polymers used, the amount of BV added, and the use of controlled-release membranes. The presence of BV had a minimal effect on thickness, transparency, adhesiveness, and moisture permeability of nanosheets, permitting their application to any area of skin for a long period of time. Therefore, this biocompatible polymeric nanosheet formulation represents a novel and promising topical and transdermal drug delivery device, which has potential to deliver drugs regardless of the area of skin.

Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model.

BACKGROUND: The hypoxia-inducible factor (HIF) pathway, regulated by prolyl hydroxylase, is central to tissue adaptation to ischemia. The authors tested whether the prolyl hydroxylase inhibitor dimethyloxalylglycine reduces skin flap necrosis. METHODS: Dorsal skin flaps were raised on hairless rats, with dimethyloxalylglycine delivered intraperitoneally and/or topically for 7 days before and after surgery. After 14 treatment days, percentage of flap necrosis was compared grossly and tissue perfusion compared with an in vivo imaging system. Angiogenesis was compared using immunohistochemical CD31 staining and enzyme-linked immunosorbent assay for tissue vascular endothelial growth factor. Expression levels of HIF-1α and terminal deoxynucleotidyl transferase-mediated dUDP end-labeling were compared using immunohistochemical staining. Complete blood counts and gross necropsy specimens were obtained to assess systemic toxicity. RESULTS: Dimethyloxalylglycine administration significantly improved postoperative flap viability, with combined topical and intraperitoneal dimethyloxalylglycine administration leading to reduced necrosis on postsurgical day 7 at 6 mg/kg/day, 12 mg/kg/day, 24 mg/kg/day, and 48 mg/kg/day versus controls (all p < 0.05). Compared with controls (unperfused, 39.9 ± 3.8 percent), dimethyloxalylglycine treatment led to a dose-dependent decrease in unperfused tissue at 6 mg/kg/day (11.4 ± 1.7 percent), 12 mg/kg/day (9.4 ± 4.2 percent), 24 mg/kg/day (4.7 ± 2.6 percent), and 48 mg/kg/day (1.4 ± 0.9 percent) (all p < 0.001). Topical dimethyloxalylglycine application alone administered at 48 mg/kg/day was sufficient to improve flap viability (p = 0.005). Dimethyloxalylglycine-treated flaps exhibited higher CD31 staining (p = 0.004), tissue vascular endothelial growth factor (p = 0.007), HIF-1α staining (p < 0.001), and reduced terminal deoxynucleotidyl transferase-mediated dUDP end-labeling staining (p = 0.045). There were no differences in hematocrit or macroscopic organ changes on gross necropsy. CONCLUSION: Topical and systemic targeting of the HIF-1 pathway may be a promising therapeutic approach to improve flap resistance to ischemia.

Pharmaceutical jewelry: Earring patch for transdermal delivery of contraceptive hormone.

Lack of adherence to medication dosing schedules is a significant cause of morbidity and mortality with large associated financial costs. This is especially true for contraceptive hormones, which provide almost perfect prevention of pregnancy when used correctly, but have significant failure rates in typical use, due largely to poor adherence. To increase medication acceptability and adherence, we introduce pharmaceutical jewelry, in which a transdermal patch is incorporated into jewelry worn on skin. To demonstrate the approach, we incorporated transdermal patches containing the contraceptive hormone levonorgestrel (LNG) into an earring, a ring, a necklace, and a wrist watch. Transdermal delivery of LNG from earring patches across porcine skin ex vivo achieved a steady state flux of 1.7 µg/cm2·h. Pharmacokinetic analysis in hairless rats yielded LNG delivery rates that maintained serum LNG levels near 1500 pg/ml throughout the 1-week patch application period, which is well above the human contraceptive threshold concentration of 200 pg/ml. When patches were applied cyclically for 16 h on and 8 h off to simulate earring removal at night, serum LNG concentrations dipped during off periods, but remained well above the human contraceptive threshold. Earring patches were well tolerated by the rats. We conclude that pharmaceutical jewelry can provide a novel method of drug delivery, especially for contraceptive hormones, that has the potential to improve acceptability and increase medication adherence.

Enhanced transdermal permeation and anti-inflammatory potential of phospholipids complex-loaded matrix film of umbelliferone: Formulation development, physico-chemical and functional characterization.

In the present study, umbelliferone - phospholipids complex - loaded matrix film (UPLC - MF) was developed with a goal of improving transdermal permeation and anti-inflammatory potential of umbelliferone (UMB). Umbelliferone - phospholipids complex (UPLC) was prepared using solvent evaporation method. UPLC-MF was prepared by simple and reproducible solvent casting method. Prepared UPLC and UPLC-MF were both physico-chemically characterized by Fourier transforms infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), proton nuclear magnetic resonance spectroscopy (1H NMR), weight variation, thickness, tensile strength, folding endurance, % elongation, moisture content and uptake Functional characterization of UPLC and UPLC-MF was carried out by solubility analysis, in vitro dissolution, diffusion, and ex vivo permeation via dialysis and biological membrane. UPLC - MF was also evaluated for in vivo anti-inflammatory activity using carrageenan-induced Albino rat paw model. Design-based optimal values for formulation and process variables of UPLC were observed to be 1:1.78, 50 °C and 2 h, respectively. Physico-chemical characterization confirmed the formation of the complex and the film. UPLC demonstrated a higher aqueous solubility (~11-fold), compared to pure UMB. Rate and extent of dissolution of UMB from UPLC was enhanced significantly to that of pure UMB. Compared to UMB-MF, the diffusion and permeation rate of UMB from UPLC-MF enhanced significantly. The UPLC - MF improved the anti-inflammatory potential of UMB by significant enhancement of edema inhibition (%), compared to UMB-MF. The obtained results showed that the present combined formulation system could be employed as a promising strategy for improving transdermal permeation of UMB.

A novel method to assess the severity and prognosis in crush syndrome by assessment of skin damage in hairless rats.

PURPOSE: Crush syndrome (CS), a serious medical condition characterised by damage to the muscle cells due to pressure, is associated with high mortality, even when patients receive fluid therapy during transit to the hospital or admission to the hospital. There is no standard triage approach for earthquake victims with crush injuries due to the scarcity of epidemiologic and quantitative data. We examined whether mortality can be predicted based on the severity of skin damage so that assess the severity and prognosis in crush syndrome by assessment of skin damage in hairless rats because we have previously observed that CS results in oedema and redness of the skin in rats. METHODS: Anaesthetised rats were subjected to bilateral hind limb compression [1 kg (mild) and 2 kg (severe) loads] with a rubber tourniquet for 5 h. The rats were then randomly divided into three groups: sham, mild CS, and severe CS. RESULTS: The mild and severe CS groups had mortality rates of 20 and 90%, respectively. The severe CS group demonstrated higher rates of hyperkalaemia, hypovolemic shock, acidosis, and inflammation. Skin damage was significantly worse in the severe CS group compared to the mild CS group. Skin damage showed good correlation with pathological severity. CONCLUSIONS: Skin damage is a valid measure of transepidermal water loss and severity of CS. We suggest that these models may be useful to professionals who are not experienced in disaster management to identify earthquake victims at high risk of severe CS.

A Novel Small-Animal Model of Irradiated, Implant-Based Breast Reconstruction.

BACKGROUND: There is currently a need for a clinically relevant small-animal model for irradiated, implant-based breast reconstruction. Present models are inadequate in terms of suboptimal location of expander placement and mode of radiation delivery, correlating poorly with the human clinical scenario. The authors hypothesized that by delivering fractionated radiation and placing an expander under the scalp of the animal, they would achieve soft-tissue changes histologically analogous to those seen in human irradiated, implant-based breast reconstruction. METHODS: This study consisted of 11 immunocompetent, hairless rats divided into three groups as follows: untreated control (n = 3), tissue-expanded scalps (n = 4), and fractionated irradiation plus tissue expansion of the scalp (n = 4). At the completion of the experiment for each group, skin tissue samples were analyzed histologically for vascularity, epidermal and dermal thickness, and collagen fiber alignment or scar formation. RESULTS: Expanded rat epidermis was significantly thicker and dermis was more vascular than nonexpanded skin. The authors observed a greater degree of collagen fiber alignment in the expanded group compared with nonexpanded skin. The combination of irradiation and expansion resulted in significant dermal thinning, vascular depletion, and increased scar formation compared with expanded skin alone. CONCLUSIONS: The authors describe a novel small-animal model for irradiated, implant-based breast reconstruction where histologic analysis shows structural changes in the skin consistent with known effects of radiation therapy and expansion in human skin. This model represents a significant improvement from previous ones and, as such, holds the potential to be used to test new therapeutic agents to improve clinical outcomes.

Design of a Topically Applied Gel Spray Formulation with Ivermectin Using a Novel Low Molecular Weight Gelling Agent, Palmitoyl-Glycine-Histidine, to Treat Scabies.

Palmitoyl-glycine-histidine (Pal-GH) is a new low molecular weight gelling agent. It exhibits thixotropic behavior, low viscosity, and high dissolving properties for a wide range of hydrophilic to lipophilic drugs. Orally administered ivermectin (IVM) is used to treat scabies. However, this treatment is associated with well-known side effects, thus a study is awaited to search for alternative routes of administration. Although a topical formulation of IVM could be a candidate, it requires whole body application except the head and face for several hours on a daily basis. Therefore, in this study, we prepared a gel spray formulation containing IVM as an approach for application to large skin areas with a single spray application without further contact with the applied formulation. Pal-GH gel spray formulations were prepared from its aqueous solution by a heating and cooling method. Rheological behavior and physical appearance (spraying, spreading ability, volume of spraying, and homogeneity) of the prepared formulations were evaluated. Pal-GH gel with propylene glycol demonstrated impressive rheological properties (typical thixotropic behavior) with high hysteresis area among all the tested Pal-GH gels and spreading ability. The obtained IVM concentration in the skin after topical application of 0.1% IVM-containing Pal-GH formulation onto hairless rats was much higher than the reported therapeutic concentration obtained from oral administration in humans. These results suggested that topical application of IVM using a Pal-GH gel spray formulation could be an alternative to the conventional oral forms for the scabies treatment.

Low systemic exposure and calcemic effect of calcipotriol/betamethasone ointment in rats with imiquimod-induced psoriasis-like dermatitis.

Vitamin D3 (VD3) analogues-containing ointments are known to occasionally cause hypercalcemia in psoriasis patients, and the frequency of hypercalcemia is suggested to vary based on the VD3 analogue used. In this study, to address the differences in calcemic effects of VD3-containing ointments, the calcemic effects of marketed VD3-containing ointments, including calcipotriol (Cal), maxacalcitol (Max), tacalcitol (Tac), calcipotriol/betamethasone dipropionate (Cal/BDP) and maxacalcitol/betamethasone butyrate propionate (Max/BBP) ointments, were evaluated in a rat model of imiquimod-induced dermatitis. The topical application of Tac, Max and Max/BBP ointments, but not Cal and Cal/BDP ointments, to the imiquimod-induced skin lesions significantly induced an increase in the serum calcium level compared with the vaseline-treated group. Calcemic effect of VD3 analogues in rats treated with VD3-containing ointments was analyzed by evaluating the expression of vitamin D receptor target genes, such as Cyp24a1, Trpv5 and CalbindinD28k, in the intestine and kidney. Real-time reverse transcription PCR (RT-PCR) analysis showed that the renal and intestinal Cyp24a1 expressions in the Cal- and Cal/BDP-treated groups were significantly lower than those in the Tac-, Max- and Max/BBP-treated groups, suggesting that systemic exposure of VD3 analogues in the Cal- and Cal/BDP-treated groups were lower than those in the other ointment-treated groups. In addition, the renal Trpv5 and CalbindinD28k expressions, calcium-transporting genes, were increased in the Max- and Max/BBP-treated groups compared with the Cal- and Cal/BDP-treated groups. Thus, because of the low systemic exposure of VD3 analogues, Cal and Cal/BDP ointments have lower calcemic effect than the other VD3-containing ointments in rats with psoriasis-like dermatitis.