Differences of the tumour cell glycocalyx affect binding of capsaicin-loaded chitosan nanocapsules.

The glycocalyx regulates the interaction of mammalian cells with extracellular molecules, such as cytokines. However, it is unknown to which extend the glycocalyx of distinct cancer cells control the binding and uptake of nanoparticles. In the present study, exome sequencing data of cancer patients and analysis of distinct melanoma and bladder cancer cell lines suggested differences in cancer cell-exposed glycocalyx components such as heparan sulphate. Our data indicate that glycocalyx differences affected the binding of cationic chitosan nanocapsules (Chi-NCs). The pronounced glycocalyx of bladder cancer cells enhanced the internalisation of nanoencapsulated capsaicin. Consequently, capsaicin induced apoptosis in the cancer cells, but not in the less glycosylated benign urothelial cells. Moreover, we measured counterion condensation on highly negatively charged heparan sulphate chains. Counterion condensation triggered a cooperative binding of Chi-NCs, characterised by a weak binding rate at low Chi-NC doses and a strongly increased binding rate at high Chi-NC concentrations. Our results indicate that the glycocalyx of tumour cells controls the binding and biological activity of nanoparticles. This has to be considered for the design of tumour cell directed nanocarriers to improve the delivery of cytotoxic drugs. Differential nanoparticle binding may also be useful to discriminate tumour cells from healthy cells.

Sex differences in the pharmacology of itch therapies-a narrative review.

BACKGROUND: Chronic itch is the most common skin-related condition, associated with a high psychosocial and economic burden. In recent years, increasing evidence of sex differences in the perception, clinical presentation and treatment requirements of itch points towards potential benefits when using sex-adapted therapies. It is well-known that body composition, absorption, metabolism, elimination and adverse drug reactions (ADRs) differ between sexes, but only little is known about the impact of sex in the pharmacology of itch treatments, which could help to rationalise sex-adapted treatment strategies. AIM: To evaluate and review sex effects in the pharmacokinetics and /-dynamics of drugs used to treat itch. METHODS: In this narrative review we performed a PubMed and MEDLINE (Ovid) search using the terms (itch OR pruritus) AND (gender OR sex) AND (drug OR medication OR pharmacokinetics OR pharmacodynamics). Additional searches were performed for the topical and systemic drugs recommended by the European Guideline on Chronic Pruritus. RESULTS: We found numerous reports with variable levels of evidence of sex effects with respect to the pharmacokinetics and/or pharmacodynamics of 14 drug classes used for the treatment of itch, including a total of 19 systemic and 3 topical drugs. Women seem to present higher plasma levels of several drugs used in itch treatment, including tri- and tetracyclic antidepressants (e.g. doxepin, amitriptyline, mirtazapine), serotonin reuptake inhibitors (e.g. paroxetine, sertraline, fluoxetine), immunosuppressive drugs (e.g. cyclosporine, mycophenolate mofetil), serotonin receptor antagonists (e.g. ondansetron) and betablockers (e.g. propranolol). Adverse drug reactions (ADRs) were generally more common in women. Being female was reported to be an independent risk factor for QTc-prolongation associated with antihistamines and tetracyclic antidepressants. Additionally, women seem to be more prone to sedative effects of antihistamines, and to suffer from a higher frequency as well as severity of side effects with systemic calcineurin inhibitors, opioid agonists, and opioid antagonists. Women were also sensitised more often to topically applied drugs. Of note, apart from only one experimental study with capsaicin, none of these reports were designed specifically to assess the effect of sex (and gender) in the treatment of itch. DISCUSSION/CONCLUSION: Our review supports previous reports that sex is of importance in the pharmacokinetics and /-dynamics of several drugs used to treat itch although those drugs were mostly evaluated for non-itch indications. However, the results are limited by methodological limitations evident in most studies such as underrepresentation of women in clinical trials. This emphasises the need to study the impact of sex (and gender) in future itch trials to yield better outcomes and prevent ADRs in both sexes.

Computational design strategy: an approach to enhancing the transdermal delivery of optimal capsaicin-loaded transinvasomes.

The aim of this study was to design and develop simultaneous optimal transinvasome formulations (OTV) to enhance the transdermal delivery of capsaicin. Using a central composite experimental design with duplicate centroids, 10 model formulations of transinvasomes (TVs) were demonstrated. The lipid compositions of the TV formulations were determined as formulation factors (Xn) and response variables (Yn), respectively. TV formulations containing a constant concentration of phosphatidylcholine, cholesterol, 0.15% capsaicin, and various percentages of d-limonene (X1) and cocamide diethanolamine (X2) were prepared. The physicochemical characteristics, e.g. the vesicle size, size distribution, zeta potential, entrapment efficiency, and skin permeability, of the TV formulations were experimentally investigated. The relationship among the formulation factor, the response variables, and the OTV was predicted using Design Expert® software. The accuracy and reliability of the OTV predicted using computer software were experimentally confirmed and investigated as an experimental transinvasome formulation (ETV). The results indicated that the skin permeability of the ETV was close to the OTV and was significantly higher than that of conventional liposomes and commercial products. The response surfaces estimated by the computer software were helpful in understanding the complicated relationship among the formulation factor, the response variables, and the stability of the TV formulation.

Capsaicin delivery into the skin with lipidic nanoparticles for the treatment of psoriasis.

The study aims to explore the potential of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) in improving the topical delivery of capsaicin (CAP) by in vitro and in vivo studies. The lipidic nanoparticles were prepared by solvent diffusion method and were characterized for average particle size, zeta potential and entrapment efficiency. TEM photomicrographs revealed that the particles were nanometric in size. Higher amount of CAP can be encapsulated in the NLCs (87.4 ± 3.28) as compared with SLNs (79.7 ± 2.93%). The cumulative amounts of CAP permeated through the skin and retained in the SC were higher in the case of NLCs as compared with plain drug solution and SLNs. SLNs and NLCs exhibited minimum to no irritation. All the results concluded that NLCs and SLNs have shown a good ability to increase drug accumulation in the various skin layers but NLCs may be a more potential carrier for topical delivery of CAP for an effective therapy of psoriasis.

Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model.

Phosphodiesterase (PDE) 4 inhibition is a well-known anti-inflammatory mechanism, but the development of PDE4 inhibitors has been hampered by side effects such as nausea and emesis. Local delivery of a PDE4 inhibitor to the site of inflammation may overcome these issues. The purpose of this study was to assess the therapeutic potential of E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino)carbonyl]benzoate), a novel PDE4 inhibitor developed as a topical agent for atopic dermatitis (AD). E6005 potently and selectively inhibited human PDE4 activity with an IC50 of 2.8 nM and suppressed the production of various cytokines from human lymphocytes and monocytes with IC50 values ranging from 0.49 to 3.1 nM. In mice models, the topical application of E6005 produced an immediate antipruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. On the basis of these observed effects, topical E6005 ameliorated the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting inhibitory effects comparable to that of tacrolimus. The use of ¹4C-labeled E6005 showed rapid clearance from the blood and low distribution to the brain, contributing to the low emetic potential of this compound. These results suggest that E6005 may be a promising novel therapeutic agent with antipruritic activity for the treatment of AD.

Selective CB2 agonists with anti-pruritic activity: discovery of potent and orally available bicyclic 2-pyridones.

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.

Pharmacokinetic study of borneol and menthol in rats after oral administration of qingyan drop pills.

Both borneol and menthol are bioactive substances derived from Chinese herbal medicines. In order to understand the pharmacokinetics of borneol and menthol in Qingyan drop pills, a rapid, sensitive, and simple gas chromatographic (GC) method with flame ionization detection (FID) was developed for the simultaneous determination of borneol and menthol in rat plasma. Sample preparations were carried out by liquid-liquid extraction (LLE) with an internal standard solution of naphthalene. The analytes and internal standard (IS, naphthalene) were separated well on an HP-1 capillary column. The pharmacokinetic parameters were estimated by a compartmental method using the Phoenix WinNonlin software program (Version 6.0). The standard curves were linear over a wide concentration range of 2.5-50.0 ng/µL ( R = 0.9963), 8.7-62.2 ng/µL ( R = 0.9994) for both borneol and menthol in plasma, respectively. The limits of quantification (LOQ) of borneol and menthol in plasma were 2.4 ng/µL and 5.0 ng/µL, respectively. The intra-day precisions for borneol and menthol were < or = 10.0 % R. S. D. at the LOQ and < or = 6.0 % at higher concentrations. The average value of CMAX was 18.97 ± 2.71 ng/µL with a TMAX at 20.00 ± 0.00 min for borneol after oral administration of the drop pills; for menthol, the average value of CMAX was 79.02 ± 11.40 ng/µL with a TMAX at 25.00 ± 4.40 min. This validated assay method was successfully applied to a pharmacokinetic study of borneol and menthol after oral administration of Qingyan drop pills in rat. The results showed that the kinetics of borneol and menthol can be described by an open one-compartment model. The pharmacokinetic parameters provide some information for clinical administration of Qingyan drop pills.

Topical capsaicin. The fire of a 'hot' medicine is reignited.

IMPORTANCE OF THE FIELD: Capsaicin and its receptor, TRPV1, occupy a central place in current neurophysiological studies regarding pain transmission and have opened new avenues for understanding the role of transient receptor potential (TRP) receptors in itch processing. Substantial efforts in drug discovery are at present directed at vanilloid receptors for finding new remedies for pain and itch. AREAS COVERED IN THIS REVIEW: We provide an overview of the major clinical indications of capsaicin, primarily targeting pain and itch of various origins, with an emphasis on the usefulness of capsaicin in treating pruritus and dermatological conditions. In particular, we cover the most relevant findings in recent years, from 2000 onward (although seminal discoveries and studies are discussed irrespective of their date of publication if deemed essential for understanding capsaicin's actions). WHAT THE READER WILL GAIN: Readers are offered a broad perspective on the areas of clinical application of capsaicin, emphasizing its usefulness in the treatment of neurophatic pain and pruritus of various origins. TAKE HOME MESSAGE: Capsaicin has been proven a truly exciting molecule and remains a valuable drug for alleviating pain and itch, widely surpassing its role as a simple spicy ingredient.

Skin disposition of d-camphor and l-menthol alone and together.

The terpenes camphor and menthol are often used in topical preparations, although some data indicate concern about their skin penetration after application in most commonly used vehicles. The cutaneous disposition of these substances applied alone and together in either an oily solution or a hydrogel was evaluated ex vivo using full human skin mounted in flow-through diffusion cells. After 0.5, 1 and 2 h of application, the skin was progressively tape-stripped into three fractions of stratum corneum (SC) and the remaining epidermis with the dermis. The content of terpenes in the skin layers was determined using gas chromatography. Different penetration into the skin layers was observed depending on the type of vehicle. The highest SC absorption was noted when terpenes were applied in hydrogel, where the total content in the SC was 200 microg/cm2 for camphor and 400 microg/cm2 for menthol, and the total skin absorption was 310 and 460 microg/cm2, respectively. The SC penetration of both terpenes from the oily solution was the same (approximately equal to 35 microg/cm2). When both terpenes were present in the hydrogel the SC absorption decreased, the amounts of camphor and menthol in the SC being 50 and 190 microg/cm2, respectively (total skin accumulation was 120 and 220 microg/cm2, respectively). Such an effect was not observed for the oily solution.

Drop-to-drop solvent microextraction coupled with gas chromatography/mass spectrometry for rapid determination of trimeprazine in urine and blood of rats: application to pharmacokinetic studies.

A simple and rapid method based on drop-to-drop solvent microextraction (DDSME) coupled with gas chromatography/mass spectrometry (GC/MS) has been successfully applied for the pharmacokinetic studies of trimeprazine in 8 microL of urine and blood samples of rats. Several factors that influenced the extraction efficiency of DDSME, such as selection of organic solvent, extraction time, exposure volume of organic phase, addition of salt and pH, were optimized. Linearity was obtained over the concentration ranges of 0.2-10, 0.25-7.0 and 0.5-6.0 microg/mL with correlation coefficients of 0.998, 0.996 and 0.993 in deionized water, urine and blood samples of rats, respectively. The limits of detection (LODs) of trimeprazine were 0.05, 0.06 and 0.1 microg/mL in deionized water, urine and blood samples. The concentrations of trimeprazine obtained in urine and blood samples of rats were 0.21-1.25 and 2.72-0.22 microg/mL, respectively, after a single intravenous administration of this drug. The enrichment factors and LOD values obtained by DDSME coupled to GC/MS were compared with those of hollow fiber liquid-phase microextraction (HF-LPME) combined with GC/MS. We believe that this novel approach can be very useful in clinical application since only one microdrop of biological samples was required to perform the pharmacokinetic studies from rats, so the sample pretreatments for animal experiments can be very easy too.

Percutaneous absorption of crotamiton in man following single and multiple dosing.

PURPOSE: Crotamiton is a topical drug used in the treatment of scabies and pruritus. We determined its percutaneous absorption following single and multiple dosing in normal skin. METHODS: We used in vivo measurement of percutaneous absorption of [14C] crotamiton in a multidose regimen by measuring urinary excretion and liquid scintillation counting in three groups of four healthy volunteers. The Feldmann urinary excretion method was utilized to ascertain percutaneous absorption. Our results showed that tape stripping does not increase percutaneous absorption of crotamiton; upon repeated application.

Antihistamines and their role as antipruritics.

Antihistamines that bind to the histamine 1 receptor (H1) serve as important therapeutic agents to counter the effects of histamine in the skin. Two generations of antihistamines exist; however, second-generation agents are more advantageous because they cause less sedation, have a longer half life and are more selective for the H1 receptor. While H1 antihistamines have proven to be effective at reversing the pruritus and cutaneous lesions of chronic urticaria, their ability to treat pruritus associated with other cutaneous and systemic diseases is unproven.

Pharmacokinetics and dialysability of naltrexone in patients undergoing hemodialysis.

The disposition of naltrexone (NLT) (REVIA), an opioid antagonist intended for patients with impaired renal function and with severe intractable itching refractory to regular antipruritic therapy, was characterized. Hemodialysis effects on both efficacy and elimination of NLT also were assessed. We developed a simple, sensitive and selective reverse-phase high-performance liquid chromatographic (HPLC) method for measuring NLT plasma concentration in hemodialysis patients treated to relieve pruritus. NLT and the internal standard, naloxone (NLX) were extracted from plasma using a solid-phase extraction method with sep-pack C18 cartridge. The method was employed to determine both naltrexone pharmacokinetics and dialysability parameters during 4-h in dialyzed patients with chronic renal impairment. Thus, seven patients (2 men, 5 women) with end-stage renal disease and pruritus on regular hemodialysis were included. They received one tablet of NLT (Revia, 50 mg) orally prior dialysis session. The Cmax at the inlet and at the outlet the dialyzer were higher (255+/-117 ng/mL and 206+/-137 ng/ml respectively) in comparison with healthy subjects (9 - 44 ng/mL). The decrease hepatic first-pass metabolism of NLT consecutive to end-stage renal disease and the renal impairment could explain the increased levels of the drug in plasma. Tmax before and after dialysis plates remain unchanged as healthy subjects (approximately 1h). With regard to dialysability, a high dialyzer extraction ratio averating 30 % was found with a low dialysis clearance of 58.70+/-17 mL/min. The amount removed by dialysis is only 1.27 mg. We concluded that hemodialysis has little effect on NLT blood levels, and consequently on drug pharmacokinetics, when the drug is delivered to dialyzed patients following oral route. Thus, dosage adjustement is not required in the presence of advanced dialysis-dependant renal failure. In patients with end-stage renal disease, hemodialysis does not result in clinically significant alterations in the disposition of NLT. Post-dialysis supplementation is not required. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but in view of NLT plasma concentration levels in the patients, a clinician could determine whether dosage adjustment are necessary and, if so, make the required calculations accurately.

Pharmacokinetics of loratadine and its active metabolite descarboethoxyloratadine in healthy Chinese subjects.

AIM: To investigate the pharmacokinetics of loratadine (LOR) and its active metabolite descarboethoxyloratadine (DCL) in healthy Chinese subjects. METHODS: Twenty healthy Chinese male subjects received a single oral dose of LOR 20 mg. A sensitive liquid chromatography-tandem mass spectrometry method (LC/MS/MS) was used for the determination of LOR and DCL in plasma. RESULTS: Mean maximum concentration (C(max)) was found (17+/-14) microg/L for LOR at 1.2 h and (16+/-9) microg/L for DCL at 1.5 h. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was (47+/-49) microg x h x L(-1) for LOR and (181+/-122) microg x h x L(-1) for DCL, respectively. The apparent elimination half-life (T1/2) of LOR was (6+/-4) h, and that of DCL was (13.4+/-2.6) h. The ratios of AUC(DCL)/AUCLOR ranged from 0.36 to 54.5. CONCLUSION: LOR was rapidly absorbed and transformed to DCL. AUC of the parent drug was extremely variable, while AUC of the active metabolite DCL was moderately variable after an oral dose of LOR to Chinese subjects.

Disposition of a specific cyclooxygenase-2 inhibitor, valdecoxib, in human.

Valdecoxib is a potent and specific inhibitor of cyclooxygenase-2, which is used for the treatment of rheumatoid arthritis, osteoarthritis, and the dysmenorrhea pain. Eight male human subjects each received a single 50-mg oral dose of [(14)C]valdecoxib. Urine, feces, and blood samples were collected after administration of the radioactive dose. Most of the radioactivity in plasma was associated with valdecoxib and the hydroxylated metabolite of valdecoxib (M1). The estimated terminal half-life for valdecoxib was about 7 h. About 76.1% of the radioactive dose was recovered in urine and 18% of the radioactive dose was recovered in feces. Valdecoxib was extensively metabolized in human, and nine phase I metabolites were identified. The primary oxidative metabolic pathways of valdecoxib involved hydroxylation at either the methyl group to form M1 or N-hydroxylation at the sulfonamide moiety to form M2. Further oxidation of M1 led to the formation of several other phase I metabolites. Oxidative breakdown of the N-hydroxy sulfonamide function group in M2 led to the formation of corresponding sulfinic acid and sulfonic acid metabolites. The O-glucuronide conjugate of M1 and N-glucuronide conjugate of valdecoxib were the major urinary metabolites, which accounted for 23.3 and 19.5% of the total administered dose, respectively. The remaining urinary metabolites were glucuronide conjugates of other phase I metabolites. Only 3% of the administered dose was recovered in urine as unchanged parent, suggesting that renal clearance is insignificant for valdecoxib. Absorption of valdecoxib was excellent since the recovery of unchanged valdecoxib in feces was <1% of the administered dose.

Pharmacokinetics of menthol and carvone after administration of an enteric coated formulation containing peppermint oil and caraway oil.

Enteric coating of peppermint oil/caraway oil capsules avoids subjective discomfort to the patient caused by gastroesophageal reflux. In order to confirm bioequivalence of an enteric coated formulation containing peppermint oil and caraway oil (CAS 277309-55-4, Enteroplant) and an immediate release formulation of both oils, the pharmacokinetics of menthol and carvone after oral administration of the two formulations were studied in a randomized, two-period cross-over study in 16 healthy male volunteers. The subjects received 180 mg peppermint oil and 100 mg caraway oil, once as 2 enteric coated capsules of the fixed enteric coated combination preparation containing 90 mg peppermint oil (WS 1340) and 50 mg caraway oil (WS 1520) each (test) and once in the form of 5 capsules of an immediate release formulation (reference) containing 36 mg peppermint (WS 1340) oil and 20 mg caraway oil (WS 1520) each. The capsules were taken with 250 ml water after a 10 h fast. Both substances were determined in plasma by GC/MS after extraction. The limit of quantification was 10 ng/ml for menthol and 0.5 ng/ml for carvone. The mean maximum plasma levels for menthol were 1196 ng/ml after administration of the test medication and 1492 ng/ml after administration of the reference medication. The bioavailability with respect to the AUC was comparable after administration of test and reference preparation, the 90% confidence interval was 97 to 105%. As expected, there were considerable differences for Tmax. After application of the enteric coated form the maximum concentration was reached significantly later (3.0 h vs. 1.7 h) compared to the immediate release capsule. Corresponding data were also calculated for carvone. After application of the test medication the maxima of 14 ng/ml for both formulations were reached later (2.5 h vs. 1.3 h). The 90% confidence interval of the AUC for carvone was 79 to 119% and therefore slightly outside the acceptable range for bioequivalence of 80 to 125%. However, this fact should not be relevant, in particular since the dosage of the enteric coated capsule lies at the upper limit of the model text and positive clinical studies, also on the therapeutic equivalence of the two formulations, are available.

Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: a pilot study.

The purpose of this study was to determine the safety and pharmacokinetics of a eutectic mixture of local anesthetics (EMLA) used to ameliorate postburn pruritus after application onto newly formed, intact skin in children. EMLA was applied once to an itchy site where healed skin had formed. Serial blood samples were collected to measure lidocaine, prilocaine, o-toluidine, and methemoglobin. Maximal plasma concentration, minimal plasma concentration, time to achieve the maximal plasma concentration, elimination half-life, and area under the concentration-time curve were calculated. Vital signs, oxygen saturation, clinical signs of hypoxia, and itch intensity were measured. Five children had 15.7 +/- 2.54 g (+/- SD) of EMLA applied to a skin surface area of 93.0 +/- 37.0 cm2. Lidocaine and prilocaine concentrations were below toxic levels; o-toluidine was not detected. Methemoglobin remained between 1 and 3%; patients did not exhibit any clinical signs of hypoxia. Mean oxygen saturation was 98.9 +/- 0.01%. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2 prestudy control days compared with study day 3 (P = 0.01 and P = 0.03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. In this small pilot study, EMLA seems to be a safe, novel treatment for postburn pruritus in burned children when applied to newly healed, intact skin.

Physicochemical studies of lidocaine-menthol binary systems for enhanced membrane transport.

The melting properties of lidocaine and l-menthol binary systems were studied using differential scanning calorimetry (DSC). A eutectic mixture was obtained for the lidocaine:menthol ratio of 30:70 (w:w) with a eutectic point of 26 degrees C. The binary melt systems formed within a range of 30:70-50:50 (w:w) remained as homogeneous oils at ambient temperature. The solubilities of pure lidocaine and lidocaine from the binary melt systems were determined with and without propylene glycol in pH 8.0 phosphate buffer. Lidocaine from the melt systems was less soluble in the buffers due to the partition of lidocaine between the oil and aqueous phases. The addition of propylene glycol to the buffer significantly increased both the solubility and heat of solubilization of lidocaine. The permeation rates of lidocaine from the binary melt systems across shed snake-skin were concentration dependent and significantly higher than those from the reference solutions.