Cutaneous Administration Research Articles

Development of a new topical system: Drug-in-cyclodextrin-in-deformable liposome

A new delivery system for cutaneous administration combining the advantages of cyclodextrin inclusion complexes and those of deformable liposomes was developed, leading to a new concept: drug-in-cyclodextrin-in-deformable liposomes. Deformable liposomes made of soybean phosphatidylcholine (PC) or dimyristoylphosphatidylcholine (DMPC) and sodium deoxycholate as edge activator were compared to classical non-deformable liposomes. Liposomes were prepared by the film evaporation method. Betamethasone, chosen as the model drug, was encapsulated in the aqueous cavity of liposomes by the use of cyclodextrins. Cyclodextrins allow an increase in the aqueous solubility of betamethasone and thus, the encapsulation efficiency in liposome vesicles. Liposome size, deformability and encapsulation efficiency were calculated. The best results were obtained with deformable liposomes made of PC in comparison with DMPC. The stability of PC vesicles was evaluated by measuring the leakage of encapsulated calcein on the one hand and the leakage of encapsulated betamethasone on the other hand. In vitro diffusion studies were carried out on Franz type diffusion cells through polycarbonate membranes. In comparison with non-deformable liposomes, these new vesicles showed improved encapsulation efficiency, good stability and higher in vitro diffusion percentages of encapsulated drug. They are therefore promising for future use in ex vivo and in vivo experiments.

Safety of hookworm infection in individuals with measurable airway responsiveness: a randomized placebo‐controlled feasibility study

BackgroundEpidemiological evidence suggests that hookworm infection protects against asthma. However, for ethical and safety reasons, before testing this hypothesis in a clinical trial in asthma it is necessary to establish whether experimental hookworm infection might exacerbate airway responsiveness during larval lung migration.ObjectiveTo determine whether hookworm larval migration through the lungs increases airway responsiveness in allergic individuals with measurable airway responsiveness but not clinical asthma, and investigate the general tolerability of infection and effect on allergic symptoms.MethodsThirty individuals with allergic rhinoconjunctivitis and measurable airway responsiveness to adenosine monophosphate (AMP) but not clinically diagnosed asthma were randomized, double-blind to cutaneous administration of either 10 hookworm larvae or histamine placebo, and followed for 12 weeks. The primary outcome was the maximum fall from baseline in provocative dose of inhaled AMP required to reduce 1-s forced expiratory volume by 10% (PD10AMP) measured at any time over the 4 weeks after active or placebo infection. Secondary outcomes included peak flow variability in the 4 weeks after infection, rhinoconjunctivitis symptom severity and adverse effect diary scores over the 12-week study period, and change in allergen skin test responses between baseline and 12 weeks.ResultsMean maximum change in PD10AMP from baseline was slightly but not significantly greater in the hookworm than the placebo group (−1.67 and −1.16 doubling doses; mean difference −0.51, 95% confidence interval −1.80 to 0.78, P=0.42). Symptom scores of potential adverse effects were more commonly reported in the hookworm group, but infection was generally well tolerated. There were no significant differences in peak-flow variability, rhinoconjunctivitis symptoms or skin test responses between groups.ConclusionHookworm infection did not cause clinically significant exacerbation of airway responsiveness and was well tolerated. Suitably powered trials are now indicated to determine the clinical effectiveness of hookworm infection in allergic rhinoconjunctivitis and asthma.

Allergen dose dependency of the early‐ and late‐phase cutaneous response in the cynomolgus monkey

Cutaneous administration of allergen provides a means to confirm an allergic status, investigate the pathogenesis of allergic diseases, and/or provide a mechanism to evaluate the benefit of new potential therapeutics. Studies were performed to characterize the allergen-induced cutaneous early- and late-phase response (EPR and LPR) in the cynomolgus monkey. Following intradermal injections of Ascaris suum allergen, the cutaneous weal and flare EPR was measured 15 min post-injection, and skin biopsies were collected at 8-24 h to determine the optimal time of LPR occurrence. Biopsies were analysed for epidermal and dermal inflammatory changes. The EPR was dose related with a reproducible, measurable response at 1 : 10 000 and maximal at a 1 : 100 allergen dilution. In contrast, the threshold dose required for a reproducible LPR was much greater requiring a dilution of 6 : 100, suggesting independent mechanisms for the EPR and LPR. The LPR 20 h post-allergen injection induced an inflammatory response in the upper and deep dermis. The response was characterized by a moderate perivascular to diffuse inflammation consisting of mononuclear cells, neutrophils and eosinophils. Dexamethasone, while having no effect on the EPR, reduced dermal inflammation (upper dermis, P=0.004; deep dermis, P=0.03). Similarly, dermal eosinophilia was also reduced (upper dermis, P<0.001; deep dermis, P=0.02). Collectively, the results indicate the dose dependency of the EPR and LPR. Furthermore, our observations indicate the value of the LPR response in the cynomolgus monkey to evaluate new therapeutics for the treatment of allergic diseases such as atopic dermatitis.

Cutaneous delivery of prophylactic and therapeutic vaccines: historical perspective and future outlook

The skin has long been recognized as an attractive target for vaccine administration. A number of clinical studies have tested the epidermal and dermal routes of delivery using a variety of vaccines over the years. In many cases, cutaneous administration has been associated with immunological benefits, such as the induction of greater immune responses compared with those elicited by conventional routes of delivery. Furthermore, there is a growing body of evidence to suggest that such benefits may be particularly important for certain higher-risk populations, such as the elderly, the immunocompromised and cancer patients. Despite the potential advantages of vaccination via the skin, results have sometimes been conflicting and the full benefits of this approach have not been fully realized, partly due to the lack of delivery devices that accurately and reproducibly administer vaccines to the skin. The 5-year outlook, however, appears quite promising as new cutaneous delivery systems advance through clinical trials and become available for more widespread clinical and commercial use.

Poster 235: Cutaneous Administration of Local Anesthetic for Spine Injection Procedures: A Prospective, Randomized Controlled Trial of Patient Preferred Method

Objective: To determine patient discomfort with administration of cutaneous local anesthetic prior to interventional spine procedures by 1 of 3 techniques. Design: Prospective, randomized, controlled. Setting: Outpatient academic physiatric spine center. Interventions: Patients were randomly assigned 1 of 3 techniques on a rotating basis: (1) local anesthetic injected with a 25-gauge 1.5in or 27-gauge 1.25in needle using traditional technique: formation of a subcutaneous wheal with 0.25cc of 1% Lidocaine, then 0.75cc of 1% Lidocaine is injected along the planned needle trajectory to the needle hub depth; (2) local anesthetic injected with a 25-gauge 1.5in or 27-gauge 1.25in needle using an alternative technique: needle is inserted in the planned needle trajectory to hub depth, then 1cc of 1% Lidocaine is injected as the needle is withdrawn, creating a small point wheal at the skin prior to needle removal; (3) no anesthetic is used.

394. Evaluation of Cutaneous Administration of DNA Vaccines Delivered by Electroporation

394. Evaluation of Cutaneous Administration of DNA Vaccines Delivered by Electroporation

Aktuelles zur Pflastertechnologie unter spezieller Berücksichtigung des Rotigotinpflasters

Die kutane Applikation von Arzneistoffen hat in den vergangenen Jahren beträchtlich an Bedeutung gewonnen. Es lassen sich über diesen Weg unter Umgehung des First-past-Effektes kontrollierbare, konstante Blutspiegel erzielen, und die geringere Applikationshäufigkeit insbesondere mit transdermalen Pflastern wirkt sich positiv auf die Compliance aus. Der Wirkstoff Rotigotin bietet aufgrund seiner physikalisch-chemischen Eigenschaften wie hohe Lipophilie, niedriger Schmelzpunkt und damit gute Löslichkeit im Stratum corneum und dem niedrigen Molekulargewicht gute Voraussetzungen für die kutane Applikation mit angestrebter systemischer Wirkung.

An unusual terminal hair growth on the nose tip associated with gefitinib therapy

Conflicts of interest: none declared. Sir, The epidermal growth factor receptor (EGFR) pathway, a key driver in regulating normal epithelial cell growth and differentiation, also plays a role in promoting proliferation of malignant epithelial cells1 by increasing proliferation, adhesion and invasive capacity, and also by blocking apoptosis.1–4 For this reason, EGFR expression is associated with metastasis, late‐stage disease, resistance to therapy and poor prognosis. Therapies targeting EGFR are now under development, such as antibodies to EGFR or EGFR‐specific tyrosine kinase inhibitors. Gefitinib, also known as ZD 1839 or Iressa®, is a low‐molecular‐weight compound that inhibits the activation of EGFR tyrosine kinase through competitive binding of the receptor.1–4 A 65‐year‐old woman presented with a 2‐month history of asymptomatic, brown to black hairs on the nose tip that had been gradually thickening and lengthening (Fig. 1). Six months before, she had been diagnosed with metastatic lung adenocarcinoma and had undergone treatment with radiotherapy (whole brain and femur, 3000 cGy × 2 cycles) and chemotherapy (docetaxel 100 mg daily every 3 weeks for 2 months). Two months before, she began treatment with gefitinib 250 mg daily. One week after starting treatment, she noticed tiny brown to black spots on her nose tip. Ever since, hairs have been growing at these sites. When she presented to our department, the hairs were 1–3 mm in length, localized to the nose tip. There were no vellus hairs, which normally there should be. There was no abnormality of hair density or length at other body sites. She denied a personal history of other cutaneous problems, trauma or administration of any drugs such as might induce hair growth. Skin biopsy revealed multiple hair follicles in anagen phase that were located in the superficial dermis (Fig. 2). The hair shaft was 0·054 mm in diameter and was myelinated, indicative of terminal hair. There was also solar elastosis and a mild inflammatory infiltrate in the papillary dermis. On the basis of these findings, the patient was diagnosed with terminal hair growth associated with gefitinib and was recommended to discontinue gefitinib. However, as the patient's lung adenocarcinoma had had a poor response to radiochemotherapy, gefitinib could not be discontinued and the hairs have continued to grow.

Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun

Conventional anti-inflammatory strategies induce multiple side effects, highlighting the need for novel targeted therapies. Here we show that knockdown of the basic-region leucine zipper protein, c-Jun, by a catalytic DNA molecule, Dz13, suppresses vascular permeability and transendothelial emigration of leukocytes in murine models of vascular permeability, inflammation, acute inflammation and rheumatoid arthritis. Treatment with Dz13 reduced vascular permeability due to cutaneous anaphylactic challenge or VEGF administration in mice. Dz13 also abrogated monocyte-endothelial cell adhesion in vitro and abolished leukocyte rolling, adhesion and extravasation in a rat model of inflammation. Dz13 suppressed neutrophil infiltration in the lungs of mice challenged with endotoxin, a model of acute inflammation. Finally, Dz13 reduced joint swelling, inflammatory cell infiltration and bone erosion in a mouse model of rheumatoid arthritis. Mechanistic studies showed that Dz13 blocks cytokine-inducible endothelial c-Jun, E-selectin, ICAM-1, VCAM-1 and VE-cadherin expression but has no effect on JAM-1, PECAM-1, p-JNK-1 or c-Fos. These findings implicate c-Jun as a useful target for anti-inflammatory therapies.

Thiamine and Cyanocobalamin Relieve Neuropathic Pain in Rats: Synergy with Dexamethasone

Treatment of neuropathic pain is an area of largely unmet medical need. Therefore, this pain may require the development of novel drug entities. In the search for alternatives, B vitamins have been found to be a clinically useful pharmacological tool for patients with neuropathic pain. However, preclinical studies supporting this use are lacking. In this study, we assessed the possible antiallodynic effects of thiamine, pyridoxine, and cyanocobalamin as well as dexamethasone and their combination on spinal nerve ligation induced allodynia. Sub cutaneous administration of thiamine (75–600 mg/kg), pyridoxine (75–600 mg/kg), cyanocobalamin(0.75–6 mg/kg), and dexamethasone (4–32 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with 600 mg/kg of thiamine (∼58%), 600 mg/kg of pyridoxine (∼22%), 6 mg/kg of cyanocobalamin (∼73%), and 32 mg/kg of dexamethasone (∼68%). Since a small antiallodynic effect was observed with pyridoxine, this drug was not further analyzed in the combinations. Coadministration of thiamine or cyanocobalamin and dexamethasone remarkably reduced spinal nerve ligation induced allodynia (∼90%), showing a synergistic interaction between either thiamine or cyanocobalamin and dexamethasone. Our data indicate that thiamine and pyridoxine as well as the combination of B vitamins and dexamethasone are able to reduce tactile allodynia in rats and suggest the possible clinical use of these drugs in the treatment of neuropathic pain in human beings.

Insuffisance rénale aiguë secondaire à la povidone iodée

Povidone iodine is a widely-used antiseptic agent, especially for cutaneous lesions. Despite its apparent innocuousness, some cases of acute renal failure are reportedly due to iodine toxicity. We report a case of an acute renal failure secondary to povidone iodine exposure in a 37-year-old woman. She underwent a hysteroscopy for diagnosis of primary sterility, and povidone iodine was used as the contrast agent. She developed acute renal failure with oliguria during the postoperative period. Treatment with diuretics and hemodialysis led to a favorable outcome and return of normal kidney function. Mucosal administration of povidone iodine appears to lead to greater iodine toxicity than cutaneous administration. The clinical feature of our patient suggested tubular necrosis caused by iodine, after the other possible causes of acute renal failure were ruled out. Acute renal failure secondary to povidone iodine administration is possible, especially through mucosal surfaces. Outcome is favorable after the conclusion of exposure and symptomatic treatment.

Evolving the concept of regulation of vascular tone in humans

Elucidation of mechanisms regulating microcirculatory vascular tone is a key issue in the knowledge of human pathophysiology. Anandamide is an endogenous lipidic cannabinoid (CB) characterized by potent vasodilator activity acting mainly through the activation of CB receptors, located on the vessel walls, and the vanilloid receptor 1, located on sensory peptidergic nerve endings within the external layers of vessel walls. In humans, cutaneous anandamide administration causes forearm skin vasodilation by activating vanilloid receptor 1 presumably on primary sensory nerves, while intrabrachial infusion of the same compound is devoid of effect on forearm muscle microcirculation. Taken together, these results indicate that, apart from a possible distrectual difference, the effect of anandamide is specific for the abluminal, but not for the endoluminal, part of the vessel wall. Thus, it is conceivable that, at least in the peripheral microcirculation, this compound could act as an autocrine/paracrine agent and not as a circulating hormone. In line with this possibility, it has been demonstrated that anandamide can be produced by macrophages and therefore its biological effect might increase in clinical conditions characterized by augmented activity of this cell line, including cardiogenic, hemorrhagic and endotoxic shock and even in atherosclerosis, inflammation and ischemia. Moreover, increased serum values of anandamide have been found in patients with endotoxic shock. However, decisive information concerning the role of anandamide in humans will be obtained when specific antagonists or inhibitors will be available. In that case, the anandamide system might represent a potential target for the treatment of important cardiovascular conditions, including severe shock.

Protective Immunization against Inhalational Anthrax: A Comparison of Minimally Invasive Delivery Platforms

A new anthrax vaccine under clinical investigation is based on recombinant Bacillus anthracis protective antigen (rPA). Here, we investigated microneedle-based cutaneous and nasal mucosal delivery of rPA in mice and rabbits. In mice, intradermal (id) delivery achieved up to 90% seroconversion after a single dose, compared with 20% after intramuscular (im) injection. Intranasal (inl) delivery of a liquid formulation required 3 doses to achieve responses that were comparable with those achieved via the id or im routes. In rabbits, id delivery provided complete protection against aerosol challenge with anthrax spores; in addition, novel powder formulations administered inl provided complete protection, whereas a liquid formulation provided only partial protection. These results demonstrate, for the first time, that cutaneous or nasal mucosal administration of rPA provides complete protection against inhalational anthrax in rabbits. The novel vaccine/device combinations described here have the potential to improve the efficacy of rPA and other biodefense vaccines.

It's not just about rubbing—topical capsaicin and topical salicylates may be useful as adjuvants to conventional pain treatment

Drugs can be injected (subcutaneously, intramuscularly, intravenously, intrathecally, epidurally); given by mouth (orally, sublingually), intranasally, or rectally; or inhaled. They can also be applied to the skin. The transdermal method...

Tracking the ‘General’: tagging skin-derived dendritic cells

Dendritic cells (DCs) are the sentinels of the immune system; their migration, maturation and mobilization are fundamental to immunity and tolerance. The recent tracking of DCs from the skin to lymph node (LN) and their enumeration using a Cre/loxP system demonstrate the recruitment of a higher than expected number of DCs to the draining LN after cutaneous administration of DNA-coated gold particles. The longevity of the migrated DCs was also longer than previously reported.

Formulation Study and Anti-Inflammatory Efficacy of Topical Semi-Solids Containing a Nitro Ester of Flurbiprofen

A new nitro-oxybutylester of flurbiprofen (NO-FP) is a promising anti-inflammatory drug in the treatment of dermatological disorders, and the feasibility of its cutaneous administration was evaluated. Four different semi-solid formulations were evaluated in order to assess the influence of the composition on the drug amount retained in the stratum corneum and epidermis (SCE). The lipophilic ointment induced the highest NO-FP amount retained in the SCE and, therefore, skin permeation enhancers (Transcutol^®, Lauroglycol^®, oleic acid and isopropyl myristate) were added to this formulation. The in vitro NO-FP amounts retained in the SCE were correlated with the solubility parameters, and a good linear correlation was found (r² = 0.925). The formulation of the lipophilic ointment was optimized, and the activity of this preparation was verified in methyl-nicotinate-induced contact urticaria and UV-induced erythema obtaining good results in terms of efficacy and safety.

Reversal of epidermal hyperproliferation in psoriasis by insulin-like growth factor I receptor antisense oligonucleotides.

Epidermal hyperplasia is a key feature of the common skin disorder psoriasis. Stimulation of epidermal keratinocytes by insulin-like growth factor I (IGF-I) is essential for cell division, and increased sensitivity to IGF-I may occur in psoriasis. We hypothesized that inhibition of IGF-I receptor expression in the psoriasis lesion would reverse psoriatic epidermal hyperplasia by slowing the rate of keratinocyte cell division. Here we report the use of C5-propynyl-dU,dC-phosphorothioate antisense oligonucleotides to inhibit IGF-I receptor expression in keratinocytes. We identified several inhibitory antisense oligonucleotides and demonstrated IGF-I receptor inhibition in vitro through an mRNA targeting mechanism. Repeated injection of these oligonucleotides into human psoriasis lesions, grafted onto nude mice, caused a dramatic normalization of the hyperplastic epidermis. The findings indicate that IGF-I receptor stimulation is a rate-limiting step in psoriatic epidermal hyperplasia and that IGF-I receptor targeting by cutaneous administration of antisense oligonucleotides forms the basis of a potential new psoriasis therapy.

Glutathione Metabolism in Mice Is Enhanced More With Hapten-Induced Allergic Contact Dermatitis Than With Irritant Contact Dermatitis

Cutaneous inflammation induced by electrophilic compounds involves irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). Reduced glutathione (GSH) and related thiols have been postulated to play important roles in detoxification of electrophilic xenobiotics, protection of tissues against reactive oxygen species, and modulation of immunologic functions in normal and diseased subjects. The dynamic aspects of GSH metabolism, however, and its significance in patients with ICD and ACD remain to be clarified. The current study was carried out to elucidate the pathogenesis and possible involvement of GSH in both types of inflammation. Normal mice and mice sensitized with dinitrochlorobenzene (DNCB) were challenged by cutaneous administration of DNCB, and changes in GSH metabolism in skin and liver were determined. Kinetic analysis revealed that 24 h after challenge with DNCB, levels of hepatic glutathione and its secretion increased more markedly in the sensitized mice than in the unsensitized animals. Administration of buthionine-L-sulfoximine (BSO), a specific inhibitor of GSH synthesis, inhibited the increase in glutathione levels in the liver and the skin of both groups. Histologic examination revealed that cutaneous inflammation was enhanced by BSO more significantly in mice with ACD than with ICD. These results suggest that GSH might play an important role in the suppression of the immune reaction in mice with ACD.

Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviors in the rat formalin test.

The present study demonstrates that local cutaneous administration of either the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 or the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) significantly attenuates formalin-induced nociceptive behaviors. Specifically, pretreatment with either drug reduced the magnitude and time course of lifting and licking behavior in the late phase of formalin pain; however, flinching behavior was not affected. In contrast, post-treatment of formalin pain with either antagonist did not affect lifting and licking behavior, although flinching behavior was mildly attenuated. We hypothesize that these actions result from blocking of peripheral glutamate receptors located on unmyelinated axons at the dermal-epidermal junction. These data suggest that peripheral glutamate receptors on cutaneous axons can be manipulated to reduce certain aspects of pain of peripheral origin. This route of administration offers the advantage of avoiding the side effects of systemic administration.

Anti-allergic and Anti-inflammatory Reaction by Topical Application of Chelating Agents.

In order to examine the participation of calcium in contact sensitization pathways, sensitizing tests and human patch test were conducted by means of cutaneous administration of chelating agents with several allergens.Experiments were conducted by adjuvant patch tests in guinea pigs, using ethylenediaminetetra acetic acid (EDTA) as the chelating agents and paraphenylenediamine (PPD) as the sensitizing agent. Groups for PPD only sensitization, mixture of PPD and EDTA sensitization, EDTA only sensitization and vehicle as a control were established, then these materials administered on individual animals for eliciting. In this way the influence of EDTA administration on induction and on allergic inflammatory responses was examined.As a result, in the 1.0% PPD induction group, both the sensitizing factor and eliciting responses did not show variation from the values of the control groups; but in the case of 0.1% PPD induction goups, both sensitizing factor and eliciting responses showed a decrease with the cutaneous administration of EDTA. Therefore it is thought that EDTA was operating in an anti-inflammatory and/or sensitizing controlling capacity.In addition 48-hour patch tests using 1-carvone and some chelating agents were conducted on a human subject with allergic contact dermatitis to 1-carvone. In these results as well, decreased skin responses in cases with chelating agents were noted.From these results we report interesting information regarding the relationship between calcium and the mechanism of Type IV allergy and the anti-allergic property of chelating agents.