Topical Application Of Drugs Research Articles

Antibacterial drugs in the form of sprays for the topical treatment of pyodermas and dermatoses complicated with a secondary infection

The article covers issues related to the application of topical antibacterial drugs for the treatment of pyodermic skin diseases. The author describes mechanisms of action and advantages of the topical form of antibiotics and GCS for the topical treatment of pyodermas. The article substantiates indications for the administration of topical GCS drugs in a combination with antibacterial drugs. The efficacy and safety of antibacterial and combination topical drugs such as Neomycin, Oxycort and Polcortolon TC in the form sprays for the treatment of pyodermas and complicated forms of chronic dermatosis.

Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids

Feline demodicosis due to Demodex cati is a rare skin disease often associated with concurrent disease and generalized immunosuppression. Local immunosuppression due to the application of topical immunomodulatory drugs, such as glucocorticoids and tacrolimus, or by tumour cells has been suggested as a potential trigger for development of localized demodicosis in humans and animals. The goal was to describe two cats with asthma that developed localized demodicosis on the muzzle as a result of chronic therapy with a glucocorticoid administered via dispensing inhaler mask. In both cats, the muzzle area exposed to the fluticasone-dispensing chamber exhibited patchy alopecia, mild erythema, crusting and scaling. Deep skin scraping revealed D. cati. Discontinuation or reduction of fluticasone and administration of milbemycin resulted in resolution of clinical signs within 2months in both cats. A negative skin scrape was obtained after 7months of milbemycin in one of the cats. Demodicosis should be considered as a possible differential diagnosis in cats with primary alopecia or other skin lesions on the face exposed to inhalant glucocorticoids. Minimization of contact between the inhalant glucocorticoid and the skin can be achieved by wiping residual powder from the face and by keeping the mask tightly pressed to the skin to avoid contact with the surrounding area.

Topical Combinations to Treat Microvascular Dysfunction of Chronic Postischemia Pain

Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56). The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.

Mathematical Model to Predict Skin Concentration after Topical Application of Drugs

Skin permeation experiments have been broadly done since 1970s to 1980s as an evaluation method for transdermal drug delivery systems. In topically applied drug and cosmetic formulations, skin concentration of chemical compounds is more important than their skin permeations, because primary target site of the chemical compounds is skin surface or skin tissues. Furthermore, the direct pharmacological reaction of a metabolically stable drug that binds with specific receptors of known expression levels in an organ can be determined by Hill’s equation. Nevertheless, little investigation was carried out on the test method of skin concentration after topically application of chemical compounds. Recently we investigated an estimating method of skin concentration of the chemical compounds from their skin permeation profiles. In the study, we took care of “3Rs” issues for animal experiments. We have proposed an equation which was capable to estimate animal skin concentration from permeation profile through the artificial membrane (silicone membrane) and animal skin. This new approach may allow the skin concentration of a drug to be predicted using Fick’s second law of diffusion. The silicone membrane was found to be useful as an alternative membrane to animal skin for predicting skin concentration of chemical compounds, because an extremely excellent extrapolation to animal skin concentration was attained by calculation using the silicone membrane permeation data. In this chapter, we aimed to establish an accurate and convenient method for predicting the concentration profiles of drugs in the skin based on the skin permeation parameters of topically active drugs derived from steady-state skin permeation experiments.

Hypertrichose cervicale antérieure sporadique

Anterior cervical hypertrichosis is a rare and little-known form of congenital localized hypertrichosis. It is characterized by the presence of a tuft of terminal hairs in the anterior cervical region. We report four typical clinical observations of this condition. Four patients aged from 5 to 21 years were seen for a tuft of terminal long hair on the neck, next to the cricoid cartilage, recorded at birth or during early childhood. There was no indication of previous trauma or topical drug application. No similar familial history was found. In one case, histological examination performed for suspicion of an "atypical" smooth muscle hamartoma contributed nothing of note. No neurological abnormalities were observed. In one case there was a history of chronic juvenile idiopathic arthritis and familial thyroid disease. Treatment with 5 sessions of laser hair removal was proposed in one case and the improvement was considered satisfactory by the patient. Anterior cervical hypertrichosis constitute a specific clinical picture of a benign nature, and is sometimes associated with neurological, orthopaedic or ocular abnormalities. Although rarely reported, its frequency is probably underestimated.

Tacrolimus does not alter the production of several cytokines and antimicrobial peptide in Malassezia furfur‐infected‐keratinocytes

Topical immunosuppressant therapy is widely used in the treatment of inflammatory skin diseases, such as atopic dermatitis and psoriasis. Besides its beneficial therapeutic effects, application of topical anti-inflammatory drugs may render the epidermis more vulnerable to invading pathogens by suppressing innate immune responses in keratinocytes (KCs). Cytokines, chemokines and antimicrobial peptides (AMPs) produced by epithelial cells enable them to participate in innate and acquired immune responses. The aim of the present work was to study the influence of tacrolimus (FK506) on KCs infected with Malassezia furfur (M. furfur), evaluating the expression of pro-inflammatory cytokines IL-1α and IL-6, chemokine IL-8, anti-inflammatory cytokines transforming growth factor beta1 (TGF-β1) and IL-10 and AMP β-defensin-2. Human KCs were obtained from surgical specimens of normal adult skin. The expression of mRNAs in KCs: FK506-treated, FK506-treated and M. furfur-infected as well as only M. furfur-infected was quantified by real-time quantitative polymerase chain reaction. Next, the production of the AMP β-defensin-2 and of the above-mentioned pro-inflammatory and anti-inflammatory cytokines was evaluated using enzyme-linked immunosorbent assay. In this study, FK506 did not alter cytokine and AMP production by KCs; this led us to hypothesise that it may not enhance the risk of mycotic skin infections.

Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues

Attempts to prevent HIV infection through pre-exposure prophylaxis (PrEP) include topical application of anti-HIV drugs to the mucosal sites of infection; however, a potential role for local drug metabolizing enzymes in modulating the exposure of the mucosal tissues to these drugs has yet to be explored. Here we present the first report that enzymes belonging to the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) families of drug metabolizing enzymes are expressed and active in vaginal and colorectal tissue using biopsies collected from healthy volunteers. In doing so, we discovered that dapivirine and maraviroc, a non-nucleoside reverse transcriptase inhibitor and an entry inhibitor currently in development as microbicides for HIV PrEP, are differentially metabolized in colorectal tissue and vaginal tissue. Taken together, these data should help to guide the optimization of small molecules being developed for HIV PrEP.

Mucosal Expression of the Cytochromes P450 (CYP) and Nucleotide Kinases Involved in the Biotransformation of Drugs Used in Human Immunodeficiency Virus (HIV) Pre‐exposure Prophylaxis (PrEP)

Attempts to prevent HIV infection through PrEP have included topical application of anti‐HIV drugs to the mucosal sites of infection. However, clinical studies have revealed marked anatomic variability in drug exposure in vaginal tissue versus colorectal tissue. Thus, studies were performed to determine whether the CYPs and nucleotide kinases responsible for the metabolism and activation of drugs used in HIV PrEP were differentially expressed in human vaginal versus colonic tissue. Quantitative reverse transcriptase‐PCR revealed that colonic mRNA expression of CYPs 1A1, 2B6, and 3A4/5 were 14‐, 37‐ and 4‐fold greater, respectively, than vaginal mRNA. Immunoblotting confirmed the presence of CYPs 3A4 and 3A5 protein in vagina. The vaginal mRNA abundance of adenylate kinase 2, the primary enzyme responsible for the activation of the HIV PrEP drug tenofovir, was 1.5‐fold greater than in colonic tissue. Cytidine monophosphate kinase mRNAs were 8‐fold greater in colonic tissue and phosphoglycerate kinase mRNAs were 4‐fold greater in vaginal tissue. These kinases have been proposed to activate emtricitabine, which is also under development as a topical microbicide for HIV PrEP. These data indicate that enzymes that modulate exposure to anti‐HIV drugs may be differentially expressed in mucosal tissues that are sites of topical drug application for PrEP. Funding: NIH U01 AI068613 (HIV Prevention Trials Network).

Topical Gel: A Recent Approach for Novel Drug delivery

Gel formulation provides better application property and stability in comparison to cream and ointment. Topical gel drug administration is a localized drug delivery system anywhere in the body through ophthalmic, rectal, vaginal and skin as topical routes. Skin is one of the most extensive and readily accessible organs on human body for topical administration and is main route of topical drug delivery system. Topical application of drugs offers potential advantages of delivering the drug directly to the site of action and acting for an extended period of time. Topical gels are intended for skin application or to certain mucosal surfaces for local action or percutaneous penetration of medicament or for their emollient or protective action. Gels are evaluated by following parameters such as pH, homogeneity, grittiness drug content, viscosity, spreadability, extrudability, skin irritation studies, invitro release, in Stability

ABC Transporters in the Eyes of Dogs and Implications in Drug Therapy

Purpose: The current study aims to quantifies the level of expression of selected adenosine triphosphate-binding cassette (ABC) efflux transporters and the major drug metabolizing enzyme CYP450 3A12 in the eyes of dogs.Materials and methods: The levels of expression were quantified by real-time polymerase chain reaction in the cornea, conjunctiva and retinal tissue.Results: ABCB1 mRNA is present at high levels in all analysed tissues. ABCC1, ABCC3 and ABCC4 are expressed predominantly in the conjunctiva and at very low levels in the cornea. ABCC2 could not be detected in any of the tissues. CYP3A12 expression was found in the retina and conjunctiva.Conclusion: These data are presented for the first time for ocular tissues of dogs of different breeds and a comparison with other species such as humans and rabbits demonstrated remarkable species differences, which might be of clinical relevance. The impact of these findings is discussed with reference to topical and systemic drug application in the treatment of ophthalmological diseases.

<i>In vivo</i> study of biomechanical properties in psoriasis vulgaris: Effectiveness of sulfur spa therapy

Psoriasis is a prolonged inflammation of the skin. The causes of psoriasis are still unclear. The treatment options depend on the severity of the disease and may include topical agents (such as topically-applied drugs, sulfur spa therapy, phototherapy) and systemic agents (orally or percutaneously administered). The aim of this study was to investigate the mechanical properties of the skin in psoriatic plaques before and after treatment with sulfur therapy (Thermae Luigiane, Guardia Piemontese—Acquappesa, Italy), in comparison with the skin of healthy subjects. The study has been performed on 20 psoriatic plaques (10 on upper arm, 10 on upper back) and 10 control subjects (healthy males aged 47 ± 15). The efficacy of sulfur therapy was observed through the evaluation of the biomechanical properties of the skin. Investigation was performed with a Skin meter, an instrument useful to determine the physiological parameters by the means of a suction method, a non-invasive in vivo suction. The apparatus was equipped with 2-mm measuring probe. Unlike the optical method, in our test the color and/or distribution of the skin micro-circulation didn’t interfere with the measurement. The evaluation of mechanical properties of the psoriatic plaques after treatment showed a significative recovery of the parameters analysed, with an increase of the elasticity parameters (Ur, Ua, Ua/Uf, Ur/Uf) and a decrease of the viscoelasticity module (Uv/Ue).

Dermal Cell Damage Induced by Topical Application of Non-Steroidal Anti-Inflammatory Drugs is Suppressed by Trehalose Co-Lyophilization in <i>Ex Vivo</i> Analysis

ABSTRACT Topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) is generally considered safer than oral administration, although the former can occasionally induce cutaneous irritation. We hypothesized that the cutaneous irritation by topical NSAIDs might be suppressed by trehalose, which has protective effects on biological membranes. Using the three-dimensional cultured human skin model, Living Skin Equivalent-high, we found that cutaneous damage due to NSAIDs was reduced by concomitant use of trehalose and that this effect of trehalose was reinforced by co-lyophilization of NSAIDs with trehalose. The anti-inflammatory effect of co-lyophilized NSAIDs with trehalose was comparable to that seen with NSAIDs alone in a rat model. Our results suggest that co-lyophilization of NSAIDs with trehalose might be a novel procedure that can help prevent NSAIDs-induced skin irritation.

94 Symptomatic therapy of mild to moderate osteoarthritis of the knee with light emitting diodes

Vessels in the skin are arranged into superficial and deep horizontal plexuses and they are involved in thermoregulation, oxygen and nutritional support. The skin has a large number of functions and broad appeal spanning basic mechanistic and clinical research. Indeed, the skin can be used as a marker of normal and impaired vascular control and, owing to its accessibility and frequent involvement, is easy to investigate non-invasively. A large number of non-invasive methods are available for investigating the skin, ranging from those that permit the visualisation of microvessels, to those that monitor blood flow or one of its derivatives (e.g., skin temperature and transcutaneous oxygen). Such methods can be combined with non-invasive, dynamic stimuli (e.g., the use of cold or warm stimuli, activation of the peripheral nervous system or local neuronal systems, and the topical application of vasoactive drugs) and this potentially enables the differentiation of underlying disorders (e.g., primary from secondary Raynaud's phenomenon) and also to quantify changes over time or following intervention. The present article outlines the non-invasive methods and dynamic tests that can be used to investigate the microcirculation of the skin.

Evaluation of novel nystatin nanoemulsion for skin candidosis infections

One of the most common fungal skin infections is candidosis. Topical application of drugs at the pathological sites offers potential advantage of direct drug delivery to the site of action. The main aim of this work was to evaluate an optimal nystatin nanoemulsion for topical application avoiding undesirable side effects as systemic absorption and toxicity. Surface morphology and droplet size distribution of nystatin nanoemulsion was determined by transmission electronic microscopy and dynamic light scattering. Vertical diffusion Franz-type cells and high-performance liquid chromatography were used to perform the in vitro release and ex vivo human skin permeation studies. Transdermal permeation parameters were estimated from the permeation values using different theoretical approaches. Microbiological studies were performed to evaluate the antifungal effect. Nanoemulsion exhibited a spherical shape with smooth surface and mean droplet size between 70 and 80 nm. The pharmacokinetic release showed the nanoemulsion is faster than commercial ointment Mycostatin(®) improving the potential therapeutic index. Permeation studies demonstrated nystatin was not absorbed into systemic circulation and the retained amount in the skin was sufficient to ensure an antifungal effect. This antifungal effect was higher for nystatin loaded nanoemulsion than nystatin itself. A therapeutic improvement of the nystatin nanoemulsion treatment compared with the classical ones was achieved.

The Cell and Molecular Biology of Glaucoma: Axonopathy and the Brain

Many ophthalmologists and members of the lay public alike view glaucoma in its historical context—that is, as exclusively a disease of the eye. This view has been (and remains) overwhelmingly pervasive because the etiology of the disease involves so many factors associated with the eye: intraocular pressure (IOP), corneal thickness, optic disc morphology, and so on. Glaucoma is associated with sensitivity to IOP, and lowering IOP through either topical application of hypotensive drugs or surgery is the only form of treatment. Studies of animal models of glaucoma generally incorporate elevations in IOP as a way of mimicking the sort of injury that seems relevant to the human disease. However, although managing IOP can slow disease progression, it is not a cure, and vision loss in glaucoma often continues despite hypotensive regimens. 1 What is most damaging about glaucoma occurs outside of the eye, with degeneration of the optic nerve and its connections to the brain. This process involves the progressive loss of retinal ganglion cell (RGC) axons, some 1.5 million of which comprise the optic nerve in humans. Smaller eyes in experimental models have correspondingly fewer axons. Axon loss is followed eventually by apoptotic elimination of the RGC soma population in the retina. The rate at which degeneration progresses depends on many factors, including treatment efficacy. In the worst case, the loss of RGC neurons and their connections in the optic projection represents a substantial injury to the brain. Some 50% to 60% of the cerebral cortex spread over 40 to 45 distinct visual areas processes information from the retina via the optic nerve. In this sense, glaucoma is the premier age-related optic neuropathy and is becoming more prevalent as the population ages. Since the retina and optic nerve are part of the central nervous system, they lack the limited but intrinsic capacity of peripheral nervous system neurons for self-repair. Thus, identifying new neurocentric therapies for glaucoma is important, not only for preserving vision as the population ages, but also for translation to new treatments for other age-related brain diseases such as Alzheimer’s and Parkinson’s disease. Much of what we learn in glaucoma research from a neurobiological standpoint is now informing research for these other devastating conditions. 2

Fixed drug eruption induced by topical olopatadine ophthalmic solution

Fixed drug eruption (FDE) usually develops after oral administration and is described as a cutaneous reaction recurring at the same location each time the drug is taken. Olopatadine is both a H1 histamine receptor antagonist and a mast cell stabilizer, indicated for the treatment of allergic conjunctivitis. Here, we report a 14-year-old male patient who developed FDE localised on the lateral side of periorbital rim bilaterally, whilst applying olopatadine 0.1% ophthalmic solution for the treatment of allergic conjunctivitis. As far as we know, FDE due to olopatadine has not been previously reported in the literature. We deem it appropriate to report this case because FDE that results from the application of topical drugs is a rare event in the literature.

Paclitaxel-loaded ethosomes®: Potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses

Topical application of anticancer drugs for the treatment of malignancies represents a new challenge in dermatology, potentially being an alternative therapeutic approach for the efficacious treatment of non-melanoma skin cancer, that is, actinic keratoses, and malignant lesions of the skin caused by ultraviolet radiation. Anti-proliferative and antimitotic drugs, including many of the taxanes, are currently under investigation for the treatment of cutaneous malignant transformation of actinic keratoses, particularly the squamous cell carcinoma. Paclitaxel-loaded ethosomes® are proposed as topical drug delivery systems for the treatment of this pathology due to their suitable physicochemical characteristics and enhanced skin penetration ability for deep dermal delivery. Our in vitro data show that the skin application of paclitaxel-loaded ethosomes® improved the permeation of paclitaxel in a stratum corneum-epidermis membrane model and increased its anti-proliferative activity in a squamous cell carcinoma model as compared to the free drug. The results obtained encouraged the use of the paclitaxel-loaded ethosomes® as the formulation for the potential treatment of squamous cell carcinoma, a malignant transformation of actinic keratoses.

The Use of an Artificial Skin Model to Study Transdermal Absorption of Drugs in Inflamed Skin

Studies on drug disposition in inflamed skin are important for safe and effective application of topical drugs. Here, the absorption of flurbiprofen (FP) through inflamed skin was examined in vivo and in a skin-mimicking artificial model system. The model skin system consisted of a silicone membrane acting as a model stratum corneum, laminated dialysis membranes acting as a model of viable skin, and 2 microdialysis probes-one used for determination of FP concentration and one acting as a model vessel. This model system could be used for quantitative evaluation of complicated permeation processes. In the in vivo experiments, FP absorption was suppressed in rats with inflamed skin induced by an intracutaneous injection of a mixed solution of λ-carrageenan, zymosan, and casein. Bovine serum albumin solution was placed between the dialysis membranes in the model skin system to mimic protein leaching in skin; the results suggested that the delayed absorption of FP in inflamed skin was due to binding to serum proteins leaching in the tissue. Such a combination of in vivo experiments and a model skin system is useful for understanding complex phenomena in inflamed and damaged skin and reduces experimental animal use.

The Cutaneous Vascular System in Chronic Skin Inflammation

The blood and lymphatic vasculature play an important role in skin homeostasis. Angiogenesis and lymphangiogenesis – the growth of new vessels from existing ones - have received tremendous interest because of their role in promoting cancer spread. However, there is increasing evidence that both vessel types also play a major role in acute and chronic inflammatory disorders. Vessels change their phenotype in inflammation (vascular remodeling). In inflamed skin, vascular remodeling consists of a hyperpermeable, enlarged network of vessels with increased blood flow, and influx of inflammatory cells. During chronic inflammation, the activated endothelium expresses adhesion molecules, cytokines, and other molecules that lead to leukocyte rolling, attachment and migration into the skin. Recent studies reveal that inhibition of blood vessel activation exerts potent anti-inflammatory properties. Thus, anti-angiogenic drugs might be used to treat inflammatory conditions. In particular, topical application of anti-angiogenic drugs might be ideally suited to circumvent the adverse effects of systemic therapy with angiogenesis inhibitors. Our recent results indicate that stimulation of lymphatic vessel growth and function unexpectedly represents a novel approach for treating chronic inflammatory disorders.

Percepção da administração tópica ocular de drogas: aplicador facial x gotas

OBJETIVOS: Avaliar por meio de questionario, qual o grau de dificuldade para aplicacao topica de medicacoes oculares, com ou sem o auxilio do apoio facial. Observar qual metodo foi tecnicamente melhor utilizado para aplicacao de drogas topicas oculares. METODOS: O estudo foi um ensaio clinico controlado e randomizado, realizado em 50 pacientes no decorrer de 2009 e 2010 na Unidade de Saude da Familia - Lapa. Foi utilizado um frasco de colirio Oftane® e o mesmo foi acoplado ao dispositivo de apoio facial. Cada participante aplicou em cada um dos olhos, a solucao com ou sem o uso do dispositivo, sendo que a selecao foi feita atraves de um processo randomizado. Foi perguntado ao paciente questoes pre-formuladas sobre a praticidade de ambos os metodos. RESULTADOS: Considerando o grau de dificuldade de administracao topica ocular: 12% acharam dificil ou muito dificil a aplicacao com o objeto de apoio facial e 22% sem o apoio (p=0,0024). As dificuldades descritas pelos pacientes foram relatadas por 22 % dos pacientes para aplicacao com o dispositivo de apoio facial e por 46% para aplicacao sem o mesmo. Ja 34% dos pacientes necessitaram de mais de uma instilacao para aplicacao do colirio sem o apoio, enquanto que 54% dos pacientes precisaram de mais de uma aplicacao para que a gota atingisse o olho com o auxilio do apoio facial (p= 0,04). Em 56% dos pacientes houve toque da ponta do colirio com os tecidos oculares, quando o objeto de apoio facial nao foi usado, porem quando ele foi utilizado, apenas 2% dos pacientes observados tocaram os tecidos oculares (p=0,0001). CONCLUSAO: E mais facil a instilacao de colirios com o auxilio do dispositivo de apoio facial. Este tambem dificulta o contato da ponta do frasco com os tecidos oculares, prevenindo a contaminacao do frasco.