Topical Application Of Drugs Research Articles

Tongue angioedema in vivo: Antagonist response of anti-inflammatory drugs

Introduction. The toxicity of Dieffenbachia picta, an ornamental plant, arises from its ability to cause painful edema of oral mucous membranes, buccal ulcerations, and tongue hypertrophy after chewing on the stem or contact with the sap. Objectives. We compared the anti-inflammatory effect of eugenol (2-methoxy-4-(2-propenyl)phenol) to different drugs, and investigated the role of oxalate crystals in the development of the inflammation reaction. Methods. Tongue edema in live mice were measured with a digital tachymeter, 2 h after topical application (0.1 mL) or tissue injection (0.05 mL) of D. picta sap. The mice were treated by intraperitoneal or topical application of drugs, 15 min after edema induction. Vascular permeability was quantified based on abdominal skin plasma extravasation of Evans blue dye in response to intradermal administration of D. picta sap. The proteolytic assay was carried out as previously described (Kunitz M. Crystalline soybean trypsin inhibitor. General properties. J Gen Physiol 1947; 30:291–310.). Results. Arachidonate cascade antagonists and eugenol showed anti-edematogenic effects. High doses of eugenol (50 μg/kg) and sodium cromoglycate (100 mg/kg), but not a combination of the two, inhibited plasma extravasations. The sap without crystals, its methanol extract, or the ethanol-washed crystals in saline-reconstituted solution did not reproduce the tongue edema seen with the original sap. Topical application of 10% sodium bicarbonate completely abolished the tongue edema. Conclusions. The inflammatory response induced by D. picta may be due to mechanical tissue damage resulting from the physical presence of calcium oxalate crystals. We were, however, unable to exclude the possibility of an insoluble toxicity present within the sap as an etiological agent. We realized that emergency treatment should also aim to inhibit antidromic vasodilation and axon reflex flare, reducing mastocyte degranulation and release of tachykinins from nerve endings. We speculate that eugenol showed better antiedematogenic results because it seems to function not only as a classic non-steroidal anti-inflammatory drug, but also as a local anesthetic, blocking neurotransmission in the damaged tissue.

Lipid-based colloidal systems (nanoparticles, microemulsions) for drug delivery to the skin: materials and end-product formulations

Drug delivery to or via the skin presents both unique opportunities and obstacles due to skin structure, physiology, and barrier properties. The skin, the largest organ of the body, may be viewed either as a natural protective barrier against penetration of toxic exogenous compounds, excessive loss of water and other essential compounds, or as a promising portal of entry for drugs for local and/or systemic action. Many novel lipid nanocarriers have been designed for topical application of drugs since they allow these molecules to overcome the skin barrier and improve cutaneous bioavailability. The increased drug absorption is often a consequence of a reversibly disrupted barrier function of the skin by the vehicle itself or by specific ingredients figuring in the topical formulation that act as penetration enhancer. Micro/nanoemulsions and lipid nanoparticles are known to provide several advantages over conventional formulations in terms of stability and skin penetration enhancement. However, their characteristics in the original form are low viscous liquids and colloidal dispersions. Therefore, their topical application may be limited in some cases. This review describes recent works in formulating lipid nanocarriers, especially in the semi-solids and hydrogels forms, and reports their special features for biomedical and dermocosmetic applications.

Oil components modulate the skin delivery of 5-aminolevulinic acid and its ester prodrug from oil-in-water and water-in-oil nanoemulsions

The study evaluated the potential of nanoemulsions for the topical delivery of 5-aminolevulinic acid (ALA) and methyl ALA (mALA). The drugs were incorporated in oil-in-water (O/W) and water-in-oil (W/O) formulations obtained by using soybean oil or squalene as the oil phase. The droplet size, zeta potential, and environmental polarity of the nanocarriers were assessed as physicochemical properties. The O/W and W/O emulsions showed diameters of 216–256 and 18–125 nm, which, respectively, were within the range of submicron- and nano-sized dispersions. In vitro diffusion experiments using Franz-type cells and porcine skin were performed. Nude mice were used, and skin fluorescence derived from protoporphyrin IX was documented by confocal laser scanning microscopy (CLSM). The loading of ALA or mALA into the emulsions resulted in slower release across cellulose membranes. The release rate and skin flux of topical drug application were adjusted by changing the type of nanocarrier, the soybean oil O/W systems showing the highest skin permeation. This formulation increased ALA flux via porcine skin to 180 nmol/cm2/h, which was 2.6-fold that of the aqueous control. The CLSM results showed that soybean oil systems promoted mALA permeation to deeper layers of the skin from ∼100 μm to ∼140 μm, which would be beneficial for treating subepidermal and subcutaneous lesions. Drug permeation from W/O systems did not surpass that from the aqueous solution. An in vivo dermal irritation test indicated that the emulsions were safe for topical administration of ALA and mALA.

Disposition of Nanoparticle-Based Delivery System via Inner Ear Administration

The inner ear is difficult to access by conventional systemic drug delivery due to formidable physiological and anatomic barriers. There is an increasing interest in the treatment of inner ear disorders by topical application of drugs to the inner ear. One of the most important issues to overcome before full clinical application is the development of smart delivery systems for drugs to the target sites and controlled release in the inner ear. This is an area where nanoparticles will play an extremely important role. These submicron particles have exhibited improved biocompatibility, in vivo stability, target specificity, and cell/tissue uptake and internalization of the encapsulated therapeutic agents, leading to a decrease in the dose required and a decrease in side effects. This unique combination of properties makes nanoparticles a novel delivery device, which fulfils the requirements for inner ear application. This review will summarize recent findings and applications of various nanoparticle-based systems like poly (D, L-lactic/glycolic acid) nanoparticles, magnetic nanoparticles, lipid nanoparticles, liposomes, polymersomes, hydroxyapatite nanoparticles, and silica nanoparticles in the field of inner ear drug delivery. Moreover, the review will provide an insight into the future strategies of nanoparticle-based cochlear drug delivery. In conjunction, physiological considerations related to inner ear administration will be highlighted. The routes and applications for local inner-ear drug delivery will also be mentioned. In closing, this review will give an overview of the potential future development in inner ear administration with nanoparticles.

Nanotechnology and dermatology: Part II—risks of nanotechnology

Atopic dermatitis (AD) is a chronic disease that affects the skin, and that is characterized by highly itchy inflammation, frequent eczematous lesions, and a fluctuating course. The current treatment consists of a multi-stage approach that aims to establish persistent disease control towards the improvement of the quality of life of the patients. Topical therapy is the basis of AD treatment, however, due to the difficulty of crossing the skin barrier, topical application of drugs remains a challenge. In fact, in addition to the low skin bioavailability, and limited accessibility to deeper skin of the drugs − due to difficulty in penetrating the epidermis − implemented drugs in the clinical are associated with serious adverse effects, which are responsible for safety and efficacy limitations, leading to a reduction in patients' compliance. Nanotechnology arises as an emerging approach for the treatment of AD, allowing for controlled release, targeted delivery, improved penetration, and bioavailability of drugs assets, resulting in marked improved therapeutic efficacy and reduction of adverse effects. Although its promising outputs, additional studies are needed to recognize the toxicological characteristics, cost-benefit, and long-term safety of nanocarriers applied to this end. Advanced drug delivery systems, particularly nanoemulsions, liposomes, ethosomes, transfersomes, solid lipid nanoparticles, nanostructured lipid carriers, nanocrystals, polymeric nanoparticles, and polymeric micelles have been used, and are thoroughly addressed in this review as promising nanoformulations towards the topical treatment of AD.

Topische nasale Therapie nach endonasaler NNH-Op: pulsierende Inhalation versus Pumpspray

To evaluate which way of topical drug application would result in a better deposition pattern after FESS. We compared the deposition pattern of a nasal steroid after application with a metered pump spray or inhalation using the Pari sinus device. Visualization was achieved via colouring using 1% Sodium-fluorescein solution. All patients had a well healed sinus system with an endoscopically wide open access after FESS. We looked for the deposition with Blue-light-endoscopy directly after application and after washing out using a nasal douche. Analysis was performed blinded by two independent experienced sinus surgeons via representative single shots. Data of 11 patients revealed, that deposition after metered pump spray application was superior than after inhalation for all localisations. By far most part of the drug was deposited in the anterior nasal cavity, followed by the head of the middle turbinate, ethmoid. Small amounts reached the maxillary sinus, the anterior wall of the sphenoid sinus, the olfactory cleft and the entrance to the frontal sinus. The frontal sinus itself was not reached in any case. Washing out led to a decrease of deposition intensity, in some cases to a better distribution into the maxillary and sphenoid sinus and frontal recess. Postoperative deposition of topical nasal steroids after FESS is insufficient. We need better methods and devices to optimize efficacy of topical treatment.

Numerical Simulations of Ethacrynic Acid Transport from Precorneal Region to Trabecular Meshwork

Topical application of drugs for treatment of intraocular diseases is often limited by inadequate transport and induced toxicity in corneal tissues. To improve the drug delivery, a mathematical model was developed to numerically simulate the transport process of ethacrynic acid (ECA), a potential drug for glaucoma treatment, in the anterior segment of a typical human eye. The model considered diffusion of ECA in all tissues and the aqueous humor (AH) as well as convection of ECA in the AH. The simulation results showed that ECA concentration in the eye depended on the rate of AH production, the half-life of ECA in the precorneal tear film, and the transport parameters in the model. In addition, the main pathway for ECA clearance from the eye was the trabecular meshwork (TM) and the rate of clearance was approximately proportional to the AH production rate. The model predicted that the most effective approach to improving topical drug delivery was to prolong its half-life in the precorneal tear film. These simulation results and model prediction, which could be verified experimentally, might be useful for improving delivery of ECA and other therapeutic agents to the TM as well as other tissues in the anterior segment of the eye.

Effect of gel composition and phonophoresis on the transdermal delivery of ibuprofen: In vitro and in vivo evaluation

The objective of this study was to evaluate the effect of formulation composition and continuous ultrasound at 1.5 W/Cm2 intensity on the permeation of ibuprofen across polymeric and biological barriers. In vitro studies were performed using cellulose membrane and rabbit skin, whereas in vivo studies were performed on rabbits. Overall, higher transport data were obtained with the cellulose membrane. Nonetheless, with both barriers, transport was higher with the gel formulation than oleaginous or emulsion based preparations, which was also dependent on the viscosity of the gel and the concentration of the formulation additives. Transport increased with the increase in alcohol concentration and decreased with the addition of propylene glycol. Ultrasound had a significant effect on ibuprofen transport. For example, an 11-fold increase in drug permeation across cellulose membrane was observed after the application of ultrasound. Similar effect was observed in animal studies. Ibuprofen plasma concentration increased with the concentration of the drug in the gel, which significantly increased after the application of ultrasound. It was concluded that aqueous gel formulations act as ideal coupling agents for topical application of drugs. Nonetheless, in addition to ultrasound, the composition of the gel is expected to have a significant effect on the transdermal delivery of drugs.

Nucleoside-derived antagonists to A 3 adenosine receptors lower mouse intraocular pressure and act across species

The purpose of the study was to determine whether novel, selective antagonists of human A 3 adenosine receptors (ARs) derived from the A 3-selective agonist Cl-IB-MECA lower intraocular pressure (IOP) and act across species. IOP was measured invasively with a micropipette by the Servo-Null Micropipette System (SNMS) and by non-invasive pneumotonometry during topical drug application. Antagonist efficacy was also assayed by measuring inhibition of adenosine-triggered shrinkage of native bovine nonpigmented ciliary epithelial (NPE) cells. Five agonist-based A 3AR antagonists lowered mouse IOP measured with SNMS tonometry by 3–5 mm Hg within minutes of topical application. Of the five agonist derivatives, LJ 1251 was the only antagonist to lower IOP measured by pneumotonometry. No effect was detected pneumotonometrically over 30 min following application of the other four compounds, consonant with slower, smaller responses previously measured non-invasively following topical application of A 3AR agonists and the dihydropyridine A 3AR antagonist MRS 1191. Latanoprost similarly lowered SNMS-measured IOP, but not IOP measured non-invasively over 30 min. Like MRS 1191, agonist-based A 3AR antagonists applied to native bovine NPE cells inhibited adenosine-triggered shrinkage. In summary, the results indicate that antagonists of human A 3ARs derived from the potent, selective A 3 agonist Cl-IB-MECA display efficacy in mouse and bovine cells, as well. When intraocular delivery was enhanced by measuring mouse IOP invasively, five derivatives of the A 3AR agonist Cl-IB-MECA lowered IOP but only one rapidly reduced IOP measured non-invasively after topical application. We conclude that derivatives of the highly-selective A 3AR agonist Cl-IB-MECA can reduce IOP upon reaching their intraocular target, and that nucleoside-based derivatives are promising A 3 antagonists for study in multiple animal models.

A stochastic model for transepidermal drug delivery

Topical drug application has been widely used to manage skin diseases as well as to treat a variety of local and systemic disorders. To evaluate the efficiency of transepidermal drug delivery, an efficient model is needed to study the process of percutaneous transport. A stochastic model based on Monte Carlo methods and Cellular Automata is presented in this work to study the molecular transport through the stratum corneum of the human skin, which is a typical process in transepidermal drug delivery. To validate the model, an in vitro experiment on percutaneous absorption of radioactive 17beta-estradiol was performed. The simulation results agree with the experimental data. The use and power of the presented approach in studying the process of transepidermal drug delivery were demonstrated.

Liposomes in dermatology today

Liposomes are vesicles consisting of spherical phospholipid bi-layers with specific properties making them useful for topical application of drugs. Liposome research has expanded considerably over the last 30 years and nowadays, it is possible to construct a wide range of liposomes varying in size, phospholipids composition and surface characteristics to suit the specific application for which they are intended. In dermatology, the topical application of liposomes has proven to be of therapeutic value. Liposomes can be used as carriers for hydrophilic as well as lipophilic therapeutic agents because of their amphipathic character. They may improve stabilization of instable drugs by encapsulating them and serve as penetration enhancers facilitating the transport of compounds that otherwise cannot penetrate the skin. Liposomes help in reducing skin irritation by sustaining the release of drugs and by hydration of the epidermis. They also have the potential to target drugs into the pilosebaceous structures and hence they have an additional advantage for treatment of hair follicle-associated disorders. Clinical data indicate that 5-ALA encapsulated in liposomes improves the quality of Fluorescence Diagnosis by ALA-induced Porphyrins (FD) and optimizes the results of Photodynamic Therapy (PDT).

Effects of Diclofenac Epolamine Patch on Postoperative Sore Throat in Parturients After Cesarean Delivery Under Endotracheal General Anesthesia

Postoperative sore throat is a common problem. The efficacy of topical application of non-steroidal anti-inflammatory drugs in alleviating postoperative sore throat has not been established. Our aim was to evaluate the analgesic effects of diclofenac epolamine patch on postoperative sore throat. The study was conducted in a prospective, randomized, double-blind, and placebo-controlled manner. Two hundred and twenty women undergoing elective cesarean section (because of previous cesarean section) were randomized into two equal groups: the diclofenac epolamine patch group and the placebo group. The surgery was performed under general anesthesia after rapid sequence induction. Data of the baseline characteristics, the incidence and severity of sore throat and the adverse effects of diclofenac patch were collected. The participants were similar in baseline characteristics. The incidence of sore throat, as assessed 12, 24 and 48 hours after using the patch was significantly lower in the diclofenac patch group than in the placebo patch group, with p values 0.04, < 0.001 and 0.015, respectively. None of the participants dropped out of the study because of complications. The diclofenac epolamine patch is effective and safe in prevention of sore throat following intubation general anesthesia in cesarean section.

Topical application of antifibrinolytic drugs for on-pump cardiac surgery: a systematic review and meta-analysis

This systematic review aimed to evaluate the efficacy and safety of topical application of antifibrinolytic drugs to reduce postoperative bleeding and transfusion requirements in patients undergoing on-pump cardiac surgery. We searched The Cochrane Library, MEDLINE, EMBASE and SCI-EXPANDED for all randomized controlled trials on the topic. Trial inclusion, quality assessment, and data extraction were performed independently by two authors. Standard meta-analytic techniques were applied. Eight trials (n = 622 patients) met our inclusion criteria. The medication/placebo was applied into the pericardial cavity and/or mediastinum at the end of cardiac surgery. Seven trials compared antifibrinolytic agents (aprotinin or tranexamic acid) versus placebo. They showed that, on average, topical use of antifibrinolytic agents reduced the amount of 24-h postoperative chest tube (blood) loss by 220 ml (95% confidence interval: -318 to -126, P < 0.00001, I (2) = 93%) and resulted in a saving of 1 unit of allogeneic red blood cells per patient (95% confidence interval: -1.54 to -0.53, P < 0.0001, I (2) = 55%). The incidence of blood transfusion was not significantly changed following topical application of the medications. One study comparing topical versus intravenous administration of aprotinin found comparable results between the two methods of administration for the above-mentioned outcomes. No adverse effects were reported following topical use of the medications. This review suggests that topical application of antifibrinolytics can reduce postoperative bleeding and transfusion requirements in patients undergoing on-pump cardiac surgery. These promising findings need to be confirmed by more trials with large sample size using patient-related outcomes and more assessments regarding the systemic absorption of the medications.

Comparative study in swines' vocal cords healing after excision of fragment with CO2 laser with mitomycin and 5-fluorouracil postoperative topical application

To evaluate the deposition of collagen fibers at pig's vocal folds after topical use of mitomycin or 5-fluorouracil, when partial exeresis of mucosa layer had been promoted by CO2 laser. There were used 18 Larger white pigs which were anesthetized and submitted to mucosa fragment's exeresis, bilaterally, at its free border. The animals were divided into 3 groups, each one with 6 animals: control group, without topical drug application; mitomycin group; and 5-fluorouracil group. After 30 days, the animals were subjected to euthanasia, and samples of the vocal folds were collected and stained by picrosirius red technique with polarization for quantification of total collagen deposition. In control group, the mean rate of right vocal fold's collagen deposition at submucosa consisted in a 3428.66 micrometers area. There was found an area whose size had, in average, 2196.36 micrometers, in mitomycin group, and 2269.19 micrometers, in 5-fluorouracil group. Mitomycin and 5-fluorouracil had promoted beneficial change in vocal fold's cicatrization with less collagen deposition, but there was no significant statistically difference when they were compared between themselves.

Sympathetic influence on the pupillary light response in three red‐eared slider turtles (Trachemys scripta elegans)

We investigated the effects of phenylephrine and its combination with vecuronium bromide on the iris of turtles to determine if the pupillary light response is affected by sympathetic innervation. Three red-eared slider turtles, Trachemys scripta elegans. Diameters of light-adapted pupils were tracked before and after topical application of drugs to eyes. Phenylephrine was applied independently; in a second group of trials, vecuronium bromide was applied with phenylephrine. Rates of pupil dilation in response to drugs were quantified by fitting data with time constant (tau) equations. Phenylephrine dilated the pupil 24%, tau = 29 min. Combination of phenylephrine with vecuronium bromide increased the pupil size 35%, and dilation was more rapid, tau = 14 min. We also were able to predict these time constants by performing different mathematical operations with an equation developed from a prior study using only vecuronium bromide. When this equation was subtracted from the equation for eyes treated with both vecuronium bromide and phenylephrine, the difference gave the observed tau for phenylephrine; when added to phenylephrine, the sum closely matched the tau for eyes treated with vecuronium bromide and phenylephrine. Further, the tau for vecuronium bromide treated eyes was predicted by subtracting the equation for phenylephrine from that of eyes treated with both vecuronium bromide and phenylephrine. Our results suggest that sympathetic innervation interacts with the parasympathetic pathway to control the pupillary light response in turtles.

Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage

Melanoma incidence continues to rise at an alarming rate while effective systemic therapies remain very limited. Microphthalmia-associated transcription factor (MITF) is required for development of melanocytes and is an amplified oncogene in a fraction of human melanomas. Microphthalmia-associated transcription factor also plays an oncogenic role in human clear cell sarcomas, which typically exhibit melanoma-like features. Although pharmacologic suppression of MITF is of potential interest in a variety of clinical settings, it is not known to contain intrinsic catalytic activity capable of direct small molecule inhibition. An alternative drug-targeting strategy is to identify and interfere with lineage-restricted mechanisms required for its expression. Here, we report that multiple histone deacetylase (HDAC)-inhibitor drugs potently suppress MITF expression in melanocytes, melanoma and clear cell sarcoma cells. Although HDAC inhibitors may affect numerous cellular targets, we observed suppression of skin pigmentation by topical drug application as well as evidence of anti-melanoma efficacy in vitro and in mouse xenografts. Consequently, HDAC inhibitor drugs are candidates to play therapeutic roles in targeting conditions affecting the melanocyte lineage.

Aqueous humor concentration of voriconazole after topical administration in rabbits

Voriconazol is a triazole antifungal drug with in vitro fungicidal activity against all Candida spp., Fusarium spp. and Aspergillus spp. which are frequent causes of fungal keratitis depending on geographic location. We investigated the penetration of voriconazole through the cornea into the aqueous humor (AH) after topical administration. A 1% voriconazole solution was applied onto each rabbit's cornea. Topical drug application was processed at different time intervals: single drug application with AH sampling after 30 min, 1 h, 2 h, 3 h and 6 h. In addition, we evaluated AH samples after repeated topical application of voriconazole every 30 min after 1, 2, 4 and 6 h. Furthermore, after repeated drug application every hour, we analyzed voriconazole concentration after 2, 3, 4 and 6 h. All samples were analyzed by high-performance liquid chromatography (HPLC)-UV. A single application showed a maximum peak in AH of 3.58 microg/ml (N = 9) after 30 min. Within 3 h the concentration decreased to 0.04 microg/ml (N = 11). Application of voriconazole every half an hour revealed a peak value of 6.73 microg/ml (N = 10) after 2 h; after 4 h the value decreased to 6.19 microg/ml (N = 10) and was constant after 6 h (6.12 microg/ml, N = 6). When administrated every hour, only lower AH concentrations of voriconazole were reached with a maximum level of 2,06 microg/ml (N = 8) after four hours. In AH, therapeutic drug levels that cover the minimum inhibitory concentrations (MIC) of most fungi can be reached. To achieve a sustained high level of voriconazole as an effective antifungal therapy for corneal keratitis, voriconazole should be topically administered every 30 min.

Influence of nanosized delivery systems with benzyl nicotinate and penetration enhancers on skin oxygenation

Many novel nanosized delivery systems have been designed for topical application of drugs since they can overcome the skin barrier and improve drug bioavailability. The increased absorption is often a consequence of a reversibly disrupted barrier function of the skin by the vehicle itself or by specific ingredients that act as penetration enhancers. This paper reports the effects of two nanosized systems (microemulsion and liposomes), in the presence and absence of penetration enhancers (PE), on the topical delivery of a lipophilic drug in vivo and compares that to classical hydrogel formulation. A vasodilator benzyl nicotinate (BN), which increases the blood flow of the skin, was incorporated into the formulations, and skin oxygenation was followed by electron paramagnetic resonance oximetry. It was found that microemulsions and liposomes (with or without PE) accelerate the rate of BN action when compared to hydrogel. However, incorporation of PE in microemulsion also improves the effectiveness of BN action. To understand why PE enhances the action of BN, its effect on the structure of the stratum corneum was investigated in vitro. The increased fluidity of the stratum corneum lipids provides an explanation for the greater penetration of BN into the skin when the drug and PE are together incorporated into the appropriate formulation.

Polymers used in ocular dosage form and drug delivery systems

Topical application of drugs to the eye is most popular and well-accepted route of administration for the treatment of various eye disorders. A variety of ocular dosage form and drug delivery systems, including a controlled release of the drug, drug targeting, and penetration enhancement of the drug, have been investigated. Polymers have been widely used as the drug carrier for controlled-release systems. Polymers release the drug as they themselves degrade and are sometimes finally absorbed within the body. In this article, several ocular drug delivery systems have discussed using different kinds of polymers and their acceptance over conventional.

Anaphylaxis and toxic epidermal necrolysis or Stevens–Johnson syndrome after nonmucosal topical drug application: fact or fiction?

Anaphylaxis and toxic epidermal necrolysis or Stevens–Johnson syndrome after nonmucosal topical drug application: fact or fiction?