Dose-dependent effect on skin permeation of polar and non-polar compounds.

The study of the relationship between the amount of drug applied to the skin and fraction of drug absorbed can improve our understanding of finite-dose percutaneous absorption in the development of topical products and risk assessment of hazardous chemical exposure. It has been previously shown that an increase in the dose applied to the skin leads to a decrease in the fraction of drug permeated the skin (dose-dependent effect). The objective of this research was to examine the dose-dependent effect using permeants of varying physiochemical properties. The dose-dependent effect was studied using human epidermal membrane under finite dose conditions in Franz diffusion cell with model permeants at doses ranging from 0.1 to 200 µg. The dose-dependent effect was evident with model permeants caffeine, corticosterone, dexamethasone, and estradiol, consistent with the relationship of decreasing fraction of dose permeated the skin at increasing the applied dose. However, no significant dose-dependent effect was observed for the polar model permeants urea, mannitol, tetraethyl ammonium, and ethylene glycol, suggesting different transport mechanisms for these permeants. It was also found that, at relatively high doses, estradiol, dexamethasone, and corticosterone could increase the permeation of polar and lipophilic permeants, which could counter the dose-dependent effect under the conditions studied.

Efficacy and Safety of Newer Topical Therapies in Psoriasis: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Psoriasis is a chronic immune-mediated skin disease. Several clinical trials have studied some topical drugs aiming at new therapeutic targets. However, the comparative efficacy and safety of different concentrations and frequencies of newer topical drugs for psoriasis remain unclear. The aim of our study is to assess the comparative efficacy and safety of some newer topical treatments in patients with psoriasis. METHODS: A systematic review and network meta-analysis (NMA) was conducted using eligible randomized controlled trials (RCTs). Treatments included topical therapeutic aryl hydrocarbon receptor (AhR)-modulating agent (TAMA), topical phosphodiesterase type 4 (PDE-4) inhibitors, and topical janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors. The primary efficacy assessment criterion was the proportion of patients' achieving Physician's Global Assessment 0/1 (PGA response). Secondary criterion was ≥75% reductions in the Psoriasis Area and Severity Index (PASI75). Adverse events (AEs) to represent the safety were also summarized. RESULTS: Among 6 including newer topical drugs, odds of achieving both PGA response and PASI75 were higher with all regimens of TAMA and roflumilast cream versus vehicle. In terms of safety outcomes, odds of AEs were also higher with all regimens of TAMA. There were no statistically significant differences between topical JAK-STAT inhibitors and vehicle for any outcome, except ruxolitinib ointment 1% once daily (QD). CONCLUSION: TAMA had a good therapeutic effect on plaque psoriasis but a relatively low treatment safety. Roflumilast cream had both promising efficacy and higher safety.

In vitro percutaneous penetration test overview.

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug-in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades-results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

Efficacy of Topical Treatments for the Management of Symptomatic Oral Lichen Planus: A Systematic Review.

Oral lichen planus (OLP) is a chronic mucosal inflammatory disease associated with T-cell-mediated immunological dysfunction. Symptomatic OLP is a painful condition, and complete healing is often not achieved. The aim of this systematic review was to assess the effectiveness of topical drugs, medications, and other interventions compared to placebo or to other treatments in pain reduction and clinical resolution in adult patients with symptomatic OLP. A detailed electronic literature search was performed through the MEDLINE (PubMed) database between 1 January 2005 and 30 September 2022. Eligible studies were selected based on the inclusion criteria, and a quality assessment was conducted. From 649 titles, 121 articles were selected as abstracts, 75 papers were assessed as full text, along with 15 other papers obtained through a manual search. A total of 15 RCTs were finally included in the review process. Because of the significant heterogeneity in the study design of the included studies, no meta-analysis of the data could be performed. Topical corticosteroids represent the first-line treatment in the management of symptomatic OLP due to their efficacy and minimal adverse effects. Calcineurin inhibitors seem to be equally effective and are indicated in recalcitrant cases, extensive lesions, patients susceptible to oral candidiasis, or cases unresponsive to corticosteroids. Other treatments, such as aloe vera, chamomile, isotretinoin, ozone, and laser therapy, could be beneficial as adjunct therapies in association with first-line treatments.

The Assessment of Skin Homeostasis Changes after Using Different Types of Excipients in Healthy Individuals.

Excipients are used as vehicles for topical treatments; however, there are not many studies that evaluate the impact of different excipients themselves. The aim of this research is to assess skin homeostasis changes in healthy individuals after using water/oil (W/O), oil/water (O/W), Beeler base, foam and Vaseline excipients. A within-person randomized trial was conducted that included healthy individuals without previous skin diseases. Skin barrier function parameters, including stratum corneum hydration (SCH), transepidermal water loss (TEWL), pH, temperature, erythema, melanin and elasticity (R0, R2, R5 and R7), were measured on the volar forearm before and after using each excipient. Sixty participants were included in the study, with a mean age of 32 years. After applying w/o excipient erythema decreased by 25 AU, (p < 0.001) and elasticity increased by 6%. After using the o/w excipient, erythema decreased by 39.36 AU (p < 0.001) and SCH increased by 6.85 AU (p = 0.009). When applying the Beeler excipient, erythema decreased by 41.23 AU (p < 0.001) and SCH increased by 15.92 AU (p < 0.001). Foam and Vaseline decreased TEWL and erythema. Excipients have a different impact on skin barrier function. Knowing the effect of excipients on the skin could help to develop new topical treatments and help specialists to choose the best excipient according to the pathology.

In vitro release test (IVRT): Principles and applications.

In vitro drug release test has become one of the most important tools for drug development and approval process of semisolid dosage forms. In vitro release test (IVRT) has the ability to reflect the combined effects of several physicochemical characteristics, particle or droplet size, viscosity, microstructure arrangement of the matter and state of aggregation of dosage form. Genesis of IVRT, its principles and rank order relationship with pharmacodynamic response such as vasoconstriction or dermatopharmacokinetic (skin stripping) results and the evolution of test requirements for regulatory approval is discussed. IVRT reflects various parameters and is an essential part of the stepwise approach to compare topical formulation and its ability to release active in similar quantity at similar rate. Therefore, it is an essential tool, in addition to similar qualitative and quantitative composition (Q1 Q2), to assess the similarity of microstructural arrangement (Q3) as proposed in the Topical drug Classification System (TCS) approach of classes 1 and 3. The TCS system along with evolving concept for topical dermatological drug products from Q1, Q2, Q3 sameness to Q1, Q2, Q3 similar allowing greater permissiveness in formulation changes is discussed.

The Miracles of Surfactant: Less Invasive Surfactant Administration, Nebulization, and Carrier of Topical Drugs.

Surfactant replacement therapy (SRT) has long become the standard of care in the treatment of neonatal respiratory distress syndrome (RDS), significantly decreasing acute pulmonary morbidity and mortality in preterm infants. For decades, this beneficial replacement therapy has been administered via endotracheal tube. Despite significantly improving the outcome of RDS, however, the burden of bronchopulmonary dysplasia remains, in particular, in very immature preterm infants. Acknowledging the direct relationship between exposure to and duration of invasive mechanical ventilation and chronic lung disease, the latter has been gradually replaced by noninvasive ventilation strategies in neonatal RDS. This replacement is strongly related to the demand for similarly noninvasive modes of surfactant administration. Alternative techniques in spontaneously breathing infants have evolved, including less invasive techniques using thin catheters (less invasive surfactant administration and minimally invasive surfactant treatment) as well as nebulization of surfactant, although the latter is not ready for clinical application yet. In addition, given their therapeutic delivery to the lungs and subsequent alveolar distribution, surfactant preparations represent an attractive vehicle for pulmonary deposition of drugs in preterm infants. Further improvement of SRT and expansion of the field of application of lung surfactant may hold additional benefits, especially in the treatment of the most immature preterm infants.

Efficacy of medical treatments for vernal keratoconjunctivitis: A systematic review and meta-analysis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a severe type of allergic conjunctivitis for which treatment strategies are still under debate. OBJECTIVES: This study sought to conduct a systematic review and meta-analysis to evaluate the efficacy of medical treatments for VKC. METHODS: The PubMed, Cochrane Library, Embase, and ScienceDirect databases were searched to assess the efficacy of treatments for VKC. Random-effect meta-analyses on changes in clinical scores of symptoms and signs between baseline and after treatment, stratified on treatment classes, were computed. Meta-regressions were searched for potential influencing parameters. RESULTS: Included were 45 studies (27 randomized controlled trials and 18 prospective cohort studies), 1749 patients (78% were men; mean age, 11.2 years), and 12 different treatment classes. Mast cell stabilizers (MCSs; usually considered as first-line therapy), cyclosporine, and tacrolimus were the most studied drugs (in three-quarters of studies). Overall, all clinical scores improved. Total symptom and sign score decreased for MCSs (effect size, -3.19; 95% CI, -4.26 to -2.13), cyclosporine (effect size, -2.06; 95% CI, -2.72 to -1.40), and tacrolimus (effect size, -2.39; 95% CI, -3.36 to -1.43). No significant differences were shown depending on treatment classes, concentration, age, sex, baseline activity scores, and atopy. Sensitivity analyses demonstrated similar results. CONCLUSIONS: This study confirms the efficacy of MCSs in the treatment of VKC. Efficacy of cyclosporine and tacrolimus did not differ, suggesting that tacrolimus is a good alternative to cyclosporine for severe cases of VKC. Further studies are needed to compare other drugs and their precise place in treatment strategy.

Iatrogenic allergic contact dermatitis in the (peri)anal and genital area.

BACKGROUND: Allergic contact dermatitis (ACD) from topical medication often occurs in occluded areas, for example, with wound treatment, but also in certain body locations, such as the anogenital area. OBJECTIVES: To investigate the demographics and specific lesion location of patients with ACD from topical drugs applied onto the (peri)anal/genital area, and to identify the respective causal topical pharmaceutical products and ingredients involved. METHODS: From January 2000 to December 10, 2018, 532 patients were tested with the baseline series, sometimes with additional series, and the topical medication used along with the ingredients. The relevant data were extracted from our electronic databases developed in-house. RESULTS: Forty-four patients (9%) out of 473 patients suffering from lesions in the (peri)anal/genital area had positive patch test results to topical drug preparations and/or their ingredients, sometimes in association with cosmetics for intimate hygiene. The most frequent sensitizing active principles were local anaesthetics and corticosteroids, while wool alcohols and to a minor extent benzoic acid were the most frequent culprits among the vehicle components and preservative agents, respectively. CONCLUSIONS: The local conditions (eg, occlusion, sweating, moist) in the anogenital area may favour skin sensitization to topical medication used to treat various skin diseases.

Psoriasis patient preferences for topical drugs: a systematic review.

BACKGROUND: Topical drugs are recommended first-line treatment for mild-to-moderate psoriasis. However, patient preferences for the topical drugs differ, since a wide variety of topical drugs and topical drug formulations are available. OBJECTIVES: The aim of this study was to investigate psoriasis patient preferences for topical drugs. METHODS: A systematic literature search was performed for English-language articles in Embase, Medline, PsycINFO, Cinahl, Scopus, and the Cochrane Library. RESULTS: Four surveys, six randomized controlled trials, and two prospective studies of mainly good quality were included. Seven of the studies investigated patient preferences for topical drug formulations, while five studies investigated their preferences for different topical drugs. Overall, patients preferred drugs that are easy to apply, less messy, and have a pleasant scent. CONCLUSION: Psoriasis patient preferences for topical drugs differ. There is no one topical drug or topical drug formulation that suits everyone, which shows the importance of individualized prescriptions for topical drugs that are based on shared decision-making between the prescriber and patient.

Dermatology nurses view on factors related to Danish psoriasis patients' adherence to topical drugs: a focus group study.

BACKGROUND: Topical medications are first-line treatment for mild-to-moderate psoriasis, but adherence is low, which negatively affects patients' outcomes and quality of life. Nurses can play a central role in patient care, particularly in improving adherence. OBJECTIVES: To explore the experience of dermatology nurses with psoriasis patients' adherence to topical drugs. METHODS: We conducted a semi-structured focus group study with 6 dermatology nurses and 2 dermatology nursing students. Participants were recruited from a dermatology hospital outpatient clinic. Data were analyzed by a systematic text condensation method with a phenomenological-hermeneutic approach. RESULTS: Nurses experienced that factors such as social inequality, patient-centered nursing, and patients' quality of life can have an influence on adherence. CONCLUSION: Optimal adherence to topical treatments is a complex exercise and is influenced by many different factors. Involving nurses when prescribing topical treatments may be beneficial since they are one of the most trustworthy professions and have a holistic view on psoriasis severity, patient preferences, health care resources available and socioeconomic factors.

The relationship between the number of available therapeutic options and government payer (medicare part D) spending on topical drug products.

The cost of prescription drugs has increased at rates far exceeding general inflation in recent history, with topical drugs increasing at a disproportionate rate compared to other routes of administration. We assessed the relationship between net changes in the number of therapeutic options, defined as any approved drug or therapeutic equivalent on the market, and prescription topical drug spending. Drugs were divided based on the category of use through pairing of Medicare Part D Prescriber Public Use and Food and Drug Administration (FDA) approved drug products databases. Across drug classes, we modeled the log of the ratio of total spending per unit in 2015 to total spending per unit in 2011 as a linear function of net number of topical therapeutic options over this time period. Primary outcomes include total Medicaid Part D spending on topical drugs and net change in the number of available therapeutic options within each category of use. Total spending on topical drugs increased by 61%, while the number of units dispensed increased by only 18% from 2011-2015. The greatest total spending increases were in categories with few new therapeutic options, such as topical corticosteroid and antifungal medications. Each net additional therapeutic option during 2011-2015 was associated with an reduction in how much relative spending per unit increased (95% CI 2.5%-14.4%, p = 0.013). Stimulating greater competition through increasing the net number of therapeutic options within each major topical category of use may place downward pressure on topical prescription drug spending under medicare Part D.

Effect of 2nd and 3rd generation PAMAM dendrimers on proliferation, differentiation, and pro-inflammatory cytokines in human keratinocytes and fibroblasts.

BACKGROUND: Poly(amidoamine) (PAMAM) dendrimers are of considerable interest when used as a carrier for topical drugs for the skin, although little is known about their possible side effects. Therefore, our study was about the impact of 2nd and 3rd generation PAMAM dendrimers on human keratinocytes and fibroblasts cells. METHODS: The effect of the tested compounds on collagen biosynthesis was determined using 5[3H]-proline incorporation bioassay. Morphological changes accompanying cell growth inhibition were observed using a confocal microscope. To evaluate the percentage of apoptotic/necrotic cells and the cell growth dynamic of apoptotic features, we performed Annexin V/PI double staining assay, assessed caspase activity, and performed cell cycle analysis by flow cytometry. The flow cytometry method was also used to determine the effect of dendrimers on pro-inflammatory cytokines (IL-6, IL-8 IL-1ß). RESULTS: The obtained results showed that as the concentration and the generation of dendrimers increased, collagen biosynthesis decreased. We also observed abnormalities in cell differentiation, which may have caused disturbed secretion of pro-inflammatory cytokines. We found that dendrimers cause chronic inflammation which may cause adverse changes in the skin, ultimately- leading to apoptosis in the case of dendrimers in lower concentrations or necrosis at higher concentrations (especially 3rd generation dendrimers). In addition, the inflammatory path induced by the tested compounds was caused by damage in the mitochondria, which we observed as a significant decrease in the mitochondrial membrane potential. CONCLUSION: The results of our study showed that PAMAM dendrimers can cause disorders of cell proliferation and differentiation and may be the cause of cell cycle deregulation and chronic adverse inflammation.

Nonsurgical Options for the Treatment of Basal Cell Carcinoma.

OBJECTIVES: The aim of this review article is to summarize the effectiveness, potential adverse events, and indications of the main nonsurgical treatment alternatives for basal cell carcinoma. METHODS: An extensive literature review was carried out. The most relevant articles were discussed and selected by the authors in order to provide a brief but evidence-based overview of the most common nonsurgical methods used for treating basal cell carcinoma. RESULTS: Although surgery and Mohs micrographic surgery are often considered the optimal treatment options for basal cell carcinoma, these tumors can also be treated successfully with destructive techniques (eg, curettage alone, cryosurgery, or electrodesiccation), photodynamic therapy, topical drugs (eg, 5-fluorouracil, imiquimod, or ingenol mebutate), radiotherapy, or hedgehog pathway inhibitors. When choosing between these alternatives, physicians must take into consideration the tumor's size, location, and histopathological subtype. Special care should be taken when treating recurrent tumors. Furthermore, physician experience is of great importance when using destructive techniques. Finally, patient preference, potential adverse events, and cosmetic outcome should also be considered. CONCLUSIONS: Dermatologists and physicians treating basal cell carcinoma should have knowledge of and experience with the large arsenal of therapeutic alternatives available for the successful, safe, and individualized management of patients with basal cell carcinoma.

Dry eye disease immune responses and topical therapy.

There is accumulating evidence that inflammation is one of the key components of dry eye because chronic ocular surface inflammation can be both a result as well as an initiator of dry eye. The need for continuing anti-inflammatory therapy may be determined in part by the extent that non-modifiable factors such as gender and age-related aqueous or lipid or mucus production deficiencies contribute to its chronicity. This perspective examines how the need for increased dosage of a topical anti-inflammatory drug may be determined by the degree of difficulty that a topically administered drug has in accessing different sites of tear deficiency and associated inflammation.

Allergic contact dermatitis caused by topical ophthalmic medications: Keep an eye on it!

BACKGROUND: Allergic contact dermatitis (ACD) caused by topical ophthalmic medications is often overlooked. OBJECTIVES: To study the demographic characteristics, lesion locations and associated medical conditions of the patients with ACD caused by ophthalmic drugs, and to identify the most common allergenic culprits, as well as trends in frequencies over the years. METHODS: From January 1990 until December 2016, 16 065 patients were investigated in our clinic; all patients with a positive patch test reaction to an eye medication or its ingredient(s) having caused ACD were assessed. For each allergen identified, the number of positive test results as compared with the total number of those in the total population, as well as trends across three periods, namely 1990 to 1998, 1999 to 2007, and 2008 to 2016, were studied. RESULTS: One hundred and eighteen patients (0.7%) presented with positive patch test reactions to ingredients of and/or topical ophthalmic medications. Aminoglycoside antibiotics, followed by corticosteroids, as pharmacologically active ingredients, as well as wool alcohols, thiomersal, and benzalkonium chloride, as excipients, were the most frequent culprits. Chloramphenicol showed a decreasing trend of positive reactions over time, whereas reactions to tobramycin increased. CONCLUSION: ACD caused by eye medication is mainly attributable to active principles, but other excipient ingredients, beside the products "as is," should be tested as well.

Transdermal and Topical Drug Administration in the Treatment of Pain.

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients' age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non-steroidal anti-inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti-inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes.

Allergic contact dermatitis caused by topical herbal remedies: importance of patch testing with the patients' own products.

BACKGROUND: Natural ingredients have variable compositions, so their allergenic potencies may differ. OBJECTIVES: To retrospectively analyse subjects reacting to herbal remedies over the past 27 years, with the aim of (i) evaluating demographic characteristics and lesion locations, (ii) describing the frequencies of positive patch test reactions, (iii) identifing sensitization sources, and (iv) studying concomitant sensitivity. PATIENTS AND METHODS: In total, 15980 patients were patch tested between 1990 and 2016 with the European baseline series and/or other series, product(s) used, and, whenever possible, the respective ingredients. RESULTS: Altogether, 8942 (56%) of 15 980 patients presented with at least one positive reaction. Reactions to topical herbal medicines, most often applied to treat an eczematous condition, leg ulcers, or other wounds, were seen in 125 (0.8%), that is, 1.4% of the contact-allergic subjects. Hands, legs and feet were the most frequently affected body sites. Twenty-one botanical allergens were identified, the commonest being Myroxylon pereirae (balsam of Peru), Compositae plants, and tincture of benzoin. Many patients presented with multiple positive test reactions, and some did not react to the commercial allergens but only to the products used. CONCLUSIONS: Topical herbal remedies should not be applied on damaged skin, as multiple sensitization may develop. Moreover, patch testing with the culprit products is important for the diagnosis.