Delayed Skin Testing for Systemic Medications: Helpful or Not?

Cutaneous adverse drug reactions collectively are delayed drug reactions such as morbilliform drug eruption and severe cutaneous adverse reactions (SCARs). Morbilliform drug eruption may wane over time, be the result of drug viral interactions, and be amenable to slow reintroduction or rechallenge, whereas SCARs are HLA class I restricted, T-cell-mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCARs such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality, and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCARs such as ex vivo or in vitro testing, in vivo (skin) testing, or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review" article, we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions.

Key Transdermal Patch Using Cannabidiol-Loaded Nanocarriers with Better Pharmacokinetics in vivo.

Purpose: Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes. Methods: A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications. Results: In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application. Conclusion: CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.

In Situ Patch Test and Repeated Open Application Test for Fixed Drug Eruption: A Multicenter Study.

BACKGROUND: Few studies have evaluated allergy workup in fixed drug eruption (FDE) in a large population. OBJECTIVE: To evaluate the sensitivity of a standardized allergy workup for diagnosing the cause of FDE, with a focus on in situ repeated open application tests (ROATs). METHODS: In a retrospective multicenter study, we analyzed the practice of conducting a complete allergy workup for the etiological diagnosis of FDE. It consisted of 3 steps: in situ patch tests (PTs) for all cases except pure mucosal involvement, followed by in situ ROAT if in situ PT results were negative, and finally a drug challenge (DC). The in situ ROAT involved daily application of the suspected drug on a previously affected FDE site for 7 days. RESULTS: Of 98 suspected FDE cases, 61 patients (median age 61 y; male-to-female ratio 1.8) with a complete allergy workup were included. In 4 cases, even the DC yielded negative results. Among the remaining 57 patients with a positive workup, implicated drugs included paracetamol (12 cases), ß-lactams (11 cases), imidazoles (9 cases, including 5 with metronidazole), nonsteroidal anti-inflammatory drugs (8 cases), iodinated contrast media (4 cases), cotrimoxazole (3 cases), and various other drugs in 10 patients. The diagnosis was confirmed by in situ PT in 17 of 54 cases (31.5%), in situ ROAT in 14 of 40 cases (35%) (with 4 cases showing remote reactivation of FDE sites), and DC in 26 cases. CONCLUSIONS: The sequential allergy workup involving successively in situ PT, in situ ROAT, and DC is a reliable and safe method for diagnosing the cause of FDE. In situ tests exhibited a sensitivity of over 50%.

Saline Vehicle Increases the Ability of Drug Patch Test in Cutaneous Adverse Drug Reactions.

BACKGROUND: Drug patch test to identify cutaneous adverse drug reactions (CADRs) has been widely reported. Appropriate vehicles can improve the ability of drug delivery and significantly increase positive reaction of drug patch tests. OBJECTIVE: The aim of this study was to evaluate the efficacy of drug patch tests using 0.9% saline vehicle in comparison with other traditional vehicles in CADRs. METHOD: All patients were patch tested with suspected drugs using 10-30% concentration of the commercialized form of drugs diluted in 0.9% saline, petrolatum, and water. RESULT: Of 100 patients with CADRs, 54 of those had at least one positive drug patch test. In terms of vehicles used, 43 patients had positive drug patch test with saline as compared to 35 with water (p = 0.485) and 25 with petrolatum (p = 0.007). Among CADRs subgroup, saline rendered significantly higher positive rate when compared with petrolatum in drug rash with eosinophilia and systemic symptom (DRESS) (70% vs. 20%, p = 0.025), maculopapular rash (MP) (52.4% vs. 31%, p = 0.046), and lichenoid drug eruption (46.7% vs. 0.0%, p = 0.002). 12/54 (22.2%) of CADRs patients had positive reaction with saline alone. Among these patients, 4/12 (33.3%) were lichenoid drug reaction, 3/12 (25%) were DRESS, and 2/12 (16.7%) were MP rash. Allopurinol was the drug giving positive patch test only with saline. CONCLUSION: Appropriate vehicles are essential to obtain the positive drug patch test. Using saline as a vehicle can increase the positive reaction of drug patch test, particularly in lichenoid drug eruption. We recommend the use of saline as another traditional vehicle in drug patch test.

Utility and Safety of Skin Tests in Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS): A Systematic Review.

BACKGROUND: Determination of culprit drug in drug reaction with eosinophilia and systemic symptoms (DRESS) is crucial. Skin tests have been used, although it remains unclear how sensitive these are. OBJECTIVE: To determine the value of skin tests in the assessment of drug causality in DRESS. METHODS: A systematic literature search was conducted for publications from 1996 onward of skin tests (skin prick test = SPT, patch test = PT, intradermal test = IDT) performed in clearly defined DRESS cases. Outcomes of testing, drug culpability assessments, and challenge test data were extracted. RESULTS: A total of 17 articles met inclusion criteria. In 290 patients with DRESS, patch testing was most frequent (PT = 97.2% [n = 282], IDT = 12.4% [n = 36], SPT = 3.1% [n = 9]). Positive results were noted in 58.4% (n = 160 of 282) of PTs, 66.5% of IDTs, and 25% of SPTs. When confidence of drug causality was high (n = 73 of 194), testing did not correlate well with clinical suspicion: PTs, 37.6%; IDTs, 36.5%. Direct comparison of skin testing with provocation testing (n = 12) showed 83.3% correlation. Positive IDT results were reported in 8 negative PT cases. CONCLUSIONS: Skin tests, particularly PTs and IDTs, have been reported as tools for diagnosis of causal drugs in DRESS. Heterogeneity in methodology, results analysis, and reporting of cohorts make meta-analysis to determine sensitivity and specificity of published literature impossible and highlight weaknesses in the field. We propose that international collaboration is essential to harmonize the methodology and reporting measures from hypersensitivity testing studies in larger cohorts.

5-Fluorouracil-Immobilized Hyaluronic Acid Hydrogel Arrays on an Electrospun Bilayer Membrane as a Drug Patch.

The hyaluronic acid (HA) hydrogel array was employed for immobilization of 5-fluorouracil (5-FU), and the electrospun bilayer (hydrophilic: polyurethane/pluronic F-127 and hydrophobic: polyurethane) membrane was used to support the HA hydrogel array as a patch. To visualize the drug propagating phenomenon into tissues, we experimentally investigated how FITC-BSA diffused into the tissue by applying hydrogel patches to porcine tissue samples. The diffusive phenomenon basically depends on the FITC-BSA diffusion coefficient in the hydrogel, and the degree of diffusion of FITC-BSA may be affected by the concentration of HA hydrogel, which demonstrates that the high density of HA hydrogel inhibits the diffusive FITC-BSA migration toward the low concentration region. YD-10B cells were employed to investigate the release of 5-FU from the HA array on the bilayer membrane. In the control group, YD-10B cell viability was over 98% after 3 days. However, in the 5-FU-immobilized HA hydrogel array, most of the YD-10B cells were not attached to the bilayer membrane used as a scaffold. These results suggest that 5-FU was locally released and initiated the death of the YD-10B cells. Our results show that 5-FU immobilized on HA arrays significantly reduces YD-10B cell adhesion and proliferation, affecting cells even early in the cell culture. Our results suggest that when 5-FU is immobilized in the HA hydrogel array on the bilayer membrane as a drug patch, it is possible to control the drug concentration, to release it continuously, and that the patch can be applied locally to the targeted tumor site and administer the drug in a time-stable manner. Therefore, the developed bilayer membrane-based HA hydrogel array patch can be considered for sustained release of the drug in biomedical applications.

Patch testing and cross sensitivity study of adverse cutaneous drug reactions due to anticonvulsants: A preliminary report.

AIM: To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions (ACDR) from common anticonvulsants. METHODS: Twenty-four (M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. RESULTS: Clinical patterns were exanthematous drug rash with or without systemic involvement (DRESS) in 18 (75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis (SJS/TEN) overlap and TEN in 2 (8.3%) patients each, SJS and lichenoid drug eruption in 1 (4.2%) patient each, respectively. The implicated drugs were phenytoin in 14 (58.3%), carbamazepine in 9 (37.5%), phenobarbitone in 2 (8.3%), and lamotrigine in 1 (4.7%) patients, respectively. Twelve (50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6 (50%), phenytoin alone in 4 (33.3%), phenobarbitone alone in 1 (8.3%), and both phenytoin and phenobarbitone in 1 (8.33%) patients, respectively. Cross-reactions occurred in 11 (92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three (75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. CONCLUSION: Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically.

AC electrokinetic drug delivery in dentistry using an interdigitated electrode assembly powered by inductive coupling.

AC electrokinetics (ACEK) has been shown to deliver certain drugs into human teeth more effectively than diffusion. However, using electrical wires to power intraoral ACEK devices poses risks to patients. The study demonstrates a novel interdigitated electrode arrays (IDE) assembly powered by inductive coupling to induce ACEK effects at appropriate frequencies to motivate drugs wirelessly. A signal generator produces the modulating signal, which multiplies with the carrier signal to produce the amplitude modulated (AM) signal. The AM signal goes through the inductive link to appear on the secondary coil, then rectified and filtered to dispose of its carrier signal, and the positive half of the modulating signal appears on the load. After characterizing the device, the device is validated under light microscopy by motivating carboxylate-modified microspheres, tetracycline, acetaminophen, benzocaine, lidocaine and carbamide peroxide particles with induced ACEK effects. The assembly is finally tested in a common dental bleaching application. After applying 35 % carbamide peroxide to human teeth topically or with the IDE at 1200 Hz, 5 Vpp for 20 min, spectrophotometric analysis showed that compared to diffusion, the IDE enhanced whitening in specular optic and specular optic excluded modes by 215 % and 194 % respectively. Carbamide peroxide absorbance by the ACEK group was two times greater than diffusion as measured by colorimetric oxidation-reduction and UV-Vis spectroscopy at 550 nm. The device motivates drugs of variable molecular weight and structure wirelessly. Wireless transport of drugs to intraoral targets under ACEK effects may potentially improve the efficacy and safety of drug delivery in dentistry.

Non-irritant concentrations and amounts of active ingredient in drug patch tests.

BACKGROUND: Drug patch tests (DPTs) with medicaments suspected of causing an allergic reaction represent a method of diagnostic testing that is low risk; DPTs can reproduce delayed hypersensitivity to drugs, and entail only a moderate re-exposure of patients to potential offending drugs. We assessed the non-irritating concentrations of DPTs and determined the amounts of active ingredient (AI) contained in the drugs used in the tests. OBJECTIVES: The objectives were to assess the non-irritating concentration of DPTs and determine the amounts of active ingredient (AI) contained in the drugs used in the tests. METHODS: From a retrospective, single-centre study of all patients investigated during a 6-year period with a drug eruption, each potentially responsible drug was tested with the commercially available preparation diluted to 30% in water, petrolatum, or alcohol. Data collection was performed with a customized computer database. For each type of DPT studied, the numbers of positive and negative test results were recorded. The amount of AI contained in the DPT (as a percentage) was then calculated after weighing of each tablet. RESULTS: Of the 5558 DPTs studied, all were non-irritant. The average concentration of AI was 9.8%; 25% of DPTs had an AI concentration of < 2%, and 25% had an AI concentration of > 16%. The AI concentration ranged from 0.05% (digoxin) to 30% (paracetamol lyophilisate). CONCLUSION: These data provide thresholds for the non-irritating concentration of AI of 68 different drugs, and thresholds for the non-irritating dilution for 82 drugs, and will help to standardize DPT methods.