Determination of Oxaliplatin by a UHPLC-MS/MS Method: Application to Pharmacokinetics and Tongue Tissue Distribution Studies in Rats

Oxaliplatin (OXP), a third-generation platinum-based chemotherapy drug, was often indirectly analyzed via total platinum by an ICP-MS because it was difficult to directly quantify using an LC-MS/MS method, due to its instability, bad column separability and severe MS signal inhibition. Here, we developed and validated a specific, sensitive and reproducible LC-MS/MS method for the quantification of OXP itself in rat plasma and tongue tissue on a SCIEX 4000 QTRAP® MS/MS system equipped with a Phenomenex Lux 5u Cellulose-1 column (250 × 4.6 mm, 5 μm). This method was validated at the lower limit of detection (LOD) and the lower limit of quantitation (LLOQ) of 5 ng/mL and 10 ng/mL, with linearity of 10–5000 ng/mL (r2 > 0.99) and 10–2500 ng/mL (r2 > 0.99), in rat plasma and tongue homogenates, respectively. The intra- and inter-day precision (CV%) and accuracy (RE%) were within 15% for LLOQ, low-, medium- and high-quality control samples. The mean extraction recoveries were around 50% and 80% for plasma and tongue homogenates, respectively. This assay was successfully applied to pharmacokinetics study following intravenous administration of OXP, as well as tongue tissue distribution after 1 h and 4 h of a novel oral mucosal patch application.

Pharmacokinetic Profile of Fentanyl in the Koala (Phascolarctos cinereus) after Intravenous Administration, and Absorption via a Transdermal Patch

Fentanyl was administered as a single intravenous bolus injection at 5 µg/kg to five koalas and fentanyl plasma concentrations for a minimum of 2 h were quantified by an enzyme-linked immunosorbent assay (ELISA). The median (range) fentanyl elimination half-life and clearance were 0.53 (0.38–0.91) h, and 10.01 (7.03–11.69) L/kg/h, respectively. Assuming an analgesic therapeutic plasma concentration of 0.23 ng/mL (extrapolated from human studies), an intravenous constant infusion rate was estimated at approximately between 1.7 to 2.7 µg/kg/h (using the clearance 95% confidence intervals). A transdermal fentanyl patch was applied to the antebrachium of an additional two koalas for 72 h. Fentanyl plasma concentrations were determined during the patch application and after patch removal at 80 h. The fentanyl plasma concentration was greater than 0.23 ng/mL after 12 to 16 h. While the patch was applied, the maximum fentanyl concentration was approximately 0.7 ng/mL from 32 to 72 h. Fentanyl plasma concentrations increased to 0.89 ng/mL 1 h after the patch was removed, and then decreased to a mean of 0.47 ng/mL at 80 h. The transdermal fentanyl patch is likely to provide some level of analgesia but should be initially co-administered with another faster acting analgesic for the first 12 h.

Engineered properties of polyurethane laden with beetroot and cerium oxide for cardiac patch application

The cardiac patch provides appropriate physicochemical properties and mechanical strength for the regeneration of damaged heart tissues. In this work, for the first-time, beetroot (BR) is blended with cerium oxide (CeO2) to produce nanofibrous polyurethane (PU) composite patch using electrospinning. The objective of this work is to fabricate the composite and examine its feasibility for cardiac patch applications. Morphological analysis revealed a dramatic reduction of fiber diameter of PU/BR (233 ± 175 nm) and PU/BR/CeO2 (331 ± 176 mm) compared to the pristine PU (994 ± 113 mm). Fourier transform infrared analysis (FTIR) analysis indicated functional peak intensities of the newly formed composite PU/BR and PU/BR/CeO2 were not similar to PU. The addition of beetroot rendered PU/BR hydrophilic (86° ± 2), whereas PU/BR/CeO2exhibited hydrophobic nature (99° ± 3). Atomic force microscopy (AFM) analysis depicted the reduced surface roughness of the PU/BR (312 ± 12 nm) and PU/BR/CeO2 (390 ± 125 nm) than the pristine PU (854 ± 32 nm). The incorporation of beetroot and CeO2 into PU enhanced the tensile strength compared with the pristine PU. The blood clotting time of PU/BR (APTT-204 ± 3 s and PT-103 ± 2 s) and PU/BR/CeO2 (APTT-205 ± 3 s and PT-105 ± 2s) were delayed significantly than the pristine PU(APTT-176 ± 2 s and PT-94 ± 2 s) as revealed in the coagulation study. Further, hemolysis assay showed the less toxic nature of the fabricated composites than the pristine PU. Hence, it can be inferred that the advanced physicochemical and blood compatible properties of electrospun PU/BR and PU/BR/CeO2 nanocomposite can be engineered successfully for cardiac patch applications.

Capsaicin 8% Patch and Chronic Postsurgical Neuropathic Pain

(1) Background: Surgery is a frequent cause of persistent pain, defined chronic post-surgical pain (CPSP). The capsaicin 8% patch (Qutenza®) is approved for the treatment of postherpetic neuralgia (PHN) and for diabetic peripheral neuropathy (DPN) of the feet. We propose a review of the literature on use of the capsaicin 8% patch to treat neuropathic pain associated with surgery; (2) Methods: We identified the articles by searching electronic databases using a combination of such terms as “capsaicin 8% patch”, “Qutenza®”, and “chronic postsurgical pain”; (3) Results: We identified 14 selected studies reporting on a total of 632 CPSP cases treated with capsaicin 8% patch. Treatment with the capsaicin 8% patch significantly reduced the average pain intensity. Only 5 studies reported adverse events (AEs) after the patch application. The most common AEs were erythema, burning sensation and pain; (4) Conclusions: Our review indicate that capsaicin 8% patch treatment for CPSP is effective, safe and well tolerated, but randomized controlled trials on efficacy, safety and tolerability should be conducted.

Pharmacokinetic Model Analysis of Supralingual, Oral and Intravenous Deliveries of Mycophenolic Acid

Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch. The objective of this study was to establish the pharmacokinetic (PK) and tongue tissue distribution of mucoadhesive MPA patch formulation after supralingual administration in rats and also compare the PK differences between oral, intravenous, and supralingual administration of MPA. Blood samples were collected from Sprague Dawley rats before and after a single intravenous bolus injection, a single oral dose, or a mucoadhesive patch administration on the dorsal tongue surface for 4 h, all with a dose of 0.5 mg/kg of MPA. Plots of MPA plasma concentration versus time were obtained. As multiple peaks were found in all three curves, the enterohepatic recycling (EHR) model in the Phoenix software was adapted to describe their PK parameters with an individual PK analysis method. The mean half-lives of intravenous and oral administrations were 10.5 h and 7.4 h, respectively. The estimated bioavailability after oral and supralingual administration was 72.4% and 7.6%, respectively. There was a 0.5 h lag-time presented after supralingual administration. The results suggest that the systemic plasma MPA concentrations were much lower in rats receiving supralingual administration compared to those receiving doses from the other two routes, and the amount of MPA accumulated in the tongue after patch application showed a sustained drug release pattern. Studies on the dynamic of drug retention in the tongue after supralingual administration showed that ~3.8% of the dose was accumulated inside of tongue right after the patch removal, ~0.11% of the dose remained after 20 h, and ~20.6% of MPA was not released from the patches 4 h after application. The data demonstrate that supralingual application of an MPA patch can deliver a high amount of drug at the site of administration with little systemic circulation exposure, hence lowering the potential gastrointestinal side effects associated with oral administration. Thus, supralingual administration is a potential alternative route for treating oral lesions.

Reinforcement of rectal anastomoses with a collagen-based haemostatic patch: a case series report

In this case series report of 10 colorectal cancer patients, a polyethylene glycol-coated collagen-based haemostatic patch was applied after rectal resection to reinforce rectal anastomoses and reduce anastomotic leakage. Patients underwent rectal resection and anastomoses were stapled in place. The patch—Hemopatch®—was applied to 75% of the anastomotic circumference. The surgeon judged the simplicity of application using a reinforcement of rectal anastomosis score. Mean age of patients was 68.1 (range 50–94) years. The patch was successfully applied in eight patients; in seven patients, patch application was straightforward or only slightly complex, according to the reinforcement of rectal anastomosis score. Seven of eight patients experienced no leakage or signs of stricture 6 weeks post-surgery. All patients underwent radical resection. It is possible to apply Hemopatch® during colorectal surgery. However, the patch application procedure needs to be standardized and efficacy needs to be evaluated by conducting larger clinical studies.

Pre-Existing Humoral Immunity Enhances Epicutaneously-Administered Allergen Capture by Skin DC and Their Migration to Local Lymph Nodes

Due to its richness in antigen presenting cells, e.g., dendritic cells (DC), the skin has been identified as a promising route for immunotherapy and vaccination. Several years ago, a skin delivery system was developed based on epicutaneous patches allowing the administration of antigen through intact skin. Using mouse models, we have shown that epicutaneous allergen application leads to a rapid uptake and transport of allergen-positive cells to skin-draining lymph nodes (LN). This occurred primarily in animals previously sensitized to the same allergen. In that context, we sought to better understand the role of the specific preexisting immunity in allergen capture by skin DC and their subsequent migration to LN. Specifically, we investigated the role of humoral immunity induced by sensitization and the involvement of IgG Fc receptors (FcγR). Epicutaneous patches containing fluorescently-labeled ovalbumin (OVA) were applied to naïve mice that had previously received either sera or purified IgG isolated from OVA-sensitized mice. To investigate the involvement of FcγR, animals received 2.4G2 (anti-FcγRII/RIII) blocking antibody, 24 hours before patch application. Mice that received sera or purified IgG originating from OVA-sensitized mice showed an increase in the quantity of OVA-positive DC in skin and LN. Moreover, the blockade of FcγR reduced the number of OVA-positive DC in LN to a level similar to that observed in naïve animals. Overall, these results demonstrate that preexisting specific-IgG antibodies are involved in allergen capture by skin DC following EPIT through the involvement of antigen-specific IgG-FcγR.