Half-dose glucarpidase as efficient rescue for toxic methotrexate levels in patients with acute kidney injury.

PURPOSE: High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels. METHODS: Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17-32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography-mass spectrometry (LC-MS). Toxicities were assessed according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80-455%) and showed toxic MTX plasma concentrations (range 3.1-182.4 µmol/L) before glucarpidase injection. The drug was administered 42-70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02-2.03 µmol/L. MTX rebound was detected in plasma 42-73 h after glucarpidase initiation, but concentrations remained consistent at < 10 µmol/L. CONCLUSION: Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue.

Treatment of Pegylated Asparaginase-Induced Hypertriglyceridemia with Continuous Intravenous Infusion of Insulin and Heparin: A Case Report.

BACKGROUND: Pegylated asparaginase may induce prolonged hypertriglyceridemia. To date, there is no standard management of this complication. Here, we present a case report of pegylated asparaginase-induced hypertriglyceridemia and hepatotoxicity successfully treated with continuous intravenous infusion of insulin and heparin. CASE PRESENTATION: A 51-year-old male patient with lymphoid blast crisis of chronic myelogenous leukemia was treated with pegylated asparaginase. The patient developed severe hypertriglyceridemia. Supportive therapy with low-fat diet, fibric acids, and omega-3 fatty acids was not successful, and later, the patient developed high-grade hepatotoxicity. Like hypertriglyceridemia-induced pancreatitis, continuous intravenous infusion of insulin and heparin was initiated. The level of triglyceride and cholesterol decreased rapidly within 4 days. CONCLUSION: In case of severe pegylated asparaginase-induced hypertriglyceridemia, continuous intravenous infusion of insulin and heparin can reduce rapidly and safely the triglyceride level. Controlled trials are needed to address this important issue.

Dermal and transdermal targeting of dihydroavenanthramide D using enhancer molecules and novel microemulsions.

Specific accumulation of drugs in certain skin layers or in the blood circulation is the aim of (trans-)dermal targeting. As demonstrated previously, high dermal concentrations of the model drug dihydroavenanthramide D can be reached by the addition of 1,2-alkanediols as penetration enhancer to a conventional o/w cream. The focus of the present study is on an increased permeation by the choice of a modern colloidal drug carrier. Microemulsions based on a vegetable protein surfactant and 1,2-alkanediols as co-surfactant were developed. The respective pseudoternary phase diagrams revealed an increasing area of the optical isotropic phase with increasing chain length of the glycol (C3-C4-C5). Pentylene glycol-containing systems were characterized by electrical conductivity and differential scanning calorimetry indicating the presence of water-continuous microemulsions. Two selected formulations containing pentylene glycol and propylene glycol, respectively, were further investigated by TEM, conductivity, viscosity, and temperature stability. In the subsequently performed Franz type diffusion studies using full thickness human skin dihydroavenanthramide D was applied as model drug. Both formulations showed sufficient penetration into viable skin layers and particularly high permeation rates. Compared to the previously investigated glycol-containing cream, the microemulsions revealed a smaller fraction of the model drug within viable epidermis and dermis, but a strongly increased amount in the acceptor solution. Therefore, the formulations might find different application areas depending on needs concerning localization, beginning and duration of the drug effect.

Modulation of dihydroavenanthramide D release and skin penetration by 1,2-alkanediols.

If a semisolid vehicle does not allow for the sufficient penetration of the incorporated drug, the addition of enhancers, e.g. glycols, is an option. Propylene glycol is most frequently applied in dermal products. Other 1,2-alkanediols like pentylene glycol were found to exhibit moisturizing effects and good anti-microbial activity. In the present study, the influence of propylene glycol and mainly butylene glycol (BuG) and pentylene glycol (PeG) on release and skin penetration of Dihydroavenanthramide D (DHAvD) was investigated. DHAvD release increased twice up to fourfold within 30 min if 2% of a mixture of BuG and PeG was added to a lipophilic as well as to a hydrophilic cream. Incorporation of single 1,2-alkanediols into the hydrophilic cream resulted in a linear slope of the released DHAvD amount with increasing chain length of the glycol. Trends found in the release model were also reflected in penetration studies on full thickness human breast skin using Franz diffusion cells. Here, the hydrophilic cream containing the BuG/PeG mixture was compared to the glycol-free reference. Already within 30 min the amount that penetrated into the viable skin layers doubled using the glycol-containing vehicle. After 300 min 12% of the applied dose was detected in the viable epidermis and dermis following application of the pure cream compared to 41% from the improved formulation. Dermal availability was further enhanced by administration of a polymer-stabilized hydrodispersion gel which also contained the glycol mixture. Due to their favorable biopharmaceutical and technological properties, longer chain 1,2-alkanediols represent a valuable class of ingredients for dermal products.

Microemulsions--modern colloidal carrier for dermal and transdermal drug delivery.

Microemulsions are modern colloidal drug carrier systems. They form spontaneously combining appropriate amounts of a lipophilic and a hydrophilic ingredient, as well as a surfactant and a co-surfactant. Due to their special features, microemulsions offer several advantages for pharmaceutical use, such as ease of preparation, long-term stability, high solubilization capacity for hydrophilic and lipophilic drugs, and improved drug delivery. The article summarizes the level of research with respect to dermal and transdermal application. A large number of in vitro as well as some in vivo studies demonstrated that drugs incorporated into microemulsions penetrate efficiently into the skin. The enhancing activity seems to be attributable to a variety of factors depending on the composition and the resulting microstructure of the formulations. However, an extended use in practice depends on the choice of well-tolerated ingredients, mainly surfactants, and the restriction of their amounts in order to guarantee skin compatibility.

Comparison of stratum corneum penetration and localization of a lipophilic model drug applied in an o/w microemulsion and an amphiphilic cream.

Vehicle dependent effects on the penetration behavior of drugs following topical application are well known from the literature. In this context, many reports concerning the enhancing activities for hydrophilic as well as lipophilic substances by colloidal drug carrier systems, particularly microemulsions, are available. However, there is little knowledge about the localization of the drugs within the skin and the stratum corneum, respectively. In the present study, the lipophilic dye curcumin incorporated in an oil-in-water microemulsion and in an amphiphilic cream was applied onto the skin of human volunteers. Using the method of tape stripping to remove the stratum corneum (SC), the depth profiles of the dye within the horny layer were compared. Applying the microemulsion, a deeper part of the SC was accessible by a number of 20 tapes removed and significantly smaller amounts of curcumin were found on the skin surface. Also differences in the distribution and localization of the dye within the stratum corneum were observed by laser scanning microscopy. Furthermore, curcumin was detected in hair follicles. It was obvious that the microemulsion led to a penetration into the complete follicular infundibula, whereas, following application of the cream, a fluorescence signal was only received from the follicular orifices.