High Levels of Tetrodotoxin in the Flesh, Usually an Edible Part of the Pufferfish Takifugu flavipterus, Caused by Migration from the Skin and the Regional Characteristics of Toxin Accumulation

The consumption of a pufferfish, Takifugu flavipterus or komonfugu in Japanese, formerly known as Takifugu poecilonotus, is popular in Japan. However, T. flavipterus is frequently involved in cases of tetrodotoxin (TTX) poisoning in Japan. Although victims have usually consumed inedible parts, some cases are related to consumption of flesh. To improve the risk management of pufferfish poisoning, we studied TTX level in the flesh and skin of T. flavipterus. Ninety-seven specimens obtained from the Seto Inland Sea and landed in Fukuoka Prefecture were analyzed by liquid chromatography-tandem mass spectrometry. The flesh from six specimens was toxic (>10 MU/g = 2.2 mg/kg): one was in poor condition (not freeze–thawed); three were freeze–thawed before sample preparation; and two freshly prepared and in good condition (not freeze–thawed). The fillets were divided into outer and inner portions; the TTX levels in the outer portions were notably higher. The skin of the six specimens was moderately to extremely toxic: 165 MU/g (36.3 mg/kg) in the fresh specimen not in good condition, 600–950 MU/g (132–200 mg/kg) in freeze–thawed specimens, and 4500 and 6000 MU/g (990 and 1320 mg/kg) in the two fresh specimens. We concluded that TTX in the flesh migrated from the highly toxic skin. In addition, TTX levels in the skin appeared to be regionally specific. We recommend that toxic portions of T. flavipterus are removed as soon as possible after individuals are caught, and that fish from known highly toxic areas are not consumed.

Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers

Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.

Cutaneous toxic effects of targeted therapy: clinical manifestations and correction

Targeted therapy used in oncology today is the most effective, but frequent cutaneous side effects force to reduce dose or interrupt treatment, significantly reducing the anti-tumor effect. The data on the pathogenesis of toxic skin reactions and the most frequent clinical manifestations (papular-pustular reaction, hand-foot syndrome) according to various studies are presented. The basic principles of correction are described. Examples of anticancer drug doses correlation and severity of skin reactions are presented.

Highly efficient and low toxic skin penetrants composed of amino acid ionic liquids

Herein, we introduce an amino acid ester (AAE) as a potent biocompatible counter ion to formulate ionic liquefied active pharmaceutical ingredients.