The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have a...

https://www.tandfonline.com/doi/pdf/10.1080/10717540500455975

Dermal and transdermal drug delivery systems: Current and future prospects

Terpenoids comprise tens of thousands of small molecule natural products that are widely distributed across all domains of life. Plants produce by far the largest array of terpenoids with various roles in development and chemical ecology. Driven by selective pressure to adapt to their specific ecological niche, individual species form only a fraction of the myriad plant terpenoids, typically representing unique metabolite blends. Terpene synthase (TPS) enzymes are the gatekeepers in generating terpenoid diversity by catalyzing complex carbocation-driven cyclization, rearrangement, and elimination reactions that enable the transformation of a few acyclic prenyl diphosphate substrates into a vast chemical library of hydrocarbon and, for a few enzymes, oxygenated terpene scaffolds. The seven currently defined clades (a-h) forming the plant TPS family evolved from ancestral triterpene synthase- and prenyl transferase-type enzymes through repeated events of gene duplication and subsequent loss, gain, or fusion of protein domains and further functional diversification. Lineage-specific expansion of these TPS clades led to variable family sizes that may range from a single TPS gene to families of more than 100 members that may further function as part of modular metabolic networks to maximize the number of possible products. Accompanying gene family expansion, the TPS family shows a profound functional plasticity, where minor active site alterations can dramatically impact product outcome, thus enabling the emergence of new functions with minimal investment in evolving new enzymes. This article reviews current knowledge on the functional diversity and molecular evolution of the plant TPS family that underlies the chemical diversity of bioactive terpenoids across the plant kingdom.

/pdf/terpene-synthases-as-metabolic-gatekeepers-in-the-evolution-1xk9bw6bry.pdf

Terpene Synthases as Metabolic Gatekeepers in the Evolution of Plant Terpenoid Chemical Diversity.

Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.

/pdf/trials-and-tribulations-of-skin-iontophoresis-in-4ij8rsecmi.pdf

Trials and tribulations of skin iontophoresis in therapeutics

There is considerable interest in the skin as a site of drug application for both local and systemic effect. However, the skin, in particular the stratum corneum, possesses a formidable barrier to drug penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and to increase the range of drugs for which topical and transdermal delivery is a viable option. The permeation of drug through skin can be enhanced by both chemical penetration enhancement and physical methods. In this review, we have discussed the physical and chemical penetration enhancement technology for transdermal drug delivery as well as the probable mechanisms of action.

Physical and chemical penetration enhancers in transdermal drug delivery system

Summary
Tripterygium wilfordii (Celastraceae) is a medicinal plant with anti-inflammatory and immunosuppressive properties. Identification of a vast array of unusual sesquiterpenoids, diterpenoids and triterpenoids in T. wilfordii has spurred investigations of their pharmacological properties. The tri-epoxide lactone triptolide was the first of many diterpenoids identified, attracting interest due to the spectrum of bioactivities. To probe the genetic underpinning of diterpenoid diversity, an expansion of the class II diterpene synthase (diTPS) family was recently identified in a leaf transcriptome. Following detection of triptolide and simple diterpene scaffolds in the root, we sequenced and mined the root transcriptome. This allowed identification of the root-specific complement of TPSs and an expansion in the class I diTPS family. Functional characterization of the class II diTPSs established their activities in the formation of four C-20 diphosphate intermediates, precursors of both generalized and specialized metabolism and a novel scaffold for Celastraceae. Functional pairs of the class I and II enzymes resulted in formation of three scaffolds, accounting for some of the terpenoid diversity found in T. wilfordii. The absence of activity-forming abietane-type diterpenes encouraged further testing of TPSs outside the canonical class I diTPS family. TwTPS27, close relative of mono-TPSs, was found to couple with TwTPS9, converting normal-copalyl diphosphate to miltiradiene. The phylogenetic distance to established diTPSs indicates neo-functionalization of TwTPS27 into a diTPS, a function not previously observed in the TPS-b subfamily. This example of evolutionary convergence expands the functionality of TPSs in the TPS-b family and may contribute miltiradiene to the diterpenoids of T. wilfordii.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/tpj.13410

The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily

The first proposals for the use of electric current in drug delivery date from the mid 18th century. Serious progress was made in the 19th century notably by Benjamin Ward Richardson (1828-1896), Hermann Munk (1839-1912), William James Morton (1846-1920), Stephane Leduc (1853-1939) and Fritz Frankenhauser (born 1868). Administration of metal ions as well as alkaloids was tried at that time. Until the early 20th century, current mediated drug delivery was known as "cataphoresis"; Frankenhauser is said to have introduced the term "iontophoresis" before 1908. Recently, researchers talk about "electrically-assisted transdermal drug delivery". The technique was never widely adopted but always proved useful to some extent in solving particular drug delivery problems. At the dawn of the 21st century, attempts are being made to achieve iontophoretic delivery of peptides and proteins.

The history of electrically-assisted transdermal drug delivery ("iontophoresis").

Tripterygium wilfordii is regarded as a promising traditional medicinal plant showing several, mainly antiinflammatory and cytotoxic activities. It contains unusal natural products currently under investigation as lead compounds. The species has been well known in Traditional Chinese Medicine but was recognized in Western science as an insecticide not before the 1930's and as a promising medicinal plant in the 1960's. The name refers to Charles Wilford, employed as a botanical collector at Kew Botanical Gardens, London from 1857-1860. He collected the plant on the island of Taiwan, formerly called Formosa, in June 1858, unfortunately without reporting its medicinal use in the country of origin. The plant was named according to the Linnaean system before 1862 what initially concealed its medicinal properties which had to be re-discovered in the second half of the 20th century.

Tripterygium wilfordii Hook. f. - how a traditional Taiwanese medicinal plant found its way to the West.

To reasons not yet completely understood, the pharmaceutical trademark Voltaren or Voltarol refers to the Italian scientist Alessandro Volta (1745-1827) who played an important role in the history of electricity. It is shown that electrotherapy has been used for the treatment of pain, gout and rheumatic disorders from ancient times to the present day. This therapeutic attempt was also discussed in scientific literature in the late 1960s, the time Voltaren was under development. Therefore, it is suggested that the electrotherapy of pain in history is a background for chosing this trademark.

The history of electrotherapy of pain--or: what Voltaren has to do with voltage.

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The history of electrically-assisted transdermal drug delivery ("iontophoresis").

Tripterygium wilfordii Hook. f. - how a traditional Taiwanese medicinal plant found its way to the West.

The history of electrotherapy of pain--or: what Voltaren has to do with voltage.