To the Editor:
We greatly appreciate the important and insightful comments regarding our recent article.Citation1 The aim of our article is to extend scientifically and clinically useful information about Clitocybe acromelalga intoxication. C. acromelalga typically grows in bamboo bushes or groves in autumn, and is mainly prevalent in Tohoku, Hokuriku, Kinki, and Sanin districts on Honshu Island in Japan; it is called “Dokusasako” in Japanese. Although C. acromelalga has been previously known as a mycotoxin, an effective treatment protocol has not been established yet.
The comments expound on the probable pharmacological mechanisms underlying pain development and the role of nicotinic acid in providing relief from the pain associated with C. acromelalga intoxication. We believe that not only irregular distribution of peripheral blood flow and neurovascular dysfunction but also inflammatory mediators, such as calcitonin gene-related peptides (CGRP), may be involved in the pathological condition resulting from intoxication of this mycotoxin because of the delayed improvement of burning and sharp pain regardless of normalized color of the skin.Citation1 The poisonous compounds in C. acromelalga are complex, and it contains several toxic compounds in addition to acromelic acid.Citation2,Citation3 Although clitidine is one of the poisonous constituents of C. acromelalga, its vasodilatory effects are mild.Citation4 C. acromelalga intoxication is associated with a lack of gastrointestinal symptoms and a relatively long latency period of several days between consumption and symptom onset, which is a remarkably slow course for food poisoning.Citation1 Therefore, metabolites of C. acromelalga may be involved in the development of toxic effects. However, to the best of our knowledge, thus far, no study has elucidated the exact mechanisms underlying C. acromelalga intoxication in humans.
Our observations indicate that administration of nicotinic acid may be an effective analgesic treatment for erythromelalgia associated with C. acromelalga intoxication, although the precise mechanisms underlying the therapeutic effect of nicotinic acid remain unclear. We agree with the pleiotropic actions of nicotinic acid as described in the comments. However, the metabolic pathways of C. acromelalga in humans, such as the tryptophan–niacin pathway, are considerably complexCitation5; the site of action by nicotinic acid in cases of C. acromelalga intoxication remains to be elucidated. Therefore, further studies are needed to investigate the clinical, pharmacological, and molecular biological features of C. acromelalga intoxication and explore the therapeutic potential of nicotinic acid. Furthermore, the potential analgesic effects of nicotinic acid might even be considered for other disorders.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Nakajima N, Ueda M, Higashi N, Katayama Y. Erythromelalgia associated with Clitocybe acromelalga intoxication. Clin Toxicol (Phila) 2013; 51:451–454.
- Konno K, Hayano H, Shirahama H, Saito H, Matsumoto T. Clitidine, a new toxic pyridine nucleoside from Clitocybe acromelalga. Tetrahedron 1982; 38:3281–3284.
- Yamano K, Shirahama H. The structure of a new dipeptide from the mushroom, Clitocybe acromelalga. Z Naturforsch C 1994; 49:157–162.
- Konno K. Toxic principles from the fungus Clitocybe acromelalga (Dokusasako). Nippon Nougeikagaku Kaishi 1989; 63:876–879 (in Japanese).
- Fukuwatari T, Sugimoto E, Yokoyama K, Shibata K. Establishment of animal model for elucidating the mechanism of intoxication by the poisonous mushroom Clitocybe acromelalga. Shokuhin Eiseigaku Zasshi 2001; 42:185–189 (in Japanese).