Possible Biological and Clinical Applications of Phenothiazines

Abstract

Abstract. Phenothiazines have been used in many areasPhenothiazines are unanimously one of the most versatile compounds from the view of biological activity. Since their discovery, new exploitable pharmacological properties have emerged from time to time; thus, they have an important role in many areas of medicine and beyond. This is why phenothiazines are basic compounds in pharmacology. The history of these compounds goes back to the second half of the 19th century, when a German chemist, Heinrich August Bernthsen began to study the structure of methylene blue, which was first synthesized in 1876 by Heinrich Caro. In 1885, two years after Bernthsen first managed to produce phenothiazine, he also succeeded in describing the structure of methylene blue (1). At the same time, Paul Ehrlich began to investigate the possible therapeutic use of methylene blue in malaria infections, which he first published in 1891 (2). Due to this, methylene blue was often prescribed for patients with malaria in the subsequent period (3).Research conducted in the 1930s and '40s proved the potential wide use of phenothiazines. The insecticidal (4), antihelmintic (5, 6), and antibacterial (7) effects of the compound were detected; however, it was not widely used for these purposes. In the 1940s, another novel phenothiazine derivative, namely promethazine was brought to the forefront of attention; it was investigated by Paul Charpentier at the Rhone-Poulenc laboratory in Paris (8). It was shown that promethazine had an antihistamine effect (9), which was later used in the therapy of allergic diseases and in anesthesia (10,11). A few years later in the same laboratory, chlorpromazine was discovered, which has strong anxiolytic and antipsychotic effect along with its antihistaminic effect (12). Psychiatry fully exploited this feature in psychotic patients (13), which resulted in the almost complete emptying of psychiatric hospitals in the 1950s. As a result, the discovery of chlorpromazine and the beginning of its use as an antipsychotic are considered the beginning of modern psychiatry and psychopharmacology.Since then, several antipsychotic phenothiazine compounds have been used in clinical practice, although research conducted in the last couple of decades indicated that phenothiazine compounds could have an important role in other fields of medicine as well, such as in the treatment of tumorous, infectious, or neurodegenerative diseases (3). 5983

Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing

“… 2006 ; Varga et al. 2017 ). Plasmid curing properties have also been attributed to phenothiazines (Table 1 ) (Amaral, Viveiros and Molnar 2004 ; Spengler et al.…”

Effect of novel phenothiazine derivatives on brain dopamine in Wistar rats

“…The above results were observed in some other studies performed by scientists on phenothiazine derivatives which are involved in the mechanism of inhibiting the brain dopamine level in the tested animals after repeated administration. In fact, [32] observed that a clear system exists between the structure of the phenothiazine derivatives and the capacity to inhibit the dopamine level in the brain. Likewise, it has been proved that amphetamine induced effect on neuropeptide in the rat brain [35].…”

Is Neuronal Histamine Signaling Involved in Cancer Cachexia? Implications and Perspectives

“…Histamine signaling has been implicated in tumor biology and antihistaminic treatment 9 is now viewed as an auspicious approach in cancer therapy (14,164,165). Still, this promising new treatment must be approached with caution, as pharmacologically interfering with brain histamine signaling may lead to undesirable side effects due to histamine's physiological role as a neuromodulator of a variety of neurotransmitters (19)(20)(21)93).…”