The use of cannabinoids has a history spanning thousands of years, and their pharmacological and toxicological properties, particularly those of THC and CBD, are well-documented. However, their potential to induce drug-drug interactions remains underexplored. This review aims to provide a comprehensive perspective by contextualizing the historical and pharmacological significance of cannabinoids while focusing on their capacity to modulate the metabolic activity of cytochrome P450 isoforms relevant to drug metabolism. Additionally, we look at the impact of cannabinoids in neuronal circuits impacting the hypothalamic-pituitary hormonal axis, such as the locus coeruleus and raphe nuclei and their possible consequences on the cytochrome P450 system. Recognising potential interactions between cannabinoids and other drugs could enhance understanding of their pharmacological effects, improve the efficacy and safety profiles of cannabinoid-based therapies, and encourage further exploration into this under-researched area of psychopharmacology, with implications for both preclinical research and clinical practice.

• Keywords
• cannabinoid-based therapies, cannabinoids, cytochrome P450, endocannabinoid system, hypothalamic-pituitary axis, metabolism,
• Publication type
• Journal Article MeSH
• Review MeSH

Two copper(II) mixed ligand complexes with dicarboxylate bridges were prepared and studied, namely [Cu2(μ-fu)(pmdien)2(H2O)2](ClO4)2 (complex No. 5) and [Cu2(μ-dtdp)(pmdien)2(H2O)2](ClO4)2 (complex No. 6), where H2fu = fumaric acid, pmdien = N,N,N',N″,N″ pentamethyldiethylenetriamine, and H2dtdp = 3,3'-dithiodipropionic acid. The copper atoms are coordinated in the same mode by the tridentate pmdien ligand and oxygen of water molecules, and they only differ in the dicarboxylate bridge. This work is focused on the study of the inhibitory effect of these potential antimicrobial drugs on the activity of the most important human liver drug-metabolizing enzymes, cytochromes P450 (CYP), especially their forms CYP2C8, CYP2C19, and CYP3A4. The obtained results allow us to estimate the probability of potential drug interactions with simultaneously administrated drugs that are metabolized by these CYP enzymes. In conclusion, the presence of adverse effects due to drug-drug interactions with concomitantly used drugs cannot be excluded, and hence, topical application may be recommended as a relatively safe approach.

• Keywords
• antibacterial activity, copper complexes, cytochromes P450, dicarboxylic acid, drug interactions, enzyme activity, inhibition,
• Publication type
• Journal Article MeSH

BACKGROUND: Given the increasing request for natural pharmacological molecules, this study assessed the antimicrobial capacity of Pistacia lentiscus L. essential oil (PLL-EO) obtained from the leaves of wild plants growing in North Sardinia (Italy) toward a wide range of periodontal bacteria and Candida, including laboratory and clinical isolates sp., together with its anti-inflammatory activity and safety. METHODS: PLL-EO was screened by gas chromatography/mass spectrometry. The minimal inhibitory concentration (MIC) was determined. The anti-inflammatory activity was measured by cyclooxygenase (COX-1/2) and lipoxygenase (LOX) inhibition, while the antioxidant capacity was determined electro-chemically and by the MTT assay. The WST-1 assay was used to ascertain cytotoxicity toward four lines of oral cells. RESULTS: According to the concentrations of terpens, PLL-EO is a pharmacologically-active phytocomplex. MICs against periodontal bacteria ranged between 3.13 and 12.5 µg/ml, while against Candida sp. they were between 6.25 and 12.5 µg/mL. Oxidation by COX-1/2 and LOX was inhibited by 80% and 20% µg/mL of the oil, respectively. Antioxidant activity seemed negligible, and no cytotoxicity arose. CONCLUSIONS: PLL-EO exhibits a broad-spectrum activity against periodontal bacteria and Candida, with an interesting dual inhibitory capacity toward COX-2 and LOX inflammatory enzymes, and without side effects against oral cells.

• Keywords
• Candida albicans, Candida glabrata, Oral health care products, cyclooxygenase, lipoxygenase, medicinal herbs, periodontal disease,
• Publication type
• Journal Article MeSH

Sesquiterpenes, the main components of plant essential oils, are bioactive compounds with numerous health-beneficial activities. Sesquiterpenes can interact with concomitantly administered drugs due to the modulation of drug-metabolizing enzymes (DMEs). The aim of this study was to evaluate the modulatory effects of six sesquiterpenes (farnesol, cis-nerolidol, trans-nerolidol, α-humulene, β-caryophyllene, and caryophyllene oxide) on the expression of four phase I DMEs (cytochrome P450 3A4 and 2C, carbonyl reductase 1, and aldo-keto reductase 1C) at both the mRNA and protein levels. For this purpose, human precision-cut liver slices (PCLS) prepared from 10 patients and transfected HepG2 cells were used. Western blotting, quantitative real-time PCR and reporter gene assays were employed in the analyses. In the reporter gene assays, all sesquiterpenes significantly induced cytochrome P450 3A4 expression via pregnane X receptor interaction. However in PCLS, their effects on the expression of all the tested DMEs at the mRNA and protein levels were mild or none. High inter-individual variabilities in the basal levels as well as in modulatory efficacy of the tested sesquiterpenes were observed, indicating a high probability of marked differences in the effects of these compounds among the general population. Nevertheless, it seems unlikely that the studied sesquiterpenes would remarkably influence the bioavailability and efficacy of concomitantly administered drugs.

• Keywords
• cytochrome P450 3A4, gene reporter assay, mRNA expression, precision-cut liver slices, pregnane X receptor, protein expression, sesquiterpene,
• MeSH
• Aldo-Keto Reductases metabolism   MeSH
• Hep G2 Cells MeSH
• Cytochrome P-450 CYP3A metabolism   MeSH
• Farnesol pharmacology   MeSH
• Hepatocytes metabolism   MeSH
• Liver enzymology   MeSH
• Carbonyl Reductase (NADPH) metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• RNA, Messenger metabolism   MeSH
• Metabolic Clearance Rate MeSH
• Monocyclic Sesquiterpenes pharmacology   MeSH
• Polycyclic Sesquiterpenes pharmacology   MeSH
• Pregnane X Receptor agonists   metabolism   MeSH
• Receptors, Aryl Hydrocarbon agonists   metabolism   MeSH
• Cytochrome P450 Family 2 metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sesquiterpenes pharmacology   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aldo-Keto Reductases MeSH
• caryophyllene oxide MeSH Browser
• caryophyllene MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• cytochrome P-450 CYP2C subfamily MeSH Browser
• Farnesol MeSH
• humulene MeSH Browser
• Carbonyl Reductase (NADPH) MeSH
• RNA, Messenger MeSH
• Monocyclic Sesquiterpenes MeSH
• nerolidol MeSH Browser
• Polycyclic Sesquiterpenes MeSH
• Pregnane X Receptor MeSH
• Receptors, Aryl Hydrocarbon MeSH
• Cytochrome P450 Family 2 MeSH
• Sesquiterpenes MeSH
• Cytochrome P-450 Enzyme System MeSH