Retrospective Evaluation of Drug-Drug Interactions With Erlotinib and Gefitinib Use in the Military Health System.

Background: Erlotinib and gefitinib are epidermal growth factor receptor-tyrosine kinase inhibitors approved for non-small cell lung cancer treatment by the US Food and Drug Administration. Drug-drug interactions (DDIs) with these agents are vague and poorly understood. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with erlotinib or gefitinib and describe their clinical manifestations. Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved September 2021), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved May 2022). Patients' medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients' diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with erlotinib or gefitinib, and evaluate DDIs with antidepressants. Results: Of 387 patients using erlotinib, 264 completed treatments; 28 of 33 patients using gefitinib completed treatment. The P value for erlotinib discontinuation when used alone vs concomitantly was < .001, and the P value for gefitinib discontinuation was .06. Patients who took erlotinib or gefitinib concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 1 to 75 prescription drugs, and those in the completed group were prescribed 3 to 103. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment. Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in erlotinib or gefitinib discontinuation. There were no significant DDIs determined between erlotinib or gefitinib and antidepressants.

Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine.

Objective: To evaluate drug-drug interactions (DDIs) between gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs). Methods: In vitro supersomes were used to identify CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) involved in drug metabolism, and in vitro pooled cryopreserved primary human hepatocytes were employed to investigate DDIs. Results: The isoenzymes that showed drug degradation are listed in parentheses beside the respective drug: gefitinib (CYP2D6, 3A4, 1A2, 2C9, and 2C19), losartan (CYP2C9 and 3A4), citalopram (CYP2D6, 2C19, 3A4, and 2C9), fluoxetine (CYP2D6, 2C9, and 2C19), fluvoxamine (CYP2D6, 2C9, and 2C19), paroxetine (CYP2D6, 3A4, and 2C9), sertraline (CYP2D6, 2C9, 2C19, 1A2, and 3A4), and venlafaxine (CYP2D6 and 2C19).DDIs from human hepatocytes assays revealed that gefitinib had significant metabolic changes in (1:1) combination with paroxetine or sertraline (p-value â€‹= â€‹0.042 and 0.025 respectively) and (1:1:1) combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline (p-value â€‹= â€‹0.009, 0.027, 0.048, and 0.037 respectively). Losartan showed significant changes in (1:1:1) combination with gefitinib and fluoxetine or sertraline (p-value â€‹= â€‹0.026 and 0.008 respectively). Fluoxetine, fluvoxamine, and paroxetine underwent significant changes in (1:1:1) combination with gefitinib and losartan (p-value â€‹= â€‹0.003, 0.022, and 0.046 respectively). Sertraline had significant changes within all combinations: DDIs with gefitinib alone and in combination with gefitinib and losartan (p-value â€‹= â€‹0.009 and 0.008 respectively). Citalopram and venlafaxine appeared to be unaffected by any combination. Conclusion: The study provides a clear proof-of concept for in vitro metabolic DDI testing. While identifying compounds by their inhibition potential can help better predict their metabolism, it cannot resolve problems that arise from DDIs since the overall degree of effectiveness is unknown. As shown in this study, gefitinib has been identified as a weak CYP2C19 and 2D6 inhibitor, however, gefitinib can have significant DDIs with sertraline. Furthermore, multiple drug combinations (1:1:1) can change the significance of previously determined DDIs in (1:1) combination. Thus, in vitro assays can potentially provide better guidance for multidrug regimens with minimal risk for DDIs.

Identification of Anticryptococcal Bornyl Compounds from Verbesina turbacensis and Their Structure-Activity Relationships.

Cryptococcus neoformans is an opportunistic fungal pathogen that has limited treatment options. Natural product plant extracts offer a cost-effective option for the discovery of new anticryptococcal lead compounds. The acetone bark extract of Verbesina turbacensis was found to potently inhibit C. neoformans and was subjected to bioautography. Two compounds that inhibited the growth of C. neoformans were isolated and displayed minimum inhibitory concentration values of 10 and 310 µg/mL. The compounds were identified as the bornyl hydroxycinnamic esters bornyl caffeate and bornyl ferulate, respectively. To better understand initial structure-activity relationships, anticryptococcal activity was characterized for similar compounds. All compounds were further evaluated for mammalian cell toxicity using the MTT assay with MCF-7 and HEK-293 cell lines. Overall, bornyl caffeate demonstrated promising anticryptococcal potential given its potent inhibition of C. neoformans and low mammalian cell toxicity.

Volatile Compositions and Antifungal Activities of Native American Medicinal Plants: Focus on the Asteraceae.

In the past, Native Americans of North America had an abundant traditional herbal legacy for treating illnesses, disorders, and wounds. Unfortunately, much of the ethnopharmacological knowledge of North American Indians has been lost due to population destruction and displacement from their native lands by European-based settlers. However, there are some sources of Native American ethnobotany remaining. In this work, we have consulted the ethnobotanical literature for members of the Asteraceae used in Cherokee and other Native American traditional medicines that are native to the southeastern United States. The aerial parts of Eupatorium serotinum, Eurybia macrophylla, Eutrochium purpureum, Polymnia canadensis, Rudbeckia laciniata, Silphium integrifolium, Smallanthus uvedalia, Solidago altissima, and Xanthium strumarium were collected from wild-growing plants in north Alabama. The plants were hydrodistilled to obtain the essential oils and the chemical compositions of the essential oils were determined by gas chromatography-mass spectrometry. The essential oils were tested for in-vitro antifungal activity against Aspergillus niger, Candida albicans, and Cryptococcus neoformans. The essential oil of E. serotinum showed noteworthy activity against C. neoformans with a minimum inhibitory concentration (MIC) value of 78 µg/mL, which can be attributed to the high concentration of cyclocolorenone in the essential oil.

Bigger Data Approach to Analysis of Essential Oils and Their Antifungal Activity against Aspergillus niger, Candida albicans, and Cryptococcus neoformans.

With increasing drug resistance and the poor state of current antifungals, the need for new antifungals is urgent and growing. Therefore, we tested a variety of essential oils for antifungal activity. We report the minimum inhibitory concentrations (MIC) values for a common set of 82 essential oils against Aspergillus niger, Candida albicans, and Cryptococcus neoformans. Generally, narrow-spectrum activity was found. However, C. neoformans was much more susceptible to inhibition by essential oils with over one-third of those tested having MIC values below 160 ppm. GC-MS analysis showed the essential oils to be chemically diverse, yet, the potentially active major constituents typically fell into a few general categories (i.e., terpenes, terpenoids, terpenols). While essential oils remain a rich source of potential antifungals, focus should shift to prioritizing activity from novel compounds outside the commonalities reported here, instead of simply identifying antifungal activity. Further, capitalizing on bigger data approaches can provide significant returns in expediting the identification of active components.

Antifungal and Cytotoxic Activities of Sixty Commercially-Available Essential Oils.

There is an urgent and unmet need for new antifungal therapies. Global fungal infection rates continue to rise and fungal infections pose increasing burdens on global healthcare systems. Exacerbating the situation, the available antifungal therapeutic arsenal is limited and development of new antifungals has been slow. Current antifungals are known for unwanted side effects including nephrotoxicity and hepatotoxicity. Thus, the need for new antifungals and new antifungal targets is urgent and growing. A collection of 60 commercially-available essential oils has been screened for antifungal activity against Aspergillus niger, Candida albicans, and Cryptococcus neoformans, as well as for cytotoxic activity against MCF-7 and MDA-MB-231 human breast tumor cell lines; the chemical compositions of the essential oils have been determined by gas chromatography-mass spectrometry (GC-MS). Ten essential oils showed remarkable antifungal and cytotoxic activities: Indian, Australian, and Hawaiian sandalwoods; melissa; lemongrass; cilantro; cassia; cinnamon; patchouli; and vetiver.

Chemical Composition, Enantiomeric Distribution, and Antifungal Activity of the Oleoresin Essential Oil of Protium amazonicum from Ecuador.

Background:Protium species (Burseraceae) have been used in the treatment of various diseases and conditions such as ulcers and wounds. Methods: The essential oil from the oleoresin of Protium amazonicum was obtained by hydrodistillation and analyzed by GC-MS, GC-FID, and chiral GC-MS. P. amazonicum oleoresin oil was screened for antifungal activity against Candida albicans, Aspergillus niger, and Cryptococcus neoformans. Results: A total of 54 components representing 99.6% of the composition were identified in the oil. The essential oil was dominated by δ-3-carene (47.9%) with lesser quantities of other monoterpenoids α-pinene (4.0%), p-cymene (4.1%), limonene (5.1%), α-terpineol (5.5%) and p-cymen-8-ol (4.8%). Chiral GC-MS revealed most of the monoterpenoids to have a majority of levo enantiomers present with the exceptions of limonene and α-terpineol, which showed a dextro majority. P. amazonicum oleoresin oil showed promising activity against Cryptococcus neoformans, with MIC = 156 µg/mL. Conclusions: This account is the first reporting of both the chemical composition and enantiomeric distribution of the oleoresin essential oil of P. amazonicum from Ecuador. The oil was dominated by (-)-δ-3-carene, and this compound, along with other monoterpenoids, likely accounts for the observed antifungal activity of the oil.

An In-Silico Investigation of Phytochemicals as Antiviral Agents Against Dengue Fever.

A virtual screening analysis of our library of phytochemical structures with dengue virus protein targets has been carried out using a molecular docking approach. A total of 2194 plant-derived secondary metabolites have been docked. This molecule set comprised of 290 alkaloids (68 indole alkaloids, 153 isoquinoline alkaloids, 5 quinoline alkaloids, 13 piperidine alkaloids, 14 steroidal alkaloids, and 37 miscellaneous alkaloids), 678 terpenoids (47 monoterpenoids, 169 sesquiterpenoids, 265 diterpenoids, 81 steroids, and 96 triterpenoids), 20 aurones, 81 chalcones, 349 flavonoids, 120 isoflavonoids, 74 lignans, 58 stilbenoids, 169 miscellaneous polyphenolic compounds, 100 coumarins, 28 xanthones, 67 quinones, and 160 miscellaneous phytochemicals. Dengue virus protein targets examined included dengue virus protease (NS2B-NS3pro), helicase (NS3 helicase), methyltransferase (MTase), RNA-dependent RNA polymerase (RdRp), and the dengue virus envelope protein. Polyphenolic compounds, flavonoids, chalcones, and other phenolics were the most numerous of the strongly docking ligands for dengue virus protein targets.

A molecular docking study of phytochemical estrogen mimics from dietary herbal supplements.

PURPOSE: The purpose of this study is to use a molecular docking approach to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements. METHODS: In this study, 568 phytochemicals found in 17 of the most popular herbal supplements sold in the United States were built and docked with two isoforms of the estrogen receptor, ERα and ERß (a total of 27 different protein crystal structures). RESULTS: The docking results revealed six strongly docking compounds in Echinacea, three from milk thistle (Silybum marianum), three from Gingko biloba, one from Sambucus nigra, none from maca (Lepidium meyenii), five from chaste tree (Vitex agnus-castus), two from fenugreek (Trigonella foenum-graecum), and two from Rhodiola rosea. Notably, of the most popular herbal supplements for women, there were numerous compounds that docked strongly with the estrogen receptor: Licorice (Glycyrrhiza glabra) had a total of 26 compounds strongly docking to the estrogen receptor, 15 with wild yam (Dioscorea villosa), 11 from black cohosh (Actaea racemosa), eight from muira puama (Ptychopetalum olacoides or P. uncinatum), eight from red clover (Trifolium pratense), three from damiana (Turnera aphrodisiaca or T. diffusa), and three from dong quai (Angelica sinensis). Of possible concern were the compounds from men's herbal supplements that exhibited strong docking to the estrogen receptor: Gingko biloba had three compounds, gotu kola (Centella asiatica) had two, muira puama (Ptychopetalum olacoides or P. uncinatum) had eight, and Tribulus terrestris had six compounds. CONCLUSIONS: This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity.